Carbetocin Versus Oxytocin For The Prevention of Postpartum Hemorrhage Following Elective Cesarean Section: Rizal Medical Center Experience

Carbetocin Versus Oxytocin for the Prevention of
Postpartum Hemorrhage Following Elective Cesarean

Section: Rizal Medical Center Experience*
DEBBIE-L YN UY, MD; NELINDA CATHERINE P. PANGILINAN MD, FPOGS AND CLAUDETTE RICERO-CABINGUE, MD, FPOGS
Department of Obstetrics and Gynecology, Rizal Medical Center
Postpartum hemorrhage is a preventable event in abdominal

and vaginal deliveries. Conventional incremental dosing
or continous infusion of oxytocin has been employed for
E very minute of every day, a woman dies in
pregnancy or childbirth. The biggest killer is
obstetric hemorrhage and the most frequent cause is
these. Carbetocin, as an analogue is associated with longer uterine atony with an estimated mortality rate of
half-life and has clinical benefits. 140,000 per year or 1 maternal death every 4 minutes.
Objective: The objective was to compare the effectiveness In 2000, 189 nations committed to free their
of carbetocin and oxytocin when administered after elective people from extreme poverty and multiple
uncomplicated cesarean section (CS) for the prevention
deprivations. This pledge became the eight
of postpartum hemorrhage.
Design: Randomized single blind controlled trial of Millennium Development Goals to be achieved by
patients admitted at Rizal Medical Center from June to 2015. Millennium Development Goal # 5 is to
October 2012. improve maternal health and to reach this goal, we
Participants and Methods: A total of 70 patients were should reduce maternal mortality by 75% by 2015.
randomized to carbetocin (n=35) and oxytocin (n=35) for For the Philippines, the target is to reduce Maternal
the prevention of postpartum hemorrhage and analyzed Mortality Rate (MMR) from 209 to 52 deaths from
by intention-to-treat. Baseline demographic and obstetric 100,000 livebirths. The past 20 years have shown
profile, indications for CS, estimated blood loss, hematocrit, improving maternal health at a relatively slow rate
hemoglobin, need for uterine massage, additional (209/100,000 to 162/100,000).(FHSIS 2009)
uterotonics, uterine tone and involution were compared All pregnant women are at risk of complications
immediate post-operative and 24 hours after. during the 3rd stage of labor. 3 Maternal risk factors
Results: Baseline profiles were similar between the two contribute to the development of postpartum
groups. Post-operatively, hemoglobin and hematocrit levels hemorrhage. 2 For women undergoing delivery by
in the carbetocin group were statistically significant and
cesarean section, there is an increased risk of
were associated with lesser need for additional uterotonic
postpartum hemorrhage compared to vaginal
agents, uterine massage and a well contracted uterus
immediate post-operative and 24 hours thereafter. The delivery.4 It is therefore reasonable to advise routine
estimated blood loss was significantly lower in the administration of a uterotonic drug immediately
carbetocin group however, the two groups did not after the baby has been delivered by cesarean
significantly differ in terms of blood transfusion section. 4
requirements and post-op blood pressure. Oxytocin is the drug of choice of postpartum
Conclusion: Carbetocin as a uterotonic agent is an hemorrhage. However, it has a shorter half life
acceptable alternative for the prevention of postpartum compared to carbetocin which has been reported to
bleeding in elective cesarean section. A cost-benefit decrease the need for additional uterotonic and
analysis is mandated. reduce bleeding due to uterine atony in cesarean
section. 3 Carbetocin has been approved for use
Key words: carbetocin, oxytocin, postpartum hemorrhage, immediately following an elective cesarean section
uterine tone, uterine involution, randomized trial when local or spinal anesthesia has been
administered. 5 Carbetocin has a much longer lasting
_______________ effect than oxytocin, necessitating only a single
* 2013 Research Paper Presentation, Midyear Convention, Legaspi City. dose.
June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 71

Carbetocin Versus Oxytocin for the Prevention of Postpartum Hemorrhage Following Elective Cesarean Section / Uy, et al.
In several trials, carbetocin was associated with MATERIALS AND METHODS

a decrease in postpartum hemorrhage. It reduced
the use of additional uterotonics and uterine massage Study Design, Setting and Duration
and therefore reduced the incidence of blood
transfusion. This is a randomized controlled trial comparing
The present study aimed to evaluate the role of the use of carbetocin and oxytocin for the prevention
carbetocin vs oxytocin in reducing blood loss and of postpartum hemorrhage following elective
postpartum hemorrhage. cesarean section. Single blinding was done wherein
the surgeon and the patients were blinded and only
Research Question the principal investigator knew as to what drug was
administered after delivery of the neonate. Giving
Is carbetocin effective as compared to oxytocin of additional uterotonics depended on the discretion
in the management of postpartum hemorrhage of the surgeon.
following elective cesarean section? Subjects were seen either at the outpatient
department or at the emergency room of Rizal
General Objective Medical Center. The trial was completed in five
months.
The general objective of the study was to compare
the effectiveness of carbetocin and oxytocin when Study Participants
administered after elective uncomplicated cesarean
section in preventing postpartum hemorrhage of Inclusion Criteria:
patients admitted at Rizal Medical Center from June
to October 2012. 1. With informed consent
2. At least 18 years old
Specific Objectives
3. Term uncomplicated pregnancy (>37 weeks)
undergoing elective cesarean section
1. To compare the demographic and baseline
characteristics of the 2 groups who will undergo 4. At least one risk factor for postpartum
elective CS. hemorrhage (repeat cesarean section, multiple
2. To compare the preoperative and postoperative pregnancy, >gravida 3 and with malpresentation)
hemoglobin and hematocrit levels between
carbetocin and oxytocin groups who will Exclusion Criteria:
undergo elective cesarean section at Rizal
1. Hypersensitivity to oxytocin and carbetocin
Medical Center from June to October 2012.
3. To compare whether there is a need for giving 2. < 37 weeks AOG
additional uterotonics between patients given 3. Placenta previa
carbetocin and oxytocin. 4. Abruptio placenta
4. To compare the need of doing uterine massage 5. Women undergoing cesarean section with general
after administration of drug between the 2 groups anesthesia
5. To compare the difference in uterine tone and 6. Significant disease (heart disease, thyroid disease,
early involution between the 2 groups preeclampsia, diabetes mellitus, pulmonary
6. To compare the need of giving blood products disease, liver and renal disease)
postoperatively between the 2 groups 7. Classical uterine incision
7. To compare the systolic and diastolic blood 8. Fetal distress
pressure preoperatively, after administration of
the drug and postoperatively.
Women with placenta previa or abruptio placenta
Rationale were excluded because there they were at a higher
risk for hemorrhage. Women undergoing cesarean
The best preventive strategy is to administer a section with general anesthesia were also excluded,
uterotonic drug soon after delivery of the neonate because carbetocin is licensed for use with regional
to decrease the risk of postpartum hemorrhage. anesthesia only.
72 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

Sample Size Estimation operatively and 24 hours post-operatively. Blood

transfusion was given to the 2 groups depending on
The number of samples to be collected was the 24-hour post-operative hemoglobin, hematocrit
computed using 95% level of confidence and 80% level and clinical assessment of the surgeon.
power of the study. With an estimated difference in
the intraoperative blood loss of 41ml from the study Primary Outcome
of Boucher, et al., at least 35 subjects per group were
needed. The comparison of hemoglobin and hematocrit
levels between the 2 groups.
Investigator and Patient Blinding
Secondary Outcome
To avoid potential confounders, an independent
research physician was tasked to perform the Proportion of patients requiring additional
randomization procedure. Another physician who uterotonics, uterine massage, tone, involution and
assessed outcomes was unaware of the group blood transfusion between the 2 groups.
assignments of these patients. Similarly, patients
were not aware of the meaning of the treatment codes Statistical Analysis
assigned.
The analysis was done using MEDCALC version
Data Collection 3.0. Descriptive statistics included mean and
standard deviation for continuous variables. Discrete
The study population was divided into 2 groups. data were summarized as percentages. Testing for
They were examined by the senior OB resident on sample homogeneity at baseline was done using chi-
duty. The findings, maternal risk factors and clinical square test and independent T-test. Comparison of
assessment prior to cesarean section were recorded. outcomes was done using paired Test, independent
Study group A received single intravenous injection T test for continuous data and chi-square for
of 100 microgram carbetocin while study group B categorical data. All P-values <0.05 were considered
received 8 hours infusion of oxytocin 20 units after significant.
delivery of neonate. Informed consent was obtained.
Preoperative and postoperative hemoglobin
levels were extracted at entry and 24 hours RESULTS
postpartum and sent to the laboratory. Records on
the preoperative and postoperative hemoglobin levels A total of 70 patients were randomized to
were kept. Data were collected regarding the use of carbetocin (n=35) and oxytocin (n=35) for the
additional uterotonics and uterine massage between prevention of post-partum hemorrhage. At baseline,
the 2 groups depending upon the discretion of the there was no significant difference between carbetocin
surgeon. Vital signs particularly blood pressure were and oxytocin in terms of mean age (mean 30 versus
recorded pre-operatively, after intervention, post- 31, P=.55, respectively); gravidity (P=.73);parity
operatively and at the recovery room. The additional (P=.39) and gestational weeks (P=.15). The primary
uterotonics included additional oxytocin dosage to indications for cesarean section in this study included
the drip or giving methylergometrine maleate a repeat CS, followed by malpresentation (footling
IM/IV, also a uterotonic agent. Assessment of breech) (P=.66). The number of repeat cesarean
uterine tone between the 2 groups was made by the sections did not statistically differ between the two
surgeon by palpation of the uterus whether it is groups (P=.26).
1) boggy - soft, atonic uterus, 2) firm - when gentle
pressure depressed the uterus slightly or transiently,
3) well contracted uterus -hard, non-depressible Hemoglobin and Hematocrit Levels
uterus. Likewise, assessment of uterine involution
was made 1) below the umbilicus, 2) at the level of A significant reduction in the post-operative
the umbilicus and 3) above the umbilicus. Both tone hemoglobin levels from the baseline preoperative
and involution were evaluated before delivery of the level was noted in the carbetocin group (mean 118
neonate, after inter vention, immediate post- to 108, P<.001). Likewise, the levels were also

significantly low post-operative in the oxytocin group Post-operatively, levels in the carbetocin group
(mean 116 to 96, P<.001). were statistically higher (mean 0.33 versus 0.31,
Post-operatively, levels in the carbetocin group P=.001)
were statistically higher (mean 108.6 versus 96.03,
P=.001) Blood Pressure
A significant reduction in the post-operative
hematocrit levels from the baseline preoperative level Systolic and diastolic BP were not significantly
was noted in the carbetocin group (mean 0.36 to 0.33, different immediate post intervention between the
P=.001). Likewise, the levels were also significantly two groups, immediate post-operative and while
low post-operative in the oxytocin group (mean 0.36 recovering (between group P=.37 and P=.40,
to 0.31, P=.018). respectively) (Figures 3 & 4)
Table 1. Baseline profile of pregnancies randomized to carbetocin versus oxytocin to prevent post-partum hemorrhage,
Rizal Medical Center, June to October 2012.
Characteristics Carbetocin Oxytocin P-value

N (%) N (%)
Mean age in years (SD) 30 (5.7) 31 (6.3) .55*
Gravidity
2 11 (31) 15 (43) .73**
3 12 (35) 11 (31)
4 6 (17) 6 (17)
≥5 6 (17) 3 (9)
Parity
1 13 (37) 18 (52) .39**
2 16 (45) 10 (28)
3 3 (9) 6 (17)
≥4 3 (9) 1 (3)
Gestational Weeks
37-38 18 (51.5) 20 (57.2) .15**
39-40 16 (45.7) 11 (31.5)
41 1 (2.8) 4 (11.3)
Indication for Cesarean Section

Repeat CS 28 (80) 29 (83) .66**
Malpresentation (breech) 4 (11) 6 (17)
Footling breech 3 (9) 0
Repeat Cesarean Section

First time 15 (43) 16 (46) .26**
Twice 11 (31) 16 (46)
Thrice 7 (20) 3 (8)
Four times 2 (6) 0
Duration of Cesarean Section

Mean hours (SD) 1.11 (0.40) 1.17 (0.38) .54*
Mean Preoperative SBP (SD) 117.5 (6.8) 118.3 (8.3) .68*

Mean Preoperative DBP (SD) 69.4 (7.7) 73.2 (8.5) .06*
Resident’s Year Level Doing the Operation

2nd Year 6 (17) 8 (23) .34**
3rd Year 16 (46) 15 (43)
4th Year 13 (37) 12 (31)
*No significant difference by independent T-test, ** by chi-square test

Need For Additional Uterotonics Uterine massage was less required in the same
group (5.7% versus 48.6%, P=.001).
A statistically lower proportion of women in the The estimated blood loss was significantly lower
carbetocin group required additional uterotonic in the carbetocin group (mean 585mL versus
agents post-operatively (5.7% versus 34.3%, P=.003). 702.8mL, P=.026)
(Table-2). The two groups did not significantly differ in
terms of blood transfusion requirements. (P=.17).
Figure 1. Preoperative and post-operative hemoglobin levels in Figure 3. Trend in systolic BP levels in pregnancies given
pregnancies given carbetocin versus oxytocin, Rizal Medical Center, carbetocin versus oxytocin, Rizal Medical Center, June to October
June to October 2012. 2012.
Figure 2. Preoperative and post-operative hematocrit levels in Figure 4. Trend in diastolic BP levels in pregnancies given
pregnancies given carbetocin versus oxytocin, Rizal Medical Center, carbetocin versus oxytocin, Rizal Medical Center, June to October
June to October 2012. 2012.

Uterine Tone and Involution was given (77% versus 8%, P=.001);immediate post-
operative (60% versus 26%, P=.001) and 24 hours
`The effects of the two drugs on uterine tone after post-operative (77% versus 8%, P=.001)
(Table 3) and uterine involution (Table 4) are A statistically significant higher proportion of
presented. A statistically significant higher uteri in the carbetocin group were below the
proportion of uteri in the carbetocin group were well umbilicus immediately after the intervention (66%
contracted after the delivery of the neonate (23% versus 29%, P=.007); and immediate post-operative
versus 0, P=.001); immediately after the intervention (97% versus 57%, P=.001).No significant difference
Table 2. Need for additional uterotonics, blood transfusion and uterine massage between carbetocin versus oxytocin
to prevent post-partum hemorrhage, Rizal Medical Center, June to October, 2012.
Outcome Carbetocin Oxytocin P-value
Need for Additional Uterotonics

Yes 2 (5.7) 12 (34.3) .003**
No 33 (94.3) 23 (65.7)
Uterine Massage
Yes 2 (5.7) 17 (48.6) .001**
No 33 (94.3) 18 (51.4)
Estimated Blood Loss (mL)

Mean (SD) 585.7 (190) 702.8 (237) .026*
Blood Transfusion
Yes 2 (5.7) 7 (20) .17
No 33 (94.3) 28 (80)
*Significant difference by independent T-test **Chi-square test
Table 3. Uterine tone in pregnancies given carbetocin versus oxytocin, Rizal Medical Center, June to October,
2012.
Uterine Tone Carbetocin Oxytocin P-value
After Delivery of Neonate

Boggy 7 (20) 25 (71) .001**
Firm 20 (57) 10 (29)
Well contracted 8 (23) 0
After Intervention
Boggy 0 16 (46) .001**
Firm 8 (23) 16 (46)
Well contracted 27 (77) 3 (8)
Immediate Post-operative
Boggy 1 (3) 1 (3) .014**
Firm 13 (37) 25 (71)
Well contracted 21(60) 9 (26)
24 Hours Post-Operative
Boggy 0 16 (46) .001*
Firm 8 (23) 16 (46)
Well contracted 27 (77) 3 (8)
Significant difference by independent **Chi-Square Test

immediately after the neonate was delivered (P=.053) for uterine massage following both cesarean delivery
and at 24 hours post-operative. (P=.18) (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739
women) and vaginal delivery (RR 0.70; 95% CI 0.51
DISCUSSION to 0.94; one trial, 160 women). Six trials of these
meta-analysis compared carbetocin to oxytocin in
In search of a more effective uterotonic agent, which four studies in turn examining its ability to
the present clinical trial of carbetocin versus standard prevent postpartum hemorrhage among those
oxytocin aimed to compare the two drugs in relation undergoing elective cesarean section.
to vital maternal outcomes after an elective The position of the fundus relative to the position
abdominal delivery. of the umbilicus is an indicator of the state of uterine
The trial has shown that standard doses of involution. Immediate uterine involution was
carbetocin prevented significant decreases in observed as early post-delivery of the neonate,
hematocrit and hemoglobin post-operative by having however comparative proportions were insignificant.
minimal blood loss. Carbetocin also decreased the It is to be reiterated that the rate of uterine involution
need for additional uterotonics, uterine massage and differs across parity and gravidity. The study of
the avoidance of blood transfusion. Furthermore, Dimitrov, et al. showed that the uterine involution
carbetocin was associated with good uterine in primiparous and premature vaginal deliveries starts
involution and tone immediate post-delivery when from lower values of the symphysis pubis-uterine
compared to oxytocin. fundus than in the multiparous and in cases of term
The clinical trial result supports the composite delivery. The rate of uterine involution in primiparous
findings in a meta-analysis involving 11 studies. increases gradually in the earliest day after delivery
Among women who underwent elective CS, (from 0.95 to 1.6 cm per day),10 while in multiparous
carbetocin resulted in a statistically significant this increase starts after the 4th day. When cesarean
reduction in the need for therapeutic uterotonics section is performed and in cases of preterm delivery,
compared to oxytocin, but there was no difference the rates of uterine involution are delayed and
in the incidence of postpartum hemorrhage.9 This uneven. Uterine involution described in this trial is
review revealed that compared to oxytocin, immediate, after the administration of carbetocin and
carbetocin was also associated with a reduced need oxytocin, which are adjunctive to the normal
Table 4. Uterine involution in pregnancies given carbetocin versus oxytocin, Rizal Medical Center, June to
October 2012.
Uterine Tone Carbetocin Oxytocin P-value
After Delivery of Neonate

Below umbilicus 2 (6) 0 .053
At the level of umbilicus 31 (89) 27 (77)
Above umbilicus 2 (6) 8 (23)
After Intervention
Below umbilicus 23 (66) 10 (29) .007**
Above umbilicus 1 (3) 3 (8)
Immediate Post-operative
Below umbilicus 34 (97) 20 (57) .001**
Above umbilicus 0 0
24 Hours Post-Operative
Below umbilicus 34 (97) 31 (89) .18
Above umbilicus 0 0
Significant difference by independent **chi-square test

physiologic return of the normal tonus and decrease administration of carbetocin, and further studies will
of the uterine fundic height immediately after surgery. be required to assess the cardiovascular effects of
The authors were assured that these differences in carbetocin before it can be advocated for routine use
parity and gravidity have been controlled adequately in preeclamptic patients.15 In addition, carbetocin was
by the sufficient and fair randomization of subjects. able to reduce pain perception during postoperative
A study by Borruto, et al. reported that the days improving quality of life of women. De Bonis,
fundus was below the umbilicus in more patients who et al. showed that mean scores of postoperative pain
received carbetocin at 0, 2, 6, and 24 h on the ward in the day of surgery in carbetocin group was
(P < 0.05). The latter study concluded that a single significantly lower than in oxytocin group and
100mcg IV injection of carbetocin was as effective remained significant three days after cesarean section.
as a continuous 2-h infusion of oxytocin in In the day of surgery and a day after surgery, women
controlling intraoperative blood loss after placental of the carbetocin group who needed analgesic drugs
deliver y. Mean blood loss after carbetocin were significantly lower than women of the oxytocin
administration was 30ml less than after oxytocin group.16
administration (P = 0.5). The percentage of patients The present study was limited as it failed to
with blood loss ≤ 500ml was greater with carbetocin.11 monitor uterine involution post 24 hours. This
The use of carbetocin has not been adequately technical difficulty was due to the rapid turnover and
endorsed in this institution due to many published practices of clinicians to discharge their patients as
reports on its adverse effects and its relatively high early as the 2nd post-operative day. Another
cost. However, the study of Rath, et al. showed that limitation was the author’s failure to report the
the risk of headache, tremor, hypotension, flushing, incidence of adverse effects carbetocin. The authors
nausea, abdominal pain, pruritus and feeling of surmised that of carbetocin is a synthetic analogue
warmth was similar in women who received of oxytocin, hence pharmacodynamics may be
carbetocin or oxytocin.11 The findings from two recent similar. However, the authors found a study that
double-blind randomized trials 12,13 and one contradicts other studies in terms of the safety and
retrospective study suggest that carbetocin may also tolerability of carbetocin. The study by Ortiz-
re present a good alter native to conventional Gomez17 showed that carbetocin was accompanied
uterotonic agents for prevention of postpartum by an increased incidence of side effects without any
hemorrhage even after vaginal deliveries. improvement in the prevention of obstetric
The clinical advantage of carbetocin over hemorrhage. Significant differences in uterine
oxytocin has been compared. Clinicians prefer to contraction in vaginal bleeding and the incidence
employ carbetocin because of its longer half-life of side effects, particularly headache and tremor,
which is approximately 4-10 times longer than that were more pronounced in the carbetocin group. The
reported for oxytocin. It combines the safety and authors also had no pharmaco-economic evaluation
tolerability profile of oxytocin with the sustained of the two drugs for cost-benefit analysis.
uterotonic activity of injectable ergot alkaloids. In summar y, carbetocin is associated with
Furthermore, carbetocin can be administered as a reduction in estimated blood loss, resulting to a
single dose injection either intravenously or significantly minimum drop in hematocrit and
intramuscularly rather than as an infusion over hemoglobin levels. It also resulted to good uterine
several hours as is the case with oxytocin. tone and involution as early as post delivery of the
Another clinical advantage of carbetocin in the neonate and prevented the additional administration
prevention of post-partum bleeding is that it has a of uterotonic agents.
long duration of action compared with intravenous
oxytocin alone and a better cardiovascular side effect
profile compared with syntometrine.14,15 In addition CONCLUSION
to being an effective treatment for the prevention of
postpartum hemorrhage following cesarean delivery, Post-operatively, hemoglobin and hematocrit
carbetocin may also become the drug of choice for levels in the carbetocin group were statistically higher
postpartum hemorrhage prevention after vaginal (mean 108.6 versus 96.03, P=.001 and mean 0.33
delivery in high-risk women and those who suffer versus 0.31, P=.001, respectively).Oxytocin group
from hyper tensive disorders in pregnancy. required additional uterotonic agents post-operatively
Preeclampsia is still a contraindication to the (5.7% versus 34.3%, P=.003).

A statistically significant higher proportion of 3. Smith JR. Management of Third Stage of Labor: January 6, 2012
uteri in the carbetocin group were well contracted 4. Prendiville W and Connell MO. Active management of the third stage
of labor p. 98-113.
after the delivery of the neonate (23% versus 0, 5. Attilakos G, Psaroudakis D, Ash J, et al. Carbetocin versus oxytocin
P=.001); immediately after the intervention was given for the prevention of postpartum haemorrhage following caesarean
(77% versus 8%, P=.001);immediate post-operative section: the results of a double-blind randomised trial. BJOG 2010;
(60% versus 26%, P=.001) and 24 hours post- 117 (8): 929-36.
6. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure,
operative (77% versus 8%, P=.001) function and regulation. Physiol Rev 2001; 81(2): 629-83.
Carbetocin enhanced early postpartum uterine 7. Gimpl G, Postina R, Fahrenholz F, Reinheimer T. Binding domains
involution. A statistically significant higher of the oxytocin receptor for the selective oxytocin receptor antagonist
proportion of uteri in the carbetocin group were barusiban in comparison to the agonists oxytocin and carbetocin. Eur
J Pharmacol 2005; 510(1-2): 9-16.
below the umbilicus immediately after the 8. Bajcsy AC, Szenci O, van der Weijden GC. Doornenbal A, Maassen
intervention (66% versus 29%, P=.007); and F, Bartyik J, Taverne MA. The effect of a single oxytocin or carbetocin
immediate post-operative (97% versus 57%, treatment on uterine contractility in early postpartum dairy cows.
P=.001).No significant difference in terms of the Theriogenology 2006; 65(2): 400-14.
9. Su LL, Chong YS, Samuel M.Carbetocin for preventing postpartum
degree of uterine involution immediately after the
haemorrhage.,Cochrane Database Syst Rev 2012; 18;4:CD005457.
neonate was delivered (P=.053) and at 24 hours post- 10. Dimitrov A, Nikolov A, Nashar S, Mikhova M, Pavlova E, Kristeva
operative. (P=.18) K.Puerperal uterine involution according to the method of delivery.
The estimated blood loss was significantly lower Akush Ginekol (Sofiia). 2007; 46(9): 14-8.
in the carbetocin group (mean 585mL versus 11. Borruto F, Treisser A, Comparetto C.Utilization of carbetocin for
prevention of postpartum hemorrhage after cesarean section: a
702.8mL, P=.026) however, the two groups did not randomized clinical trial. Arch Gynecol Obstet 2009; 280(5): 707-12.
significantly differ in terms of blood transfusion Epub 2009 Feb 20.
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and diastolic blood pressures (P=.37, P=.40) analogue carbetocin.Eur J Obstet Gynecol Reprod Biol 2009; 147(1):
15-20. Epub 2009 Jul 17.
Uterine massage was less required in the 13. Su LL, Rauff M, Chan YH, et al.Carbetocin versus syntometrine for
carbetocin group (5.7% versus 48.6%, P=.001). the third stage of labour following vaginal delivery--a double-blind
randomised controlled trial. BJOG 2009; 116(11): 1461-6. Epub 2009
RECOMMENDATIONS Jun 15.
14. Askar AA, Ismail MT, El-Ezz AA, Rabie NH.Carbetocin versus
syntometrine in the management of third stage of labor following
Carbetocin is a good alternative to prevent post- vaginal delivery. Arch Gynecol Obstet 2011; 284(6): 1359-65. Epub
partum hemorrhage, however its cost prohibits 2011 Feb 19.
clinicians from prescribing it. Similarly, even if there 15. Reyes OA, Gonzalez GM.Carbetocin versus oxytocin for prevention
of postpartum hemorrhage in patients with severe preeclampsia: a
is a general safety profile for patients with high
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The authors recommend that incidence of adverse D.Haemodynamic effects of carbetocin and oxytocin given as
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Sonographic Findings Predictive of Early Pregnancy
Loss: A Retrospective Review*
JACKY LOU F. MACAPAGAL, MD AND BRENDA BERNADETTE B. Z AMORA, MD, FPOGS
Department of Obstetrics and Gynecology, St. Luke's Medical Center
The objective of this study was to determine if abnormal pproximately 15% of clinically evident
sonographic findings among live embryos are predictive
of early pregnancy loss.
A pregnancies and 60% of chemically evident
pregnancies end in spontaneous abortions. Eighty
Methods: This was a retrospective cohort analytic study percent of spontaneous abortion occurs prior to 12
involving 419 pregnant women with viable first trimester weeks of gestation. 1 In 1980, Miller, et al. in
pregnancy transvaginal sonographic examination. evaluating post-implantation pregnancy wastage,
Sonographic characteristics of the choriodecidual reported that 43% of pregnancies end in failure.
appearance, gestational sac position, yolk sac size, fetal However, only one-fifth of these cases are clinically
heart rate, subchorionic hemorrhage and laterality of the recognized as spontaneous abortions. 2 In most
corpus luteum were noted. The clinical outcome of instances, the etiology of first trimester pregnancy
pregnancy was considered abnormal if a spontaneous first wastage is unknown. In general, significant
trimester pregnancy loss of less than 12 weeks' gestation embryologic malformations that result in demise can
occurred following the sonogram. Univariate and be the result of genetic or chromosomal,
multivariate logistic regression analyses were performed environmental or combined factors. 3
to estimate odds ratios for the independent predictor In many settings, transvaginal ultrasound is used
variables in the study. Sensitivity, specificity and accuracy routinely for early pregnancy confirmation.
were computed. However, the fact remains that no single test is
Results: Irregular choriodecidual appearance, low available in differentiating a pregnancy that is likely
gestational sac, macro yolk sac, presence of subchorionic to continue or not. Perhaps, ultrasonography is the
hemorrhage and laterality of corpus luteum formation were best single diagnostic test. The availability of a high
not significantly associated with early pregnancy loss. resolution transvaginal ultrasound imaging has
Fetal bradycardia <100bpm was significantly associated made it possible to visualize embryonic development
with early pregnancy loss, OR 26.672, 95%CI 9.721-73.179. from a very early stage in pregnancy.4 No single
The sensitivity and specificity of fetal bradycardia as ultrasound measurement of the different anatomical
predictors of early pregnancy loss were 41.4% and 96.7% features in the first trimester has been shown to have
respectively. It had a 48% positive predictive value, 95.7% a high predictive value for determining early
negative predictive value and 92.8% accuracy. pregnancy outcome. 5 Ultrasound parameters
Conclusion: Sonographic finding of fetal bradycardia combined with maternal serum hormone levels,
≤ 100bpm is a predictor of early pregnancy loss. It may be maternal age, smoking habits, obstetric history and
recommended that a woman with a viable early first trimester the occurrence of vaginal bleeding have all been
gestation with fetal bradycardia should have a repeat combined in multivariate analyses, with mixed
sonogram later in the first trimester to re-assess fetal results.
viability. At present, transvaginal ultrasound is the
imaging examination of choice to evaluate the
Key words: sonographic findings, fetal bradycardia, early anatomy and physiology of the human fetal parts
pregnancy loss from as early as the third week post implantation
onwards. In particular, transvaginal sonography,
_______________ with its ability to provide accurate in-vivo images of
* Finalist, 2012 POGS-Residents' Research Paper Contest, October 24, 2012. the early gestational sac, has also provided pivotal

Sonographic Findings Predictive of Early Pregnancy Loss / Macapagal and Zamora
clues to the epidemiology and pathophysiology of choriodecidual appearance, low gestational sac
early pregnancy failure. 5 In comparison to a position, macro yolk sac, fetal bradycardia and
transabdominal approach, vaginal transducers presence of subchorionic hemorrhage as well as
provide superior resolution with respect to examining laterality of the corpus luteum are predictive of early
the appearance and contents of the gestational sac pregnancy loss
as well as the ovaries and adnexa. Various
sonographic features have been discussed with respect Specific Objectives
to accuracy in predicting pregnancy outcome. They
include small sac size relative to the embr yo, 1. To determine the incidence of sonographic
embryonic bradycardia, distorted sac shape, enlarged findings of irregular choriodecidual appearance,
or abnormal yolk sac and subchorionic hemorrhage.6 low gestational sac position, macro yolk sac, fetal
Transvaginal sonography has revolutionized bradycardia, and presence of subchorionic
clinical practice by providing definite evidence of fetal hemorrhage among live embryos
viability in early pregnancy as early as six weeks. In
patients with normal pregnancies, when embryo 2. To identify the incidence of laterality of the
viability is confirmed, the rate of pregnancy loss is corpus luteum in first trimester pregnancy scans
low at a reported incidence of 3.2%. 7 One study
3. To deter mine the association of ir regular
showed that if a gestational sac was visible, the
choriodecidual appearance, low gestational sac
embryonic loss rate was 11.5%; with a yolk sac it
position, macro yolk sac, fetal bradycardia and
was 8.5%; with an embryo less than 5mm in length,
presence of subchorionic hemorrhage as well as
it was 7.2%; and with an embryonic length of 6-10
laterality of the corpus luteum with early
mm, it was 3.3%.8 Achiron, et al. in 1991 found
pregnancy loss
embryonic heart rate to be a promising parameter in
predicting embryonic outcome after ultrasound 4. To compute for the sensitivity and specificity of
proven viability. 8 Several authors have reported significant sonographic feature/s among irregular
spontaneous abortions after describing embryos with choriodecidual appearance, low gestational sac
heart rates less than 85 beats per minute.9,10,11 An position, macro yolk sac, fetal bradycardia,
unusually slow heart rate or fetal bradycardia is a presence of subchorionic hemorrhage and
cause of concern. As many as 18% of women with laterality of corpus luteum as predictor/s of early
vaginal bleeding during the first half of pregnancy pregnancy loss
have ultrasonographic evidence for a subchorionic
hemorrhage as the etiology for their bleeding.12 The 5. To identify confounding maternal characteristics
clinical significance of this type of hemorrhage is associated with early pregnancy loss among
controversial, with some investigators reporting an women with first trimester ultrasound evaluation
increased incidence of spontaneous abortion, and
others concluding that this condition does not
adversely affect pregnancy outcome. A yolk sac Definition of Terms
diameter more than two standard deviations (2 SD)
from the mean predicted abnormal pregnancy Irregular choriodecidual appearance refers to the
outcome with a sensitivity of 91.4 %, specificity of sonographic appearance of the echoes that surround
66% and a positive predictive value of 88.8%.13 an early intrauterine gestational sac which includes
Such abnormal sonographic findings on the irregular or distorted sac shape; a thin (<2mm),
embryo can be used to identify the subgroup of weakly echogenic, or irregular choriodecidual
pregnancies that are at higher risk of early pregnancy reaction; and absence of the double decidual sac sign
loss and thus require closer follow-up. when the mean sac diameter (MSD) exceeds 10 mm.14
Objectives Low gestational sac position refers to an abnormally

low position of the gestational sac within the
General Objective endometrial cavity.14
This study aimed to determine if sonographic Macro yolk sac has a diameter of >6mm which is an
findings among live embryos of irregular abnormal feature.14

Fetal bradycardia fetal heart rate less than or equal subchorionic hemorrhage (absent or present)14 and
to 100 bpm.13 laterality of the corpus luteum (right or left) were
noted.
Subchorionic hemorrhage an anechoic area on Maternal clinical characteristics were likewise
ultrasound that has a falciform shape, and is usually retrieved from their ultrasound records and this
observed behind or below the gestational sac, included maternal age (<35 years or ≥35 years) and
separating the chorion from the inner wall of the history of previous abortion/s (with or without
uterus.14 history of previous abortion/s).
The clinical outcome of pregnancy was
Abortion is the expulsion of the product of conception determined by means of follow up ultrasound
or termination of pregnancy before 20 weeks examination, interview with the referring physicians,
gestational age or at less than 500 grams telephone calls to physicians' offices and review of
birthweight. 15 delivery and/or pathology records. Normal clinical
outcome or successful pregnancy outcome was
Early pregnancy loss spontaneous early abortion or determined by normal second- or third trimester
spontaneous first trimester fetal loss (<12 weeks age sonograms, or if clinical records confirm normal
of gestation).13 pregnancy progression. The clinical outcome was
considered abnormal if a spontaneous early abortion
Advanced Maternal Age maternal age of 35 years or or first trimester pregnancy loss of less than 12 weeks'
above.16 gestation occurred following the sonogram.
This study was limited by the use of several
ultrasound machines and by the different sonologists
MATERIALS AND METHODS who interpreted the ultrasound findings.
Interobserver bias was not eliminated in this study.
This was a retrospective cohort analytic study of Data management and encoding were facilitated
pregnant women at risk of having spontaneous early using Microsoft Excel and SPSS 17.0 for Windows
abortion. programs. The descriptive statistics were determined
Subjects included all women (total enumeration) by means of the SPSS frequency, descriptives and
with first trimester pregnancy 5 to 9 weeks' gestation crosstabs procedures. For the comparison between
who underwent transvaginal sonographic means, t tests were performed. Computations and
examination between January 2010 to February 2011 analysis were carried out using Chi-square and
at the Women's Health Care Unit of St. Luke's Fisher's tests to determine association among
Medical Center. All scans were done by board- categorical variables. With the same software,
certified obstetrician-gynecologist sonologists. Only univariate and multivariate logistic regression
the first scan that showed detectable fetal cardiac analyses were performed to estimate odds ratios for
activity was included. Exclusion criteria included the independent predictor variables in the study. This
the following: ectopic pregnanc y, multiple included the estimation of the 95% confidence
pregnancies, missed abortion, fibroids or any other intervals of the event risks. A P value of < .05 was
uterine disorder. considered statistically significant. For fetal heart
Gestational age was confirmed by last menstrual rate, a Receiver Operating Characteristic (ROC)
period, if known, and by the crown-rump length curve was processed. A cut off value was explored
measurement on the study scan for between 5 to 9 in association with early pregnancy loss. The point
weeks' gestation, determining the crown-rump length in the curve where both sensitivity and specificity
measurement is considered the most accurate method have highest values nearest to the area under the
of dating. curve of 1.0 was considered as a diagnostic cut off
A real time B-mode scan was initially performed point from this study.
to define the uterine position, size and morphology.
Sonographic characteristics or descriptions of the RESULTS
choriodecidual appearance (regular or irregular) 14,
gestational sac position (normal or low) 14, yolk sac There were a total of 419 subjects included in
size (<6mm or ≥6mm, macro yolk sac)14, fetal heart this study over the 14-month study period. The
rate (>100bpm or ≤100bpm, bradycardia) 13 , maternal ages ranged from 16 to 42 years with a mean

maternal age of 30.87 ± 5.006 years. All subjects of fetal bradycardia or fetal heart rate ≤100 bpm was
were scanned between 5 to 9 weeks age of gestation found to be associated with early pregnancy loss that
and the mean age of gestation at time of first was statistically significant at P<0.001. Among the
trimester scan was 7.06 ± 1.297 weeks' gestation. The 25 cases with fetal bradycardia 48% (12/25 of cases)
fetal heart rate recorded ranged from 38 to 197 bpm had early pregnancy loss. Fetal bradycardia rendered
with a mean fetal heart rate of 143.44 ± 26.761 bpm. these women about 20 times at increased risk of
Table 1 shows the sonographic characteristics
of the first trimester scans of the subjects included Table 1. Sonographic and maternal characteristics.
in this study. The incidence of ir re gular
choriodecidual appearance and low gestational sac Variables Number Percent
position was only 0.2% each for there was only one n = 419
of 419 cases each recorded for the said sonographic Sonographic Characteristics
characteristics. Likewise, the incidence of finding
a macro yolk sac or a yolk sac >6 mm in diameter Choriodecidual appearance
was only 0.7% as there were only three recorded Regular 418 99.8%
Irregular 1 0.2%
cases. The most common abnormal sonographic
finding among the subjects scanned was presence Gestational sac position
of subchorionic hemorrhage with an incidence of Normal 418 99.8%
82.1% (344/419 cases). Fetal bradycardia or finding Low 1 0.2%
of fetal heart rate <100 bpm was found only in 25
Yolk sac size
subjects giving an incidence of 6.0%. As to the <6mm 416 99.3%
laterality of the corpus luteum, right-sided corpus ≥6mm (macro yolk sac) 3 0.7%
luteum formation was more than twice as common
as a left-sided corpus luteum formation with an Fetal heart rate
>100 bpm 394 94.0%
incidence of 69.9% and 30.1%, respectively. ≤100 bpm (bradycardia) 25 6.0%
Moreover, the table also shows the maternal clinical
characteristics obtained from the ultrasound records. Subchorionic hemorrhage
Among the 419 women included in this study, about Absent 75 17.9%
Present 344 82.1%
one-fifth (21.7%) of the subjects were more than or
equal to 35 years of age and 15.5% had a history Laterality of the corpus luteum
of previous abortion/s. Right 293 69.9%
Table 2 shows the distribution of pregnancy Left 126 30.1%
outcomes. Of the 419 subjects, 29 women (6.9%) Maternal Clinical Characteristics
had an early pregnancy loss or a spontaneous first
trimester pregnancy loss. Age
Table 3 shows the univariate analysis of the <35 years 328 78.3%
≥35 years 91 21.7%
association of the sonographic and maternal clinical
characteristics according to pregnancy outcome. History of previous abortion/s
Since there were too few cases of irregular No 354 84.5%
choriodecidual appearance, low gestational sac Yes 65 15.5%
position and macro yolk sac or yolk sac size ≥6 mm
in diameter, Chi square test may be invalid or not
reliable. Even if the finding of subchorionic Table 2. Distribution of pregnancy outcomes.
hemorrhage was the most common sonographic Pregnancy Outcome Number Percent
abnormality among the subjects, only 8.0% of these n = 419
cases had an early pregnancy loss. Results showed
that there was no association of presence of Early pregnancy loss - 1st trimester
pregnancy loss, < 12 weeks age of
subchorionic hemorrhage with early pregnancy loss gestation 29 6.9%
that was statistically significant (P=0.685). Likewise,
laterality of the corpus luteum did not show an Successful pregnancy - normal
association with early pregnancy loss that was pregnancy progression to > 12
weeks age of gestation 390 93.1%
statistically significant (P=0.780). Only the finding

having an early pregnancy loss, OR 20.471, 95%CI Table 4 shows that in a multivariate analysis of
8.124-51.517. both sonographic and maternal clinical
As to maternal clinical characteristics, history of characteristics according to pregnancy outcome, fetal
previous abortion/s was not associated with early bradycardia and advanced maternal age were still
pregnancy loss (P=0.425). It was maternal age ≥35 the same variables that were significantly associated
years which was associated with early pregnancy loss with early pregnancy loss. Fetal bradycardia, fetal
and this association was statistically significant at heart rate ≤100 bpm, rendered a woman to about 26
P=0.002. Among the 91 women aged ≥35 years, 13 times at increased risk of early pregnancy loss, OR
or 14.2% had early pregnancy loss. Advanced 26.672, 95%CI 9.721-73.179. Advanced maternal
maternal age, age ≥35 years, rendered these women age of ≥35 years rendered a woman to about 5 times
about three times at increased risk of having early at increased risk of early pregnancy loss, OR 4.666,
pregnancy loss, OR 3.303, 95%CI 1.524-7.156. 95%CI 1.891-11.513.
Table 3. Sonographic and maternal clinical characteristics according to pregnancy outcome, univariate analysis.
Variables Pregnancy Outcome P value

Early Pregnancy Loss* Successful Pregnancy **
Sonographic Characteristics
Choriodecidual appearance† ---

Regular (28/418) 6.7% (390/418) 93.3%
Irregular (1/1) 100% –
Gestational sac position† ---

Normal (28/418) 6.7% (390/41) 93.3%
Low (1/1) 100% –
Yolk sac size† ---

<6mm (27/416) 6.5% (389/416) 93.5%
≥6mm (macro yolk sac) (2/3) 66.7% (1/3) 33.3%
Fetal heart rate <0.001

>100 bpm (17/394) 4.3% (377/394) 95.7% OR 20.471
≤100 bpm (bradycardia) (12/25) 48.0% (13/25) 52.0% 95%CI
8.1234 - 51.517
Subchorionic hemorrhage 0.685

Absent (23/344) 6.7% (321/344) 93.3%
Present (6/75) 8.0% (69/75) 92.0%
Laterality of the corpus luteum 0.780

Right (19/293) 6.5% (274/293) 93.5%
Left (9/126) 7.1% (117/126) 92.9%
Maternal Clinical Characteristics
Age 0.002
<35 years (16/328) 4.9% (312/328) 95.1% OR 3.303
≥35 years (13/91) 14.3% (78/91) 85.7% 95%CI
1.524 - 7.156
History of previous abortion/s 0.425

No (23/354) 6.5% (331/354) 93.5%
Yes (6/65) 9.2% (59/65) 90.8%
* Early Pregnancy Loss - 1st trimester pregnancy loss, < 12 weeks age of gestation
**Successful Pregnancy - normal pregnancy progression to > 12 weeks age of gestation
† In cases where the events were too few, Chi square test may be invalid or not reliable

Table 4. Sonographic and maternal clinical characteristics 96.7%, respectively. A sonographic detection of fetal
according to pregnancy outcome, multivariate analysis (Qualitative). bradycardia of ≤100 bpm had a 48% positive
Variables Sig. Exp (B) 95% CI for Exp (B) predictive value and a 95.7% negative predictive
Lower Upper value. The accuracy of fetal bradycardia as a
predictor of pregnancy loss was 92.8%.
Fetal heart rate
≤100 bpm 0.000 26.672 9.721 73.179
Maternal age ≥35 years 0.001 4.666 1.891 11.513
Constant 0.000 0.026
Table 5. Sonographic and maternal clinical characteristics

according to pregnancy outcome, multivariate analysis
(Quantitative).
Variables Sig. Exp (B) 95% CI for Exp (B)

Lower Upper
Fetal heart rate 0.001 0.974 0.960 0.989
Maternal age 0.016 1.102 1.018 1.193
Constant 0.151 0.102

Figure 1. Receiver operating characteristic curve for fetal
bradycardia.
Table 5 shows that by quantitative analysis, in In the Receiver Operating Characteristic (ROC)
terms of actual maternal age, the odds of early curve, the true positive rate (sensitivity) was plotted
pregnancy loss are increased by more than 62% for in function of the false positive rate (1-sensitivity)
every 5-year increase in maternal age holding fetal for different cut-off points of the fetal heart rate as a
heart rate constant. Likewise, the odds of early parameter. Each point on the ROC curve represents
pregnancy loss decrease by more than 22% for every a sensitivity/specificity pair corresponding to a
10 beats per minute increase in fetal heart rate holding particular decision threshold. In this study
maternal age constant. population, fetal bradycardia cut-off of 98bpm was
Table 6 shows the outcomes of pregnancies with the cut-off that would give the highest possible
fetal bradycardia. There were 25 cases of fetal sensitivity and specificity combined. There were 19
bradycardia and 12 of them (48.0%) terminated in cases of fetal bradycardia, fetal heart rate ≤98bpm,
early pregnancy loss. The sensitivity and specificity and 9 of them (47.3%) terminated in early pregnancy
of fetal bradycardia, fetal heart rate ≤100 bpm, as a loss. It has a low sensitivity at 31% but has a higher
predictor of early pregnancy loss was 41.4% and specificity at 97.4%. The accuracy of fetal
Table 6. Presence or absence of fetal bradycardia according to pregnancy outcome.
Fetal Bradycardia Pregnancy Outcome P value

Early Pregnancy Loss* Successful Pregnancy **
Present 12 13 25
Absent 17 377 394
Total 29 390 419
*Early Pregnancy Loss - 1st trimester pregnancy loss, < 12 weeks age of gestation
**Successful Pregnancy - normal pregnancy progression to > 12 weeks age of gestation

bradycardia ≤98bpm was likewise 92.8%. A 88.8%.14 In this study, 66.7% of those with abnormal
sonographic detection of fetal bradycardia of yolk sac resulted in early pregnancy loss with a
≤98bpm had a 47.4% positive predictive value and a sensitivity of only 6.9%, specificity of 99.7% and
95% negative predictive value, similar to that of fetal positive predictive value of 66.7%. However, since
bradycardia at ≤100 bpm. there were only 3 cases with this abnormal
sonographic finding, a univariate analysis may not
DISCUSSION be valid to formulate conclusive association.
Subchorionic hemorrhage maybe due to partial
Transvaginal ultr asound has become an detachment of the trophoblast from the uterine wall
invaluable tool in the evaluation of the embryo as a or abruption of the edge of the chorion frondosum-
patient in early pregnancy. Several researches have decidua basalis complex. As many as 18% of women
come up with multiple parameters that will predict with vaginal bleeding during the first half of
unfavorable pregnancy outcome including those pregnanc y have sonog raphic evidence of a
cases where normal cardiac activity has already been subchorionic hemorrhage as the etiology for their
sonographically demonstrated. bleeding. The clinical significance of this type of
Harris, et al. in 2006, did a prospective study in hemorrhage is controversial, with some investigators
a series of patients with a sonographic finding of a reporting an increased incidence of spontaneous
chorionic "bump," which was an irregular, convex abor tion. 18 In this study, the incidence of a
bulge from the choriodecidual surface into the first- sonographic finding of subchorionic hemorrhage
trimester gestational sac. 17 The pregnancy outcomes was 17.9%. With only 8.0% of cases resulting in
of these cases with irregular choriodecidual early pregnancy loss, its association with poor
appearance were compared with the general outcome was not statistically significant (P=0.685).
population and infertility first-trimester control This study showed similar results as with the study
groups. The finding of an irregular choriodecidual of Lulu, et al. in 1996, reporting that subchorionic
appearance in the first trimester sonogram was hematoma in early pregnancy may not be all that
associated with a guarded prognosis for the early significant, since the presence of hematoma does not
pregnancy with a livebirth rate of <50%.17 In this necessarily imply poor outcome. It has been said
study, ther e was only one case of ir regular that subchorionic bleed likely represents an incidental
choriodecidual appearance which eventually resulted finding, therefore, and when small and asymptomatic,
in early pregnancy loss. The incidence was only 0.2% may be of no clinical significance.18
with a 100% poor outcome. Using univariate Devajaran, et al. conducted a retrospective study
analysis, the difference would have been statistically to observe the relationship between the laterality of
significant, however, due to the low incidence, the ovulation and the viability of pregnancy. It has been
chi-square test may be invalid. reported that a predominant right sided ovulation
Low gestational sac within the endometrial cavity exists in human being as has been reported in the
also predicts poor pregnancy outcome since this past and that there was no statistically significant
means that the sac is beginning to detach from its difference between the laterality of corpus luteum and
normal implantation site and serially goes down on viability of pregnancy.19 Similar to the results of this
its way to expulsion. 14 In this study, there was study, right-sided corpus luteum formation was more
likewise only one case of low gestational sac which than twice as common as a left-sided corpus luteum
also resulted in early pregnancy loss. The incidence formation, 69.9% vs 30.1%. On univariate analysis,
was only 0.2% with a 100% poor outcome. Using laterality of corpus luteum formation was not
univariate analysis, the difference would have been significantly associated with early pregnancy loss
statistically significant however as with the irregular (P=0.780).
choriodecidual appearance due to the low incidence, As to reviews on embryonic heart rate, Achiron,
the chi-square test may be invalid. et al. constructed normograms for the embryonic
A yolk sac size of more than 6mm in diameter is heart rate in 603 embryos at 5.5 to 11 weeks' gestation
considered a macro yolk sac and is a predictive of to determine whether deviation from the normal heat
poor outcome. A yolk sac more than 2 standard rate can predict fetal loss after ultrasound proven
deviations from the mean predicted abnormal viability. In their study, 15 of the 23 spontaneous
pregnancy outcome with a sensitivity of 91%, abortion cases recorded embryonic heart rates outside
specificity of 66% and a positive predictive value of the 95% confidence interval or crown-rump length.11

In another review by Benson, et al. (1994) involving predictor of subsequent early pregnancy loss, the
pregnancies of less than 8 weeks' gestation with an biologic variation and the dynamism of the
embryonic heart rate of ≤90 bpm, fetal demise corresponding heart rate for age of gestation should
occurred in all 7 embryos with heart rate < 70 bpm, likewise be considered in the further monitoring and
10 of 11 with heart rates of 70-79 bpm, and 15 of 19 observation of pregnancy progression.
with heart rates of 80-90 bpm.12 In a very large series Moreover, this investigative study also included
involving 2,164 singleton pregnancies between 6 and possible confounding clinical variables in the subjects
8 weeks' gestation, Stefos and co-workers (1998) or maternal characteristics such as the maternal age
observed subsequent embryonic demise in all embryos and any history of previous abortion/s. History of
that presented with a heart rate of ≤85 beats/ previous abortion/s was not significantly associated
minute.13 with early pregnancy loss (P=0.425). On the other
The results of this retrospective study were similar hand, in both univariate and multivariate analyses
with the findings of Benson and Doubilet in 2005 taking into consideration all possible abnormal
where among the 25 pregnancies 5 to 9 weeks' sonographic findings, advanced maternal age was
gestation, there were 12 cases of fetal bradycardia significantly associated with early pregnancy loss, OR
and all of them terminated in early pregnancy losses. 4.666, 95%CI 1.891-11.513. It cannot be
All had repeat sonograms showing early intrauterine overemphasized that advanced maternal age of ≥35
embryonic or fetal demise within a week's time from years is a risk factor for aneuploidy which
the sonographic detection of heart rate ≤100 bpm. subsequently is a common cause of early pregnancy
As in this retrospective study, using fetal heart rate loss.
≤100 bpm as cut-off for fetal bradycardia, the A quantitative analysis of the association of fetal
incidence was 6.0% and early pregnancy loss occurred heart rate and maternal age with early pregnancy
in 48.0% of cases with a sensitivity of 41.4% and a loss was likewise made in this investigative review.
sensitivity of 96.7%. Its positive and negative In terms of actual maternal age, the odds of early
predictive values were 48% and 95.7%, respectively pregnancy loss are increased by more than 62% for
with an accuracy of 92.8%. Furthermore, in the every 5-year increase in maternal age holding fetal
Receiving Operating Characteristic Curve that was heart rate constant. Likewise, the odds of early
processed, a fetal bradycardia cut-off of 98 bpm pregnancy loss decrease by more than 22% for every
likewise gave a low sensitivity at 31% but a higher 10 beats per minute increase in fetal heart rate holding
specificity at 97.4% with nearly similar positive and maternal age constant.
negative predictive values at 47.4% and 95%,
respectively. The accuracy was the same at 92.8%. CONCLUSION
As with the previous reports, there was significant
association between fetal bradycardia and early It is significant to establish a sonographic
pregnancy loss. In both univariate and multivariate parameter predictive of poor outcome or impending
analyses of the various abnormal sonographic first trimester loss so as to be guarded in the
findings in first trimester scans, fetal bradycardia at reassurance provided to patients and their further
≤100bpm, was significantly associated with early work-up and monitoring. An abnormal ultrasound
pregnancy loss, OR 26.672, 95%CI 9.721-73.179. despite viability would caution the treating physician
The dynamic changes occurring in the growth to order a subsequent sonogram in 7 to 10 days.
of the embryo as the age of gestation progresses and The incidence of irregular choriodecidual
the corresponding changes in heart rate should never appearance and low gestational sac position was low
be overlooked in interpreting this study's results. at 0.2% each. Likewise, the incidence of finding a
Doubilet, et al. reported that at 5 to 6 weeks' gestation, macro yolk sac or a yolk sac ≥6 mm in diameter was
the mean embryonic heart rate is 101 bpm, which only 0.7%. The most common abnormal
increases to 143 bpm by 8 to 9 weeks' gestation and sonographic finding among the subjects scanned was
subsequently plateaus at approximately 140 bpm. presence of subchorionic hemorrhage with an
Therefore, it is not unusual for an initially detected incidence of 82.1%. Fetal bradycardia or finding of
embryonic heart rate to be somewhat slower than fetal heart rate ≤100 bpm was found only in 25/419
the fetal heart rate recorded later in pregnancy. These subjects giving an incidence of 6.0%. As to laterality
findings further emphasize that despite a high of the corpus luteum, right-sided corpus luteum
sensitivity and specificity of fetal bradycardia as a formation was more than twice as common as a left-

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sonographic features that may be prognostic factors rate by 8 weeks at US. Radiology 2005; 236(2): 643-6.
of adverse outcomes, the investigators recommend a 14. Sumpaico W, et al. Obstetric and Gynecologic Ultrasound for the
long-term study beyond the first trimester and Practicing Physician. 2006. Manila Central University.
15. Royal College of Obstetricians and Gynecologists; Guideline no. 23.
adverse perinatal outcomes such as preterm labor,
The management of early pregnancy loss. London: RCOG. October
growth restriction and oligohydramnios be likewise 2006.
evaluated. Moreover, results of this study would 16. Booth, et al. Elderly primigravidae. BJOG 1964; 71(2): 249-54.
need further validation in a prospective review 17. Harris, et al. The chorionic bump. A first-trimester pregnancy
enrolling more patients from a multi-center study. sonographic finding associated with a guarded prognosis. J Ultrasound
Med 2006; 25: 757-63.
It is hoped that in a multi-center study, a possible 18. Lulu A, et al. Subchorionic hematoma in threatened abortion:
risk scoring index for first trimester patients coming Sonographic evaluation and significance. Ann Saudi Med 1996; 16(6):
in for an ultrasound will be formulated. 650-3.
19. Devalaran K, et al. Does the laterality of corpus luteum influence the
viabilty of pregnancy? Obstetrics and Gynaecology, St. George
Hospital, Tooting, London, United Kingdom.

Rapid Fetal Fibronectin Alone and in Combination with
Cervical Length in Predicting Preterm Delivery Among
Symptomatic Pregnant Women in a Philippine Tertiary
Hospital: A Retrospective Cohort Study from 2009 to 2012*
JOANNA PAULINE CHUA U RSUA, MD AND MA. ROSARIO CASTILLO CHENG, MD, FPOGS
Department of Obstetrics and Gynecology, The Medical City
Background: The objective of this study was to determine Conclusion: Several studies conclude that fetal fibronectin
the likelihood of delivery given a positive or negative rapid has a high negative predictive value suggesting that a
fetal fibronectin test result in symptomatic pregnant women negative result renders a patient unlikely to deliver within
in a Philippine tertiary hospital. Another objective was to 7 days. This study shows that fetal fibronectin has fair to
determine if the likelihood of delivery is increased when good strength as a short-term predictor of preterm labor
fetal fibronectin is combined with cervical length based on qualitative strength of likelihood ratios. Given a
assessment. positive fibronectin result, the likelihood that a patient will
Methods: Medical records from 2009 to 2012 of patients deliver prematurely within 7 days is 4.7 times. Given a
between 24 weeks and 34 weeks and 6 days gestation with negative result, the likelihood that a patient will not deliver
symptoms of preterm labor were retrieved and selected for is 2.5x than delivery will occur within 7 days.
this study. Rapid bedside fetal fibronectin results and
cervical length measurements obtained via ultrasonography Key words: Fetal fibronectin, cervical length, preterm labor
were gathered along with the interval duration from
fibronectin testing, cervical length measurement and
delivery.
Results: Thirty-one patients had fetal fibronectin samples
and outcome data. The admission-to-delivery interval was
33.6 days shorter in the group with positive fetal fibronectin
The worldwide estimates for preterm birth
results than in the group with negative fetal fibronectin
according to the World Health Organization
results. (20.2 + 15.48 compared with 53.8 + 26.95; P<0.05).
(WHO) is 9.6%. In Asia, it is approximately 9.6%.
The positive predictive values for delivery within 7, 14 and
In the US, preterm birth rate is 12.8% as of 2006.1
21 days were 33.3%, 50% and 50%, respectively while the
Preterm delivery rate has averaged 11.15% in
negative predictive values were 96%, 92% and 92%,
the last 15 years according to the Philippine
respectively.
Obstetrical and Gynecological Society (POGS). At
The positive likelihood ratios for delivery within 7, 14 and
the Philippine General Hospital, the average preterm
21 days were 4.7, 5.2 and 5.2, respectively. The negative
delivery rate in the last 5 years is 21.52%.1
likelihood ratios for delivery within 7, 14 and 21 days were
In The Medical City the preterm delivery rate
0.4, 0.56 and 0.56, respectively.
from 2007 to 2011 was 8.8%. In 2011 alone, the
The sensitivity combining a positive fetal fibronectin and
preterm delivery rate was 9.15%. 2 These data are
short cervical length (<25 mm) in determining delivery
comparable with preterm delivery rates reported.
before 34 weeks of gestation was 50%.
According to the Philippine Department of
Health, as of 2006, 7.4% of infant mortality is
attributed to preterm delivery. Eight percent of
_______________ deliveries in 2008, have birth weight less than
* Finalist, POGS-Residents' Research Paper Contest last October 24, 2012. 2500grams as a complication of preterm delivery.3,4

Rapid Fetal Fibronectin Alone and in Combination with Cervical Length in Predicting Preterm Delivery Among Symptomatic Pregnant Women / Ursua and Cheng
The diagnosis of preterm labor is made based The Food and Dr ug Administration in the
on the following criteria: uterine contractions of 4 United States has approved the use two fetal
in 30 minutes, cervical dilatation of at least 3cm, fibronectin assays for assessing preterm labor: the
and cervical effacement of 80% or greater.5 manual enzyme immunoassay and the rapid assay.
Studies have been made on cervical length The rapid assay is a semi-quantitative membrane
measurement and fetal fibronectin as predictors of immunoassay that uses monoclonal anti-fetal
preterm delivery. These studies determined whether fibronectin antibody (FDC-6) coupled to a blue
patients went into spontaneous labor and microsphere and an immobilized polyclonal goat
subsequently delivered within days or weeks of anti-fibronectin antibody. The control lines on the
testing.5 device are interpreted with the TLiIQ analyzer.9 Our
study used the rapid assay fibronectin test which
proves to have equivalent performance to the enzyme
Review of Related Literature immunoassay which has an 8-24 hour turn-around
time.19
Definition and Advantages of Fetal Fibronectin Fibronectin samples are collected by placing a
sterile polyester tip swab in the posterior cul-de-sac
Fetal f ibronectin was first described by for ten seconds. The swab is then placed in a
Lockwood in 1991. Fibronectins are adhesive fibronectin extraction buffer kit that uses a
glycoproteins with multiple isoforms found in monoclonal anti-fibronectin antibody (FDC-6) for
extracellular matrix and plasma.6,7 It is uniquely ten minutes. Fibronectin concentrations >50 ng/mL
found in the basement membrane, near the show as two lines on the cassette and is interpreted
choriodecidual interface, and produced by fetal as positive.16 Results are either positive or negative.
membranes. It provides adherence for the chorion Fetal fibronectin sampling is not done in patients with
to the decidua.5,6 sexual intercourse, vaginal examination or
Fetal fibronectin is nor mally found in transvaginal ultrasound done within 24 hours.
cervicovaginal fluid in the first 20 weeks of gestation Several studies claimed that fetal fibronectin
as the gestation sac implants and attaches to the is an accurate predictor of preterm delivery. In a
endometrium. After 20 weeks, when the implantation study by Tekesin, et al., in 2005, fetal fibronectin
has been completed, the presence of fetal fibronectin was found to be effective in predicting risk of
in the cervix or vagina indicates mechanical or delivery with negative predictive values of 98.4%,
inflammatory disruption of the membrane's 98.4% and 96% within 7, 14 and 21 days of testing,
attachment to the decidua. It is speculated that respectively.
cervical disruption or dilatation will result in the A multicenter trial by Peaceman, et al., in 1997,
release of fibronectin into the cervical discharge. It reported that fetal fibronectin had an even higher
was also noted that fetal fibronectin was found in negative predictive value at 99.5% for delivery within
the amniotic fluid so that its presence in the vagina 7 days. The clinical value of a negative fetal
may also indicate the presence of amniotic fluid in fibronectin suggests that preterm delivery will not
the cervicovaginal secretions.6 occur within 7 days. 8,10
A negative fetal fibronectin test result suggests Some studies were inconclusive about the value
absence of preterm labor, thus, avoiding unnecessary of fetal fibronectin. Berherella, et al., in 2008,
hospitalization, and, the side effects of tocolytics and reviewed five controlled studies and did not find any
steroids. In contrast, a positive test may indicate the evidence to either support or refute the use of fetal
presence of preterm labor. Tocolytics may then be fibronectin test for management of women with
administered thereby delaying delivery to allow time symptoms of preterm labor. The recommendation
for administration of steroids to enhance fetal lung was to conduct further research. 11
maturity or transfer of a patient to a tertiary hospital There have also been studies that disprove the
with a neonatal intensive care unit. Pregnancies may accuracy of fetal fibronectin in determining preterm
be brought closer to term thereby avoiding the delivery. Sanchez-Ramos, et al., published a meta-
adverse effects of prematurity. Studies by Peaceman, analysis in 2009, involving 32 studies, which
et al. and Tekesin, et al. have shown that a negative concluded that fibronectin has limited accuracy in
fibronectin test is of more use than a positive predicting preterm birth within 7 days of sampling
fibronectin test.6,8 (LR+ 4.2 LR- 0.29).8 Lowe, et al., also concluded

in their randomized control trial that the use of fetal Objectives of the Study
fibronectin does not affect the gestational age at
delivery, frequency of use of medical interventions, The objective was to determine the likelihood
length of stay in labor and delivery or rate of of delivery given a positive or negative rapid fetal
inpatient admissions.12 fibronectin test result in symptomatic pregnant
A local prospective study by Libiran, et al., in women at The Medical City.
2011, noted that fibronectin alone has low accuracy The authors also aimed to determine if the
of predicting preterm delivery (LR+ 1.7 and LR- 0.8). likelihood of delivery is increased when fetal
Combined fibronectin and cervical length has fibronectin is combined with cervical length
moderate accuracy in predicting preterm delivery (LR assessment.
0.14) The study concluded that a negative fibronectin
test is a good indicator that preterm delivery is
unlikely to occur. Cervical length predicts preterm MATERIALS AND METHODS
delivery more accurately than fibronectin.
Fibronectin is of value when combined with cervical Data Collection
length measurement. 23
Currently, the American College of Obstetrics This retrospective cohort study was conducted
and Gynecology recommends that fetal fibronectin from January 2009 to January 2012 at The Medical
should not be used routinely to screen low risk City. Fetal fibronectin test has only been made
asymptomatic women, but the test may be useful to available in the institution in 2009. Approval from
screen high-risk patients for preterm labor.1,8,13 the medical records section to scan through the data
was obtained.
Fetal Fibronectin and Cervical Length Assessment Subject Inclusion and Exclusion Criteria
Cervical length measurements via ultrasound are Pregnant women between 24 weeks and 34 weeks
measured in the sagittal plane and performed with and 6 days age of gestation with associated regular
an empty bladder to avoid a deceptively elongated uterine contractions, cervical dilatation and cervical
image.21 effacement, who had fetal fibronectin testing done,
Goldenberg, et al., in 1998, combined cervical with or without cervical length measurement by
length determination and fetal fibronectin to predict ultrasonography, were included in this study.
preterm birth. Among women with cervical length A gestational age cut-off of 34 weeks and 6 days
less than 25mm and positive fetal fibronectin test was used as cut-off because evidence indicates that
result, 60% delivered before 37 weeks and 50% infants delivered between 34 and 37 weeks of
delivered before 32 weeks of gestation. A short cervix gestation experience morbidity and mortality at rates
predicted subsequent positive fetal fibronectin result, similar to term infants delivered between 37 and 40
and a positive fetal fibronectin result predicted weeks.18 In the charts, the regular uterine contractions
subsequent cervical shortening. There was no single were all documented by tocodynamometry, as having
sequence of events that led to spontaneous preterm at least 4 contractions in 30 minutes. Cervical
birth. Further research was recommended to dilatation was from 0 to 3 centimeters and cervical
determine optimum multiple marker screening effacement was at least 50%. 21
test.14,15 All pregnancies were singleton and had none of
Franco, et al., in 2005,concluded that cervical the following complications or risk factors for preterm
length did not contribute to prediction of preterm delivery: preterm rupture of membranes, intrauterine
delivery within 14 days in symptomatic fetal infection, incompetent cervix, intrauterine growth
fibronectin positive women.17 restriction of the fetus, preeclampsia, suspected fetal
Iams, et al., in 1998, showed that women with asphyxia, or a major fetal anomaly.5,7,17
positive fetal fibronectin and a short cervical length
(<25 mm) had a 64% chance of delivering within Data Documentation
35 weeks. Those with a negative fetal fibronectin and
a long cervical length (> 35 mm) had a 7% chance Data collected on patient's demographic
of delivering before 35 weeks.15 information (age, gravidity, parity), fetal fibronectin

test result, digital cervical examination, gestational RESULTS

age at fetal fibronectin testing, gestational age at
delivery, fibronectin testing-to-delivery interval and A total of 31 patients met the inclusion criteria.
pregnancy outcome were tabulated. Table 1 describes the demographic and clinical
The measured outcome was delivery within 7, characteristics of the study population. No
14 and 21 days following a positive or negative fetal statistically significant differences were observed
fibronectin result. concerning maternal age, gravidity, parity, gestational
age at enrollment and gestational age at delivery. As
expected, a statistically significant difference in
Data Analysis admission-to-delivery interval was found.
The mean admission-to-delivery interval was
Fetal fibronectin test results were correlated with 53.8±26.95 days for those with negative results and
date and gestational age at delivery. A positive fetal 20.2±15.48 days for those with positive results
fibronectin test result was considered a true positive (P<0.007). This is 33.6 days shorter in the group with
if delivery occurred within 7, 14 or 21 days after the positive fetal fibronectin results. The overall preterm
positive test result, and considered a false positive delivery rates in our study population were 35% for
result if spontaneous delivery did not occur within less than 37 weeks of gestation and 16% for less than
7, 14 or 21 days.17 34 weeks.
A negative fetal fibronectin test result was
considered true negative if delivery did not occur Fetal Fibronectin
within 7, 14 or 21 days after the negative test result,
and considered false negative if delivery occurred The sensitivity, specificity and predictive values
within 7, 14 or 21 days.17 for each delivery category are shown in Table 2. The
Cervical length of less than 25mm (10th rapid fetal fibronectin assays had a sensitivity of
percentile) was categorized as short and that of more 66.7% and specificity of 85.7% in predicting risk of
than 25mm was long.15 delivery within 7 days, and a sensitivity of 60% and
Data were expressed as means and standard specificity of 88.5% for those who delivered within
deviations or number of observations with 14 and 21 days.
appropriate proportions. Nominal values were For spontaneous delivery before 34 weeks, fetal
analyzed with the X 2 test. Sensitivity, specificity, fibronectin had a sensitivity of 40%, specificity of
positive and negative predictive values were 84.6%, positive predictive value of 33.3% and a
calculated for the above outcomes. The likelihood negative predictive value of 88%. For spontaneous
ratio of a positive result [(sensitivity)/(1-specificity)] delivery before 37 weeks, fetal fibronectin had a
and the likelihood ratio of a negative result sensitivity of 33.3%, specificity of 89.5%, positive
[(1-sensitivity)/specificity)] were calculated. predictive value of 66.7% and a negative predictive
Statistical significance was assumed for P < 0.05.17 value of 68%.
Table 1. Demographic and clinical characteristics at the time of presentation among patients with positive and negative fetal
fibronectin test results.
fFN (+) fFN (-) T test

n=6 n=25 P value
Mean Maternal Age (y) 28.83±4.750 29.92±4.6 0.609

Mean Parity 0.67±0.816 0.32±0.476 0.357
Mean Gravidity 1.83±1.169 1.44±0.651 0.268
Gestational Age at Enrollment (wk) 32.3±2.37 29.7±3.33 0.75
Gestational Age at Delivery (wk) 35.1±3.73 37.4±2.65 0.9
Admission-to-Delivery Interval (d) 20.2±15.48 53.8±26.95 0.007

The positive predictive values for delivery within sensitivity of 50% and specificity of 86.7% for those
7,14 and 21 days were 33.3%, 50% and 50%, who delivered within 14 and within 21 days.
respectively. The negative predictive values for For spontaneous delivery before 37 weeks of
delivery within 7, 14, and 21 days were 96%, 92% gestation, fetal fibronectin combined with cervical
and 92%, respectively. length had a sensitivity of 42.9%, specificity of
The positive likelihood ratio was 3.17 for delivery 91.7%, positive predictive value of 75% and a
before 37 weeks of gestation and 2.6 for delivery negative predictive value of 73.3%. For spontaneous
before 34 weeks. The positive likelihood ratios (LR+) delivery before 34 weeks of gestation, fetal fibronectin
were 4.7, 5.2 and 5.3 for delivery within 7,14 and 21 combined with cervical length had a sensitivity of
days. (Table 2) 50%, specificity of 86.7%, positive predictive value
The negative likelihood ratio was 0.75 for of 50% and a negative predictive value of 86.7%.
delivery before 37 weeks of gestation and 0.71 for Positive predictive values for delivery within 7,14
delivery before 34 weeks. The negative likelihood and 21 days were 25%, 50% and 50%, respectively.
ratios (LR-) were 0.4, 0.45 and 0.45 for delivery The negative predictive values were 93.3%, 86.7%
within 7, 14 and 21 days. (Table 2) and 86.7% for delivery within 7, 14, and 21 days,
respectively.
The positive likelihood ratio was 5.17 for delivery
Fetal Fibronectin Combined with Cervical Length before 37 weeks of gestation, 3.76 for delivery before
34 weeks. The positive likelihood ratios (LR+) were
Cervical length measurement was available in 19 2.84, 3.76 and 3.76 for delivery within 7, 14 and 21
of the 31 patients tested for fetal fibronectin. The days. (Table 4)
sensitivity, specificity and predictive values for each The negative likelihood ratio was 0.62 for
delivery category are shown in Table 4. The rapid delivery before 37 weeks of gestation and 0.58 for
fetal fibronectin combined with cervical length had delivery before 34 weeks. The negative likelihood
a sensitivity of 50% and specificity of 82.4% in ratios (LR-) were 0.61, 0,58 and 0.58 for delivery
predicting risk of delivery within 7 days and a within 7,14 and 21 days.
Table 2. Efficacy of rapid fetal fibronectin for prediction of delivery within 7, 14 and 21 days and less than 37 and 34 weeks
age of gestation after specimen collection.
PPV PPV NPV NPV LR + LR -

Timing of Delivery Sensitivity (%) Specificity (%) n % n %
≤ 7 days 66.7 85.7 2/6 33.3 24/25 96 4.7 0.40
≤ 14 days 60 88.5 3/6 50 23/25 92 5.2 0.45
≤ 21 days 60 88.5 3/6 50 23/25 92 5.2 0.45
< 37 weeks 33.3 89.5 4/6 66.7 17/25 68 3.17 0.75
< 34 weeks 40 84.6 2/6 33.3 22/25 88 2.6 0.71
Table 3. Demographic and clinical characteristics at the time of presentation among patients with fetal fibronectin and
cervical length tesults.
fFN (+)/CL <25 mm fFN (-)/CL> 25 mm T-test

n=4 n=15 P value
AOG at fFN 31.18±1.984 30.59±3.231 0.736
AOG on Delivery 34.25±4.335 37.48±2.387 0.059
fFN-to-Delivery Interval 22.5±16.543 49.07±26.037 0.072

DISCUSSION In our study, the negative predictive value for

delivery within 7 days was high with a value of 96%,
Presence of Fibronectin in Patients in Preterm Labor comparable to the 99.5% obtained by Peaceman, et
al. and 98.4% obtained by Tekesin, et al. In these
Risk scoring systems, biochemical markers of respective studies, the authors concluded that a
inflammation, fetal fibronectin and cervical length negative fibronectin result was highly predictive that
determination are tools being studied to decrease delivery will not occur within 7 days. But, despite
unnecessary interventions for patients with symptoms this high negative predictive value, it can be noted
of preterm labor and to identify patients who might that the prevalence of preterm delivery in these trials
benefit from tocolysis, corticosteroids and transfer were unusually low. The high negative predictive
to a tertiary care facility. value of fetal fibronectin for delivery within 7 days
Lockwood, et al., were the first to publish that was influenced by the low prevalence of the primary
the presence of fibronectin in patients in preterm outcome in each trial. In other words, even without
labor was associated with preter m deliver y. any testing, 97% of the participants would not have
Fibronectin was present in 50.4% of women with experienced the outcome.8
preterm uterine contractions and intact membranes. Positive and negative predictive values were not
In our study, fetal fibronectin was present in 19% of used to analyze results in this study since predictive
patients with symptoms of preterm labor. values are influenced by prevalence of outcomes. The
prevalence of preterm delivery in Asia is 9.6% and
Fetal Fibronectin 9.15% in our institution. Likelihood ratios were used
in determining the accuracy of fetal fibronectin as a
In our study, sensitivity and specificity of fetal predictor of preterm labor because likelihood ratios
fibronectin in predicting pre-term delivery within 7 are not affected by prevalence. Likelihood ratios were
days of rapid fetal fibronectin testing were found to also used in studies by Sanchez, et al. and by Honest,
be 66.7% and 85.7%, respectively. Fetal fibronectin et al.20
is more specific than it is sensitive. (Table 2) Positive likelihood ratios greater than 10 and
The positive likelihood ratio (LR+) for delivery negative likelihood ratios less than 0.1 indicate that
within 7 days is 4.7. This is the likelihood that a a test is clinically useful (Table 5). Likelihood ratios
patient with a positive fetal fibronectin test result will between 2 to 5 (+LR) and 0.2 to 0.5 (-LR) yield
deliver within 7 days. This study shows that given a small increases and decreases, respectively, in the
positive fibronectin result, the likelihood that the posttest probability of a disease. In our study, the
patient will deliver prematurely within 7 days is 4.7 likelihood ratios of a positive test result for delivery
times more than she will not. (Table 3) within 7, 14 and 21 days were 4.7, 5.2 and 5.2,
The negative likelihood ratio, on the other hand, respectively. The likelihood ratios of a negative test
is 0.4. This study shows that given a negative result for delivery within 7, 14 and 21 days were
fibronectin test result, the likelihood that the patient 0.4, 0.45 and 0.45, respectively. This translates to
will deliver prematurely within 7 days is about 0.4 fetal fibronectin having fair to good strength in
or 40%. Conversely, the likelihood that she will not predicting delivery within 7, 14 and 21 days, based
deliver prematurely is 60%. So that, when the test is on likelihood ratios. (Table 3)
negative, the likelihood that she will not deliver These results are in accordance with a meta-
within 7 days is 1/0.4 or 2.5 times. (Table 3) analysis done by Sanchez, et al. In their study, the
Table 4. Efficacy of rapid fetal fibronectin combined with cervical length for prediction of delivery within 7, 14 and 21 days
and less than 37 and 34 weeks age of gestation after specimen collection.
Timing of Sensitivity Specificity PPV PPV NPV NPV (fFN+, short Cx) LR -(fFN-, long Cx)
Delivery (%) (%) n % n %
≤ 7 days 50 82.4 1/4 25 14/15 93.3 2.84 0.61

≤ 14 days 50 86.7 2/4 50 13/15 86.7 3.76 0.58
≤ 21 days 50 86.7 2/4 50 13/15 86.7 3.76 0.58
< 37 weeks 42.9 91.7 3/4 75 11/15 73.3 5.17 0.62
< 34 weeks 50 86.7 2/4 50 13/15 86.7 3.76 0.58

overall pooled positive and negative likelihood ratios combined with cervical length are in accordance with
were 4.2 (95% CI 3.53-4.99) and 0.29 (95% CI 0.22- their findings.
0.38), respectively.8 Our results are also comparable
to a meta-analysis by Honest, et al. who obtained Clinical Application of Results
positive and negative likelihood ratios of 4.01 and
0.78.20 To put into clinical use, we use Bayes' theorem,
By using likelihood ratios, this study avoided the which involves the odds of having or not having the
influence of prevalence on fetal fibronectin test disease after testing with fetal fibronectin. Using the
accuracy. prevalence of preterm birth in our institution and in
Asia, we can compute the likelihood of delivery
within 7 days, given a positive or negative fibronectin
Fetal Fibronectin Combined with Cervical Length test.
The preterm birth rate in our institution is 9.15%,
In this study, the sensitivity of a positive fetal almost similar to the preterm birth rate of 9.6% in
fibronectin result combined with short cervical length Asia. Our pre-test odds was 0.1 and our posttest odds
(< 25 mm) in determining delivery before 34 and 37 was 0.47, which, when converted, was equal to a
weeks of gestation is 50%. This is comparable to a 33% probability rate. This means that the probability
study by Goldberg, et al., wherein 60% delivered of preterm delivery increased from 9.15% to 33%
before 37 weeks of gestation and 50% delivered before given a positive fetal fibronectin result. Using the
32 weeks. same theorem, when the test was negative, the
The likelihood ratios of a positive fetal fibronectin probability that the patient would deliver decreased
and a short cervical length for delivery within 7, 14 from 9.15% to 3%.
and 21 days are 2.84, 3.76 and 3.76, respectively. The When fetal fibronectin and cervical length were
likelihood ratio of a negative fetal fibronectin and a combined, we found that the probability of preterm
long cervix for delivery within 7, 14 and 21 days are delivery decreased from 33% (with the use of
0.61, 0.58 and 0.58, respectively. (Table 4) fibronectin alone) to 22% (positive fetal fibronectin
The results for fetal fibronectin combined with and short cervical length). This may be attributed to
cervical length obtained from this study suggest fair the decrease in sample size of patients who
strength of the combination in predicting preterm underwent cervical length determination.
delivery. (Table 5) A positive fetal fibronectin result indicates a 4.7
chance that a patient will deliver within 7 days. This
may prompt the obstetrician to administer tocolytics
Table 5. Qualitative strength of the test by likelihood ratios. to delay preterm delivery and steroids to help fetal
Quality of Strength LR + LR -
lung maturity. The need for transfer to a tertiary
hospital with a neonatal intensive care unit may be
Excellent 10 0.1 indicated. A negative fibronectin result on the other
hand indicates a 2.5 chance that a patient will not
Very good 6 0.2
deliver within 7 days therefore avoiding unnecessary
Fair 2 0.5 admissions and the side effects of administering
tocolytics and steroids.
Useless 1 1
LR, likelihood ratio

Source: Elavunkal and Sinert (2009) Limitations and Recommendations of the Study
We recommend conducting a prospective study,

Although fetal fibronectin and cervical length to avoid confounders such as technicalities in
may, independently and additively, estimate risk of fibronectin sampling and cervical length
preterm delivery in asymptomatic women, cervical measurement, and to standardize the tocolytics and
length does not seem to contribute to prediction of steroids administered to the patients. We recommend
delivery within 14 days in symptomatic fetal increasing the sample size and doing cervical length
fibronectin positive women, according to the study assessment in all tested for fibronectin to correct the
done by Franco, et al. Our results for fetal fibronectin limitations of our study.

CONCLUSION 8. Sanchez-Ramos, et al. Fetal fibronectin as a short term predictor of

preterm birth in symptomatic patients: A meta-analysis. ACOG 2009;
114 (3).
This study confirms studies by Ramos-Sanchez, 9. Woodworth A. Fetal fibronectin: A marker for predicting preterm birth.
et al. that fetal fibronectin is of some value in Clinical Laboratory News 2008; 34(10).
predicting preterm delivery. This study shows that 10. Peaceman A, Andrews W, Thorp J, et al. Fetal fibronectin as a
fetal fibronectin has fair to good strength as a short- predictor of preterm birth in patients with symptoms: A multicenter
trial. Am J Obstet Gyncol 1997; 177(1).
term predictor of preterm labor based on qualitative 11. Berghella V, Hayes E, Visintine J, Baxter JK. Fetal fibronectin testing
strength of likelihood ratios. Given a positive for reducing the risk of preterm birth. Cochrane Database of Systematic
fibronectin result, the likelihood that a patient will Reviews 2008. Issue 4. Art. No.:CD006843. DOI: 10.1002/
deliver prematurely within 7 days is 4.7 times. Given 14651858.CD006843.pub2
12. Lowe, et al. Prospective randomized controlled trial of fetal fibronectin
a negative result, the likelihood that a patient will on preterm labor management in a tertiary care center. Am J Obstet
not deliver is 2.5x than delivery will occur within 7 Gynecol 2004; 190(2): 358-62.
days. 13. American Practice Bulletin. 31 October 2001, 2003.
Studies have not clearly shown the value of 14. Goldenberg RL, Iams JD, Mercer BM, Meis PJ, Moawad AH, Copper
RL, et al. The preterm prediction study: the value of new vs standard
combining fetal fibronectin and cervical length in
risk factors in predicting early and all spontaneous preterm births. Am
the prediction of preterm delivery, as in our study. It J Public Health 1998; 88: 233-8.
is therefore recommended that more comprehensive 15. Iams The Pretem Prediction Study. Recurrence risk of spontaneous
studies with larger sample sizes be conducted, to preterm birth. Am J Obstet Gynecol 1998; 178(5): 1035-40.
increase the statistical power of the outcomes and to 16. Franco, et al. Risk of preterm delivery with a positive fibronectin test
result and a normal cervical length. ACOG 2005; 105(4).
accurately assess their correlation. 17. Roman, et al. "Blind" vaginal fetal fibronectin as a predictor of
spontaneous preterm delivery. Obstet Gynecol 2005; 105(2): 285-9.
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4. Conde-Aguledo, et al. Birth spacing and risk of adverse perinatal in women with preterm labor. Am J Obstet Gynecol 2006; 194: 138-
outcomes: A meta-analysis. J Am Med Assoc 2006. 43.
5. Tekesin, et al. Assessment of rapid fetal fibronectin in predicting 22. Currie GR. Fetal fibronectin testing for the diagnosis of preterm labour:
preterm delivery. The American College of Obstetricians and A review of the economics literature and cost analysis for Alberta.
Gynecologists 2005; 105(2). Health Technologies Decision Process: Fetal Fibronectin Project. June
6. Lockwood CJ, Senyei AE, Dische MR, Casal D, Shah KD, Thung 2006.
SN, et al. Fetal fibronectin in cervical and vaginal secretions as a 23. Libiran, et al. Fetal fibronectin and transvaginal cervical length
predictor of preterm delivery. N Engl J Med 1991; 325: 669-74. sonography as predictors of preterm delivery. Phil J Obstet Gynecol
7. McKenna, et al. Cervicovaginal fetal fibronectin levels in women 2011.
with preeclampsia. ACOG 2002; 100.

A Case of Genital Tuberculosis in a 32 Year Old
Nulligravid*
ANA KARINA D. RAMIREZ, MD AND PATRICIA FLORESTIN MALAY KHO, MD, FPOGS
Department of Obstetrics and Gynecology, Makati Medical Center
Cervical tuberculosis, though rare, should be a urinary tract, bones or joints. Genital tuberculosis
consideration in cases presenting as pelvic inflammatory usually involves the upper genital tract, primarily the
disease or malignant looking lesions of the cervix. endometrium and fallopian tubes. To accurately
Symptoms may vary but a high index of suspicion should assess the actual incidence of genital tuberculosis is
be kept in mind owing to a persistently high prevalence of difficult since 11% of cases are asymptomatic.
tuberculosis in developing countries like the Philippines. Commonly involved genital organs include the
The patient in focus is a 32 year old nulligravid with a fallopian tubes in almost all cases (95% to 100%),
history of endometrial tuberculosis and prior anti-Koch's endometrium in 50% to 60%, the ovaries in 20% to
therapy, now complaining of abnormal vaginal discharge. 30%, the vulva and the vagina in 1% and the
On examination, she had a malignant looking exophytic myometrium in 2.5% of genital tuberculosis cases.
growth on the cervix which turned out to be cervical The cervix accounts for only 0.1% to 0.65% of all
tuberculosis. Further examination revealed involvement cases of tuberculosis and 5% to 24% of genital tract
of the ovaries as well. With a prior history of endometrial TB.
tuberculosis, a diagnosis of genital tuberculosis was made. Such a case is presented due to the rarity of this
The diagnosis is achieved by the interplay of clinical condition and that it clinically mimics carcinoma
assessment, risk factors and laboratory investigations. of the cervix. Moreover, the issue of multidrug
Prognosis of genital tuberculosis is generally good but an resistance in tuberculosis occurring worldwide is now
additional challenge arises with the emergence of multidrug becoming a public health burden, which makes this
resistance to standard anti-tuberculosis therapy. case worth reporting.
Key words: genital tuberculosis Clinical History
M.C. is a 32 year old single, nullig ravid,

uberculosis remains a public health concern caregiver, from Quezon City, who consulted due to
T worldwide. In 2010, the largest number of new
cases occurred in Asia, accounting for 60% of new
yellowish foul-smelling discharge.
The patient is a diagnosed case of endometrial
cases globally. Tuberculosis exists in two forms: tuberculosis in May 2003 previously treated with
pulmonary and extrapulmonary. Genital tuberculosis quadruple anti-Koch's therapy for 6 months.
is one form of extrapulmonary TB, affecting about Initially, she experienced prolonged and profuse
12% of patients with pulmonary tuberculosis and menses consuming 8 fully soaked pads per day lasting
representing 15% to 20% of extrapulmonary for 2 weeks. Histopathology result post fractional
tuberculosis. In 92% of cases, genital tuberculosis is curettage revealed endometrial tuberculosis. Close
secondary to a focus in the lungs, lymph nodes, contact with an index case of pulmonary tuberculosis
was not established. Resolution of symptoms was
_______________ noted on initiation of treatment. However, complete
* 1st Place Winner, 2013 Midyear Residents' Interesting Case Paper Presentation eradication of the tuberculous infection was not
Contest last 11 April 2013, Ballroom 2, The Oriental Hotel, Legaspi City, documented since no follow up consultation was
Albay. done.

Genital Tuberculosis / Ramirez and Kho
One month prior to consult, she noted profuse (2/27) Due to the appearance of the cervical mass,
yellowish foul-smelling vaginal discharge associated a cervical malignancy was entertained. She was
with hypogastric pain. She was treated as a case of referred to the Gynecology-Oncology subspecialty for
pelvic inflammatory disease in the province. She was cer vical mass biopsy, which revealed chronic
given Metronidazole and an unrecalled vaginal granuloma. She was referred to the Gynecology
suppository without relief of symptoms. She claimed Infectious subspecialty afterwards. An irregularly
to have low-grade fever and weight loss of about shaped, friable pink mass at the posterior cervical lip
12kg in 1 month. She denied changes in bowel or was appreciated on speculum examination. On
bladder habits. Persistence of symptoms prompted internal examination, the cervix was ballotable with
consult at a clinic where a transvaginal ultrasound a solid polypoid non-tender mass. The uterus was
was done. Results showed a cervical mass measuring not enlarged and no adnexal tenderness was
4.7cm x 4.0cm x 3.9cm. Neoplasm versus a chronic appreciated but adnexal nodularities were palpated
granulomatous process was being considered. She at the right adnexal area. A diagnosis of cervical
was then referred to a tertiary institution. tuberculosis was made. Visual acuity and liver
(2/15) The patient reported persistence of above function checked prior to initiation of treatment
symptoms with missed menses. On physical showed normal results. She was subsequently started
examination, she was averagely built and well on quadruple anti-Koch's therapy. A transvaginal
nourished weighing 52kg. General examination was ultrasound was requested which showed a normal-
normal with no evidence of pallor or sized anteverted uterus with a myoma nodule. The
lymphadenopathy. Systemic examination was non- endometrium was irregularly thickened with fluid
contributory. On examination of the abdomen, a inter phase. Both ovaries wer e nodular with
firm, fixed, non-tender pelvo-abdominal mass periovarian adhesion. Pyosalpinx was considered
spanning the hypogastric to the umbilical area was in the left adnexa. With these findings in mind, a
palpated. Speculum examination showed a barrel- diagnosis of genital tuberculosis was made.
shaped cervix with circumosal erosions and a 3cm (3/16, 28) The patient was monitored closely.
friable, irregularly shaped mass completely occluding No improvement was seen on follow-up. On
the cervical os. The same findings were noted on succeeding transvaginal ultrasound, there was an
internal examination with a slightly enlarged uterus increase in the size of the cervical and ovarian mass.
and shallow right lateral fornix. (Figure 1) The rest Multidrug resistance was considered at this time. A
of the examination findings were essentially normal. cervical punch biopsy sent for AFB smear and culture
Sputum AFB and chest x-ray showed negative yielded Mycobacterium tuberculosis susceptible to
results. Isoniazid, Rifampicin, Pyrazinamide, Ethambutol
and Streptomycin. She was subsequently referred to
the Tuberculosis Directly Observed Treatment Short
course (DOTS) program for anti-Koch's therapy.
Starting on the second month of therapy, there was
gradual decrease in the size of the mass with
resolution of vaginal discharge and other symptoms
with onset of weight gain. (Figure 2). However, her
menses failed to recur.
DISCUSSION
Tuberculosis (TB), one of the oldest diseases

known to affect humans is an infectious disease
caused by a bacterium, which primarily affect the
lungs. TB is second only to HIV/AIDS as the greatest
killer worldwide due to a single infectious agent.
Transmission usually takes place through the
airborne spread of droplet nuclei produced by persons
with infectious pulmonary tuberculosis. While both
Figure 1. Photograph of cervix prior to treatment. are preventable and curable, TB remains one of the

world's major causes of illness and death.

Tuberculosis can affect any organ in the body, exist
without any clinical manifestation and recur. In
1993, the World Health Organization (WHO)
declared TB to be a global health emergency.
According to the World Health Organization,
8.8 million people fell ill with TB in 2010 and 1.4
million died from it. Over 95% of deaths occur in
low and middle-income countries. Tuberculosis is
among the top three causes of death for women aged
15 to 44. The prevalence of genital tuberculosis is
directly proportional to the incidence of pulmonary
tuberculosis in an area.7 Most recent reports from
developed countries showed an incidence of genital
TB as 1% but in developing world where tuberculosis
is common, figures as high as 10% were noted.6
In 1744, Morgagni described the first case of
genital TB following a postmortem examination of
Figure 2. Photograph of cervix prior to treatment. a 20-year old woman who died of tuberculosis.
Figure 3. Irregular endometrium with fluid interphase. Bilateral

nodular ovaries with periovarian adhesions. Consider pyosalpinx,
left adnexa.

Figure 4. Uterus with multiple myometrial calcifications. Bilateral

tubo-ovarian complex mass. Pelvic adhesions.
Figure 5. Normal sized anteverted uterus with myoma nodules and tuberculous implants. Thin
endometrium with synechiae. Normal ovaries. Dilated left fallopian tube. Pelvic adhesions.
Mycobacterium tuberculosis accounts for 90%-95% of Gavaller and coworkers reported that in one area in
cases of genital TB. However, Mycobacterium bovis Hungary, 33% of cases of female genital TB were
may be the causal agent in about 5%-10%, of cases due to bovine bacillus, which was spread to the
especially when the organisms are acquired from the fallopian tubes by way of the lymphatics.
gastrointestinal tract.1,2 It should be emphasized Direct extension to the genital tract organs from
that genital tuberculosis is not the same as pelvic tuberculous abdominal viscera, such as the bladder,
tuberculosis. The latter involves the mesenteric or rectum, appendix and intestines, has been described.2
pelvic lymph nodes without involvement of the Some researchers believe that this spread is along the
genital tract.2 peritoneal surface. The ovaries may be involved by
Tuberculosis of the female genital tract is almost direct infection from a neighboring structure such as
always secondary to a focus elsewhere in the body.1 the bowel. 4 However, in most instances, peritoneal
The primary focus may be quiescent but secondary involvement can also be the result of spillage of
lesions may appear in the genital tract years later infected material from the fallopian tubes; thus, the
and the sequelae may be devastating especially if primary process is not always clear. It also may occur
infertility results. 3 Primary lesion may be in the when adhesions bind the bladder or intestine to the
lungs (50%), lymph nodes (40%), urinary tract (5%), fallopian tubes and perforation of a tuberculous ulcer
bones and joints (5%) or abdomen (25%). Pelvic results in direct spread to the genital organs.2
organs are infected from a primary focus by three In 1%-2% of cases, genital TB may be due to
principal routes namely hematogenous, lymphatic direct contact with infected semen.3 Primary infection
and direct spread from a neighboring viscus.1,2 of the vulva, vagina and cervix may result from
Genital tuberculosis develops in 5%-13% of direct inoculation at sexual intercourse with persons
patients with pulmonary tuberculosis.3 After the having genitourinary TB and ascending spread of
tubercle bacilli has invaded the lung, in most cases infection from these sites may occur.1 This type of
the bacilli are disseminated by way of the disease may also occur in a woman who has TB of
bloodstream within hours and deposited in various another organ and who excretes tubercle bacilli in
organs of the body. This bacillemia may persist for her stool, urine or sputum. When these excretions
6 weeks or longer, if the disease is not recognized come into contact with the external genitalia, TB of
and treated promptly with antituberculous drugs. the vulva or vagina may result, particularly if the
Tubercle bacilli also may reach the bloodstream and skin is abraded or broken. 2 The criteria necessary
thus the genital tract from extrapulmonary and for the diagnosis of primary genital tract TB are
chronic pulmonary lesions.2 The fallopian tubes are 1) the genital lesions should be the first tuberculous
believed to be the initial and most frequently affected infection in the body and 2) and regional lymph
organ involved in 90%-100% of cases of genital nodes should demonstrate the same stage of TB
mycobacterial infection.3,4 Rarely the ovary, cervix development as do the genital organs.9
and endometrium can be infected primarily from the It was reported that the fallopian tubes are
bloodstream.4 Hematogenous spread of TB bacilli involved in almost all cases (90% to 100%), the
to the tubes results in involvement of the submucosa endometrium in 50% to 60% of cases, ovaries in 20%
(endosalpingitis) at the outer ends with gradual to 30%, cervix in 5% to 15%, vulva and vagina in
spread medially to the endometrium. Direct spread 1% and myometrium in 2.5%. 1,2,3,4,5 The ovaries
of infection to the fallopian tubes results in may be involved by direct infection from a
exosalpingitis with tubercles on the surface. 1 neighboring structure such as the bowel. However,
Tuberculous peritonitis is commonly seen with in most instances, infection spreads from the tubes,
genital tract involvement and may also be associated and the process extends to the surface of the ovaries.
with rupture of a caseous abdominal lymph node The cer vix is involved by spreading from the
or, less frequently, with spread from an intestinal endometrium or as part of the hematogenous
focus.2 infection. Tuberculous infection of the vagina and
A less common mode of infection, lymphatic vulva may follow injury or abrasion to these
spread, occurs when the primary lesion is in the structures in the presence of tubercle bacilli from the
abdominal cavity. In some countries in which people upper genital tract, intestinal tract or the lungs.2,4
drink raw milk (unpasteurized), infection, which Genital TB is a challenging disease both from
spreads by way of the alimentary tract and caused diagnostic and therapeutic point of view as it has
by the bovine tubercle bacillus is still reported. few characteristic symptoms. The majority of cases
were between 20-45 years of age.1,6 Postmenopausal produce amenorrhea, particularly if it is associated
women account for 7%-11% of cases of genital TB.1 with fever and weight loss. However, active
The clinical presentation of genital tuberculosis is pulmonary TB is rarely found concomitantly with
extremely variable depending on the site involved. active genital TB. Moreover, ovarian failure due to
About 20% of patients with genital TB give a history complete destruction of the ovary rarely occurs to
of TB in their immediate family. As a rule, they cause amenorrhea. The most likely explanation is
were exposed to an adult with TB during childhood. that given by Malkani and Nogales-Ortiz and Villar,
According to most series, patients with genital TB who attributed amenorrhea to end-organ failure
will give a history of prior diagnosis or treatment of secondary to endometrial caseation.2,9 On the other
extragenital TB approximately 30% to 50% of the hand, 50% to 88% of cases report undisturbed
time.2 Constitutional symptoms such as weight loss, menstrual cycle.1
low-grade fever, fatigue or poor general health may Most cases of confirmed genital tuberculosis will
be present.1,2 In the acute phase, the presentation may have a perfectly normal clinical examination (43%),
resemble classical acute pelvic inflammatory disease while about a quarter of cases will present with an
(PID) with pelvic pain, fever and vaginal discharge.1 adnexal mass (23.6%).7 Bimanual examination will
Some patients gave a history of recurrent pelvic reveal an adnexal mass or fixation of pelvic organs.
inflammatory disease that has not responded to the Tuberculous tuboovarian masses are less tender than
usual antibiotic therapy. 2 Approximately 11% of those due to pyogenic infection, although secondary
patients with genital TB are asymptomatic and the infection may produce sharp pain and tenderness.
majority of women are diagnosed during Peritoneal involvement may give rise to ascites. 2
investigations for infertility. 1,2 In most studies, Many patients appear with a symptom complex
infertility is the presenting complaint in 40% to 50% similar to that of ovarian carcinoma presenting with
of patients.2,5 In a study by Qureshi, et al. the most abdominal distention, pelvic tumor, ascites and
common presenting symptom was infertility (42.5%). elevated CA-125 level. 7 Tuberculous lesions of the
It was primary in 78% and secondary in 22% of cervix present with postcoital bleeding, abnormal
cases.6 In a ten year clinicopathological study of discharge and on examination, have appearances
Mondal and Dutta, 65% to 70% of patients with similar to cancer of the cervix.1 The affected cervix
genital TB presented with infertility, pelvic or may be hypertrophied, ulcerated or may show friable
abdominal pain in 50%-55%, and menstrual papillary growth. 10 Most of the cervical lesions
disturbances in 20%-25%. 8 The second most appearing as an ulcer, red papillary erosion, or a
common complaint is lower abdominal or pelvic pain proliferative growth resembling cervical cancer are
present in 25% to 50% of cases.1,2,6,8 The pain is not descending infection from the upper genital tract.9
usually severe and may be present for several months The diagnosis of cervical TB is usually made by
already. The pelvic pain becomes more severe when histological examination of a cervical biopsy
progression of genital TB takes place and is usually specimen. Staining for acid fast bacilli may not be
aggravated by coitus, exercise and menses.2 The third very useful in making a diagnosis. Although isolation
most common symptom of genital TB is menstrual of mycobacterium is the gold standard for diagnosis,
irregularity in the form of menorrhagia, one third of cases are culture-negative, therefore
menometrorrhagia, intermenstrual bleeding, presence of typical granulomata is sufficient for
oligomenorrhea, postmenopausal bleeding or diagnosis if other causes of granulomatous cervicitis
amenorrhea.2 Abnormal vaginal bleeding occurred are excluded.11 The Pap smear reveals dyskaryotic
in 18% of individuals. Amenorrhea and vaginal cells, epithelial cell atypia, multiple giant cells,
discharge were present in about 5% of cases, while histiocytes and epitheloid cells arranged in clusters,
post-menopasual bleeding accounted for 2% of simulating the appearance of granulomata.2,9,10 A
patients presenting with genital tuberculosis.7 In a punch biopsy is required for histopathological
study made by Madhu and Davinder, 15 % of cases evaluation to identify the lesion and differentiate it
suffered with menorrhagia, 10% with from cancer.9,10 Histopathologic examination reveals
oligomenorrhea, 5% with secondary amenorrhea and granulomatous inflammation and sometimes marked
66% had normal periods.3 Ten percent of women inflammatory atypia along with frequent hyperplastic
suffer secondary amenorrhea due to asherman. mucosal changes. Caseation may be seen.2,9
Primary amenorrhea is extremely rare. It is well The possibility of TB infection of the genital tract
known that advanced, active pulmonary TB may should always be considered, especially in a patient
from an area where TB is endemic. Diagnosis is curettage does not exclude the diagnosis of genital
achieved most effectively through a combination of TB. Serial sections are needed to be studied because
high index of suspicion, thorough clinical assessment the lesions are frequently patchy.
and the use of appropriate investigations. High risk
factors include a history of previous pulmonary TB Management
infection, contact with a pulmonary TB sufferer,
recent travel to or migration from high prevalence Female genital tuberculosis is treated with the
countries, residence in high prevalence areas, low same long-term, combined drug therapy used in
socioeconomic background, drug abuse, HIV positive pulmonary and extrapulmonary tuberculosis. Surgery
status and individuals of black African and Asian should be undertaken only after continuous drug
descent.1 Since genital tuberculosis is considered as treatment of 12-18 months' duration. In women of
one of the secondary manifestations of tuberculosis childbearing age, an attempt can be made to preserve
with its primary site in the lungs, one may expect a one ovary. Successful pregnancy is unlikely, however,
history of pulmonary tuberculosis or x-ray evidence after complete antituberculosis treatment or
of tuberculosis. However, in many instances the tuboplastic surgery.5
primary pulmonary lesion has already been arrested.4 Six month regimens including four drugs in the
More than 75% of the patients with active, culture- initial phase (Rifampicin, Isoniazid, Pyrazinamide
proven genital tuberculosis have a normal chest and Ethambutol) followed by continuation phase
x-ray. It is important not to use chest x-ray as (Rifampicin and Isoniazid) are highly effective in
exclusion for the diagnosis of genital tuberculosis.7 patients with fully sensitive organisms. Combined
The gold standard remains the isolation of acid-fast therapy enhances compliance and reduces the risk
bacilli in biological specimens or culture, although of secondar y dr ug resistance. Although
diagnosis based on histologically characteristic chemotherapy is the mainstay of treatment, surgery
granulomata is accepted.2,7 Whenever feasible, every may be indicated where medical therapy has failed
effort should be made to send specimens and tissue to resolve symptoms and in the presence of a
for culture, in order to confirm diagnosis and persistent pelvic mass.1
establish drug sensitivities.1 Since the endometrium
is involved in the majority of cases and is readily Genital Tuberculosis and Pregnancy
accessible to sampling, it is often the first site at which
attempts at definitive diagnosis are directed. 2 Despite effective therapeutic regimens for genital
Endometrial tissue may be obtained by aspiration tuberculosis, sterility remains a major complication.
biopsy or by dilatation and curettage or directly at Medical regimens have been successful at alleviating
hysteroscopy. 1 The histologic examination of symptoms of menstrual disorders and pain.
endometrial tissues removed by biopsy or curettage, Succeeding endometrial sampling often reveals cure
especially from the cornual area where spread from however, extensive damage to the fallopian tubes and
the tubes first occurs, affords a rapid method of the endometrium is often irreversible, and chances
diagnosing genital TB in at least 50% of cases. 2,4 of successful intrauterine pregnancy are low. In one
Dilatation and curettage may increase the yield on extensive literature review in 1976, only 31 cases of
endometrial specimens merely by increasing the successful pregnancy were reported out of
amount of tissue available for histologic evaluation approximately 7000 cases of genital tuberculosis. In
and cultures.2 Endometrial biopsy is best performed these patients, with fertile partner, in vitro fertilization
at the end of the menstrual cycle, or within 12 hours should be considered. In Sweden, no intrauterine
after the onset of menstrual flow, at which time the pregnancy was reported out of 187 cases of genital
tubercles reach their maximum growth. 1,2,4 Its TB after therapy.2 If genital tuberculosis is not treated
sensitivity suffers from sampling errors but can be early in its course, irreparable damage to the tubes
ver y helpful if granulomata are found or, less may occur and the risk of ectopic pregnancy in these
commonly, if smears or cultures are positive. 2 patients is estimated to be 33% to 72%. 2
Histology demonstrates the typical caseous Microsurgical reconstructive tubal surgery is not
granulomatous lesions with giant epitheliod cells. recommended because of the risk of reactivation of
This lesion is highly suggestive of TB but is not silent infection and the poor treatment outcome. A
diagnostic, as it appears in fungal infections and study reported one extrauterine pregnancy and no
sarcoidosis.1 One negative biopsy or one negative full term pregnancy in 51 salpingoplasty operations.
If patients are adequately treated before their tubes 2.

Varma T, Glob libr women's med (ISSN: 1756-2228) 2008; DOI 10.3843/
are irreversibly damaged, the chance of successful GLOWM.10034
3. Nagpal M, Pal D. Genital tuberculosis: Present scenario, JK Science
pregnancy is reasonably good with a 20% pregnancy 2001; 3(4).
rate reported in one study. However, an appreciable 4. Sin SY, Tang LCH. Female genital tuberculosis: An update, Hong
risk of ectopic pregnancy is expected if the tubes are Kong Practitioner 1995; 17(1).
patent but extensively affected. The overall post 5. Chowdhury NN. J Indian Med Assoc 1996; 94(9): 345-6.
6. Qureshi RN, Samad S, Hamid R, lakha SF. (Department of Obstetrics
therapy fertility in patients with genital tuberculosis and Gynaecology, The Aga Khan University Hospital, Karachi.)
reported 155 full term pregnancies (2.2%), 125 Journal of Pakistan Medical Association 2001; 51:16.
extrauterine pregnancies and 67 abortions. 4 In a 7. Botha MH, Van der Merwe FH. Female genital tuberculosis. SA Fam
ten-year clinicopathological study by Mondal and Pract 2008; 50(5): 12-6.
8. Mondal SK, Dutta TK. J Nepal Med Assoc 2009; 48(173): 52-7.
Dutta on female genital tuberculosis and its impact 9. Sengupta BS, Chattopadhyay SK, Varma TR. Gynaecology for
on fertility, 9 patients conceived of which 8 suffered Postgraduates and Practitioners 2nd ed. Retrieved from http://
spontaneous abortions after therapy. Only one patient books.google.com.br/books/about/Gynaecology_for_Postgraduates_
had a successful pregnancy and the baby was born and_Practi.html?hl=pt- BR&id=ELkWa34eBz4C
10. Bhalla A , Mannan R , Khanna M , Bhasin T S . Tubercular cervicitis
through cesarean section. 8 They concluded that
clinically mimicking as carcinoma cervix: Two case reports. Journal
genital tuberculosis is an important cause of female of Clinical and Diagnostic Research [serial online] 2010 February
infertility in developing countries. Successful uterine [cited: 2012 Jul 22 ]; 4:2083-2086. Available from http:/www.jcdr.
pregnancy is rare after treatment and chances of netback_issues.asp?issn=0973709x&year= 2010&month=February
ectopic pregnancy are high.8 &volume=4&issue=1&page=2083-2086&id=636
11. Paprikar, MP, Biswas CM, et al. Tuberculosis of cervix. MJAFI
2008; 64:297-8.
REFERENCES
1. Gatongi DK, Gitau G, Kay V, Ngwenya S, Lafong C and Hasan A.
Female genital tuberculosis. The Obstetrician & Gynaecologist 2005;
7: 75-79. doi: 10.1576/toag.7.2.075.27000
Deception: A Case of Acromegaly with Concomitant
Hyperreactio Luteinalis in Pregnancy
CRISTINE GERRYFE SANTOS, MD AND TERESITA CARDENAS, MD, FPOGS
Department of Obstetrics and Gynecology, Veterans Memorial Medical Center
The incidence of hyperandrogenic state in pregnancy is muscle strength, acne, hirsutism, frontal hair thinning
low. Ovarian tumors, such as Hyperreactio luteinalis, are and deepening of voice. Possible causes include
the most frequent cause. Other disease entities may also polycystic ovary syndrome, ovarian and adrenal
cause hyperandrogenic state in pregnancy such as pituitary tumors, pituitary adenomas and certain enzyme
adenoma. We describe a 29 year old, primigravid, who deficiency.
presents with acromegalic features for the first time during Hyperreactio luteinalis is a benign, self-limiting
syndrome characterized by bilateral ovarian
pregnancy. She delivered via an emergency low transverse
enlargement associated with high levels of human
cesarean section due to cephalo-pelvic disproportion.
chorionic gonadotrophin and hyperandrogenism. It
Intra-operatively, the bilateral ovaries were cystically
is usually associated with multiple pregnancies and
enlarged with multiple cysts. Post-partum, diagnostics were trophoblastic diseases. However, about 30 cases of
started to investigate the probable cause of the aromegalic Hyperreactio lutienalis in normal singleton pregnancy
features. At 4 months post partum, there was resolution of has been reported.
the clinical features as well as normalization of the bilateral Although the maternal pituitary gland is not
ovaries. The development of Hyperreactio luteinalis as well essential for the maintenance of pregnancy 29 ,
as incidental finding of pituitary microadenoma is the physiological changes in the pituitary gland during
probable cause for the acromegalic features developed pregnancy complicates evaluation of pituitary
during pregnancy. neoplasms. The prevalence of pituitary
microadenomas is 11%.30 These tumors generally
Key words: Growth hormone, insulin-like growth factor, are too small to cause bony erosion or to put pressure
acromegaly, pregnancy, hyperreactio luteinalis on the optic chiasm. Any morbidity is caused by
excessive hormone secretion such as acromegaly.
Acromegaly is a rare condition caused by
excessive growth hormone secretion usually due to
a benign pituitary adenoma.7 Fertility is commonly
ajor hormonal changes emerge during
M pregnancy hence a variety of endocrine
disorders can complicate pregnancy and vice versa.
impaired in patients with acromegaly due to altered
gonadotropin secretion, which is caused by the
destruction of gonadotroph cells or
Virilization during pregnancy is uncommon. This
hyperprolactinemia, and hyperandrogenemia. Few
can manifest as clitoral enlargement, increased
data are available on pregnancy in acromegaly: fewer
than 100 pregnancies have been reported, usually as
isolated cases 7. Limited data are available about
_______________ pregnancy in acromegaly. Hence, the appearance of
* 2nd Place Winner, 2013 Midyear Residents' Interesting Case Paper acromegalic features for the first time during
Presentation Contest last 11 April 2013, Ballroom 2, The Oriental Hotel,
Legaspi City, Albay. pregnancy prompted review of this problem.
Acromegaly with Concomitant Hyperreactio Luteinalis in Pregnancy / Santos and Cardenas
DISCUSSION features and there was further increase in her shoe

size from size 9 to 11. At 24 weeks AOG, the patient
This is a case of R.C., 29 years old, G1P0, who started to experience easy fatigability and body
came in due to watery vaginal discharge. She was weakness, and progression of coarse facial features.
diagnosed with polycystic ovarian syndrome in 2002 She also noted appearance of coarse hair pattern in
for which she was given oral contraceptive. There her extremities. Her relatives noticed deepening of
were no other history heredo-familial disease but one her voice and loud snoring.
sister had acromegalic features during her pregnancy. At 30 weeks AOG, the patient experienced
She had irregular menses occurring every 1-2 months generalized body weakness. Consult was done and
consuming 2 -3 pads per day with associated she was subsequently admitted. On physical
dysmenorrhea on Day 2 of menses. examination, the patient was weak looking.
Coarsening of facial features was noted described as
enlargement of the nose and with frontal bossing.
There was also note of clitorimegaly and bipedal
edema. Upon admission, the patient was noted to
be hypokalemic with potassium of 2.9 mmol/L.. She
was referred to Internal Medicine for further
evaluation. Assessment was hypokalemia and t/c
acromegaly during pregnancy. Cor rection of
hypokalemia was done and she was advised work-
up post-par tum f or the acromegaly. She was
subsequently discharged after correction of
hypokalemia.
Regular pre-natal check-up followed with intake
of multivitamins and ferrous sulphate. She was also
regularly seen at the Internal Medicine with biweekly
determination of potassium. She was maintained on
Figure 1. Comparative picture of R.C. before and during
pregnancy.
kalium durule.
Admission
Pre-natal History The patient came in due to watery vaginal

discharge. This was accompanied by hypogastric
The patient had missed menses for 2 months. pain radiating to the lumbosacral area. Physical
Pregnancy test was done showing positive result. examination revealed same findings with the
Consult was done with an obstetrician where previous admission (coarsening of facial features
baseline laboratory exams were done revealing described as enlargement of the nose and with
normal results. Baseline transvaginal ultrasound was frontal bossing.) Pelvic exam still showed
done at 7 weeks AOG which revealed a single live clitorimegaly. Speculum exam revealed pooling of
intrauterine pregnancy 6w1d AOG by CRL with clear amniotic fluid. On internal examination,
good cardiac acitivity. Both ovaries were noted to cervix was 4cm dilated, 50% effaced, negative
be polycystic with note of the corpus luteum on the BOW, cephalic, station -3. On the 6th hour of labor,
right. cervix was fully dilated at station 0. There however
At 8 weeks AOG, the patient started to notice was no further descent after 2 hours. She was
gradual changes in her facial features (coarsening of therefore referred for an emergency low transverse
her facial features), increasing shoe and finger ring cesarean section with an indication of failure in
sizes (from size 7 to size 9). The patient denied any descent secondary to cephalopelvic disproportion.
maternal illnesses nor exposure to roentgen rays or She delivered to a live term baby girl, birth weight
to teratogenic agents. 3232g, Birth Length 48cm, APGAR score 9/9,
At 20 weeks AOG, the patient developed Maturity index 40 weeks, Appropriate gestational
gestational hypertension and was maintained on age. Incidental finding was enlarged multicystic
Methyldopa. There is still coarsening of her facial ovaries measuring 6cm x 6cm each.
Postoperatively, elevation in blood pressure

was managed with Amlodipine. The rest of the
hospital days were unremarkable. She and her baby
were subsequently discharged on her 4 th hospital
day.
Two weeks post-partum, there was note of
gradual resolution of the acromegalic features. On
her 16 weeks post-partum, laboratory test revealed
high normal result of growth hormone. Imaging
studies revealed bilateral polycystic ovaries (on
transvaginal ultrasound) and pituitary
microadenoma measuring 2mm (on MRI).
DISCUSSION
Figure 2a. R.C. 2 weeks post-partum
We are presented with a 29 year old, G1P1
(1001), with history of polycystic ovarian
syndrome, who developed acromegalic features and
gestational hypertension during her pregnancy.
Family history revealed she had one sister who
developed same acromegalic features during her
pregnancy with resolution of the problem post-
partum. Incidental finding of bilateral cystic ovarian
masses was noted during her cesarean delivery. Post-
partum, resolution of the acromegalic features, high
nor mal r esult of g rowth hor mone, bila teral
polycystic ovaries and pituitary microadenoma on
imaging studies, prompted the service to consider
the following differential diagnosis: Placental
aromatase deficiency, luteoma of pregnancy,
Hyper reactio luteinalis, Pituitar y adenoma
Figure 2b. R.C. Post partum with daughter (4 months post-
partum).
particularly prolactinoma and growth hormone-
secreting pituitary adenoma.
Placental aromatase deficiency is an autosomal
recessive disorder. Placental aromatase is needed
for the final aromatization of androgens to
estrogen and protect the fetus against the action
of fetal androgens. Patients with this condition
usually manifest with marked maternal virilization
during the second half of pregnancy. The female
babies born to these women will have ambiguous
genitalia. Hence, the normal genitalia of the
patient’s bab y excludes placental aromatase
deficiency.
Luteoma of pregnancy represents an exaggerated
luteinization reaction of the normal ovary to the
altered hormonal levels of pregnancy. It is typically
seen in multigravida. This condition may result in
maternal virilization. This can also manifest as
clitoral enlargement, increase muscle strength, acne,
Figure 3. Acromegalic features of R.C. hirsutism, frontal hair thinning and deepening of
the voice. Pregnancy of luteoma is considered because Acromegaly is a rare condition due to excessive
it can cause maternal virilisation and the symptom GH secretion, usually by a benign pituitary
regress post-partum. This tumor is usually solid and adenoma.7 Fertility is commonly impaired in patients
unilateral. Typical sonographic characteristics with pituitary tumors due to hormonal
include a solid, complex-appearing unilateral mass hypersecretion when the tumor is functional; or from
with cystic features that correspond to areas of the mass effect causing destruction of gonadotropin-
hemorrhage.16 They usually regress after delivery, but secreting cells or compression of both normal
may recur in subsequent pregnancies. However, this gonadotrope cells and pituitary stalk, producing
was ruled out because the ovaries seen intraoperatively hyperprolactinemia and anovulation. Therefore there
were cystic and bilateral. are very limited data available about pregnancy with
Pituitary adenoma is a benign tumor of the acromegaly, although it appears that pregnancy is
pituitary gland. It may secrete hormones or it can usually carried to term.
b e c l i n i c a l ly i n a c t ive. T h e e n d o c r i n o l o g i c Acromegaly may not manifest with clear
morbidity that is associated with these tumors is diagnostic features. Its usual presentations include:
dependent on the specific underproduction or Acral enlargement (86%), Maxillofacial changes
overproduction of hormones associated with the (74%), Excessive sweating (48%), Arthralgias
t u m o r. P r o l a c t i n o m a s a n d g r ow t h ho r m o n e (46%), Headache (40%), Hypogonodal symptoms
secreting pituitary microadenoma are considered (38%), Visual deficit (38%), Fatigue (26%), Weight
in this case beacuse these can cause acromegalic gain (18%) and Galactorrhea (9%). 3 A serum IGF-
features. I level is a good tool to assess integrated GH
Prolactinoma is a benign tumor of the pituitary secretion and is excellent for diagnosis, monitoring
gland that produces hypersecretion of prolactin. 15 and especially screening. 3 A random IGF-I value
Prolactinomas may symptomatically enlarge during (a marker of integrated GH secretion) should be
pregnancy and may cause the acromegalic features. measured for diagnosis and monitoring after a
Although the patient has pituitary adenoma, therapeutic intervention. Serum GH assays are not
menstrual irregularities and development of maternal standardized and should not be used
virilization, this was ruled out because serum interchangeably. Multiple samples, random GH,
prolactin level was normal. and GH after glucose administration have
Growth hormone (GH) secreting pituitary considerable variability and are useful, but they
adenoma usually causes acromegalic features in must be used in the clinical context. A GH value
patients, since this tumor is responsible for 98% <1 ngmL after an oral glucose tolerance test
of acromegaly. During pregnancy, the pituitary (OGTT) (75g of glucose orally followed by GH
gland increases its size by approximately 135%. measurements every 30 minutes for 120 minutes) is
One of the hormones that can be affected is the considered normal. 2,3 The latest clinical practice
growth hormone. During the 1 st trimester, the guideline for the diagnosis and treatment of
growth hormone is primarily pituitary in origin. acromegaly suggests that the serum GH nadir after
However, as early as 8 weeks, placental growth glucose administration to be lowered to 0.4ng/mL
hormone can be detected. At around 17 weeks, to increase sensitivity of testing. Once a biochemical
the placenta is the principal source of growth diagnosis of acromegaly has been made, a magnetic
h o r m o n e d u r i n g p r e g n a n c y. T h e r e a f t e r, t h e resonance imaging (MRI) scan of the pituitary
placenta contributes in the circulating GH. Thus, gland should be performed because a pituitary GH-
maternal pituitary gland is not essential for the secreting adenoma is the cause in most cases. The
maintenance of pregnancy. particular protocol was followed in this patient.
The increase in the size of the pituitary gland This case presented with acromegalic features
during pregnancy may cause existing pituitary both clinically and biochemically (high normal GH)
adenoma enlargement due to the somatotrope and cranial MRI with contrast and dynamic study
hyperplasia secondary to the stimulatory effects of revealing pituitary microadenoma. We hypothesized
the peripheral hormone such as estrogen. This tumor that probably prior to the pregnancy, the pituitary
growth may cause hypersecretion of growth hormone microadenoma which did not secrete excess growth
which in turn increases insulin growth factor 1 (IGF- hormone hence the patient was asymptomatic.
1) which is the primary mediator for the growth According to literature, menstrual irregularity is one
promoting effects of growth hormone. of the earliest signs of acromegaly in women which
is seen in the patient’s menstrual history. Normally Although usually asymptomatic, hemorrhage into
the pituitary gland enlarges to 135% with 45% the cysts may cause abdominal pain. Maternal
increment in the first trimester during pregnancy. The virilization may be seen in up to 25 percent of
increase in the volume to as much as 120% is due to women. Changes including temporal balding,
hyperplasia of mature lactotrophs. Theoretically, the hirsutism, and clitoromegaly are associated with
stimulatory effect of peripheral hormone surges (such massively elevated levels of androstenedione and
as estrogens) during pregnancy could cause adenoma testosterone. The diagnosis typically is based on
enlargement due to tumor growth or hemorrhage, sonographic findings of bilaterally enlarged ovaries
or tumor infarction in patients with growth-hormone containing multiple cysts in the appropriate clinical
secreting adenomas. 7 Probable enlargement of the settings. The condition is self-limited, and resolution
0.2cm microadenoma in the patient during pregnancy follows delivery. In some women, increased ovarian
caused the hypersecretion of growth hormone hence responsiveness to gonadotropin can be confirmed by
occurrence of the symptoms. several weeks postpartum.16
The bilateral ovarian cysts seen intra- G e n e r a l ly, t h e s e t u m o r s a r e d i s c ove r e d
oper at ively, may have been an inde pendent incidentally during cesarean section or tubal
condition in this case or may have probably l i g a t i o n . H y p e r r e a c t i o lu t e i n a l i s o c c u r s i n
augmented the symptomatology. Hyperreactio primig ravids and may occur any time during
luteinalis probably secondary to the polycystic pregnancy. Hyper reactio luteinalis cannot be
ovaries present during her pre-pregnant state was completely ruled out because of the ovarian mass
highly considered. Po lycystic ovaries cause that was seen in this case, bilateral cystically
increased sensitivity of the ovaries to gonadotrophin e n l a r ge d ova r i e s, a s we l l a s s y m p t o m s o f
leading to augmentation of androgen production virilization such as clitoromegaly, deepening of
by the theca cell causing bilateral enlargement of the voice, coarse hair growth patter n over the
the ovaries. The increase in growth hormone as well extremities.
as IGF 1 also causes insulin resistance by decreasing Insulin resistance brought about by the increase
the levels of sex hormone-binding globulins in GH/IGF1 increases the incidence of gestational
(SHBG), thus the circulating levels of free hypertension. Since insulin is a powerful regulator
testosterone are also increased leading to of potassium metabolism, for patients with
hyperandrogenemia. hypertension and those with insulin resistance, there
Hyperreactio luteinalis (Theca-lutein cysts) is shifting of extracellular potassium to intracellular
are benign ovarian lesions that result from space, causing increase in the excretion of potassium
exaggerated physiological follicle stimulation leading to hypokalemia. 31
associated with markedly elevated serum levels of There are two probable theories for the
hCG.5 It is assumed that a certain pathological state resolution of acromegalic features post-partum.
of ovaries (e.g. PCOS or multiple corpora lutea) is First, the pituitary gland returns to its normal size
the cause of internal sensitivity of the ovaries to within 6 months post-partum. Thus, the decrease
gonadotropic effects. 29 Although the cellular pattern in size of the pituitary gland post-partum decreases
of Hyperreactio luteinalis is similar to that of a the size of the pituitary adenoma to its pre-pregnancy
luteoma, they are usually bilateral cystic ovaries. size which may be small enough to cause
Theca-lutein cysts are found frequently with hypersecretion of growth hormone, thus resolution
gestational trophoblastic disease because of high hCG of the patient’s acromegalic features. Secondly,
levels. They are also more likely to be found with a Hyperreactio lutienalis is a self-limiting syndrome.
large placenta such as with diabetes, There is spontaneous resolution of symptoms and
D-isoimmunization, and multiple fetuses. Theca- regression of the ovarian cysts post-partum with
lutein cysts have also been reported in chronic renal decreasing level of human chorionic
failure as a result of reduced hCG clearance, and in gonadotrophin.
hyperthyroidism as a result of the structural Familial isolated adenoma is defined as
homology between hCG and thyroid-stimulating occurrence of at least 2 cases of acromegaly in a
hormone. But they also are encountered in women family. This condition is due to loss of
with otherwise uncomplicated pregnancies and are heterozygosity at chromosome 11q13. This should
thought to result from an exaggerated response of be considered since the patient had one sister with
the ovaries to normal levels of circulating hCG. acromegalic features during pregnancy.
Final Diagnosis 3. Katznelson L, Atkinson J, Cook D, Ezzat S, Hamrahian A, Miller K.

American Association of Clinical Endocrinologists Medical Guidelines
for Clinical Practice for the Diagnosis and Treatment of Acromegaly –
G1P1 (1001) Pregnancy Uterine delivered Via 2011 Update. Endocr Pract 2011; 17 (Suppl 4).
Emergency Low Transverse Cesarean Section I 4. Karaca Z, Tanriverdi F, Unluhizarci K and Kelestimur F. Pregnancy
secondaty to Failure in Descent secondary to and pituitary disorders. Eur J Endocrinol 162: 453–75.
5. Kanova N, Bicikova M. Hyperandrogenic states in pregnancy. Physiol
Cephalo-Pelvic Disproportion Res 2011; 60: 243-52.
Acromegaly probably secondary to 6. Verhaeghe J. Does the physiological acromegaly of pregnancy
Growth-Hormone Secreting Pituitary benefit the fetus? Gynecol Obstet Invest 2008; 66: 217-6.
7. Caron P, Broussaud S, Bertherat J, Borson-Chazot F, Brue T, Cortet-
Microadenoma Rudelli C, Chanson P. Acromegaly and pregnancy: a retrospective
Hyperreactio luteinalis multicenter study of 59 pregnancies in 46 women. J Clin Endocrinol
Gestational Hypertension Metab 2010; 95(10): 4680-7.
8. Lau SL, McGrath S, Evain-Brion D, Smith R. Clinical and biochemical
improvement in acromegaly during pregnancy. J Endocrinol
Invest 2008; 31(3): 255-61.
CONCLUSION 9. Hisano M, Sakata M, Watanabe N, Kitagawa M, Murashima
A, Yamaguchi K. An acromegalic woman first diagnosed in
This paper has presented a case of a 29 year old pregnancy.Arch Gynecol Obstet 2006; 274(3): 171-173. Epub 2005
Dec 23.
primigravid who developed acromegalic features
10. Cozzi R, Attanasio R, Barausse M. Pregnancy in acromegaly: a
during her pregnancy with subsequent resolution post one-center experience. Eur J Endocrinol 2006; 155: 279-84.
partum. Biochemical studies and imaging tests have 11. Yap AS, Clouston WM, Mortimer RH, Drake RF. Acromegaly first
proven the presence of pituitary adenoma and diagnosed in pregnancy: The role of bromocriptine therapy. Am J
hyperreactio luteinalis. Obstet Gynecol 1990; 163(2): 477-8.
Pituitary adenoma particularly growth 12. Herman-Bonert V, Seliverstov M, Melmed M. Pregnancy in
acromegaly: Successful therapeutic outcome. J Clin Endocrinol Metab
hormone-secreting tumor in women may cause 1998; 83(3): 727-31.
infertility, but in this case pregnancy ensued. The 13. Schnorr JA Jr, Miller H, Davis JR, Hatch K, Seeds J. Hyperreactio
clinicians must be aware of the possible changes that luteinalis associated with pregnancy: a case report and review of the
could affect the patient’s pregnancy. Close monitoring literature. Am J Perinatol 1996; 13(2): 95-7.
of the subsequent symptoms therefore is warranted. 14. Hennessey JV, Jackson IM. Clinical features and differential diagnosis
of pituitary tumours with emphasis on acromegaly. Baillieres Clin
Post-partum, serial growth hormone determination Endocrinol Metab 1995; 9(2): 271-314.
is recommended. Serum IGF-1 determination is also 15. Corenblum B, Griffing G. Pituitary Disease and Pregnancy. 2011
excellent for screening, diagnosing and monitoring http://emedicine.medscape.com/article/127650
of acromegaly. 16. Niranjala MWS, Wijeyaratne CN, Jayalath GKC. Virilization in a
Counselling should be done not only to discuss pregnancy. Sri Lanka J Diab Endocrinol Metab 2012; 2: 43-5.
17. Malicka J. Familial acromegaly — case study of two sisters with
treatment options (surgical, medical, radiation as
acromegaly. Polish J Endocrinol 2011; 62(6).
well as psychological therapy) but also the 18. Bideci A, Çamurdan O. Physiology of growth hormone secretion. J
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It is prudent to investigate other family members 21. Atmaca A, Dagdelen S, Erbas T. Follow-up of pregnancy in
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because it may be a hereditary disease and patient’s Endocrinol Diab 2006; 114(3): 135-9.
education is warranted to prevent delay in the 22. Bachelot A, Monget P, Imbert-Bolloré P, Coshigano K, Kopchick
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for ovarian follicular growth. Endocrinology. 2002; 143(10): 4104-12.
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2. Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis 2008; 3: familial isolated pituitary adenomas. Eur J Endocrinol 2007; 157: 371-
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cost-effectiveness analysis. J Clin Endocrinol Metab 1997; emedicine.medscape.com/article/126702.com.
82(11): 3625-32. 31. Lederer E, Batuman V. Hypokalemia. 2009.
28. Bloch B. Pituitary tumors in pregnancy: A case report. SA Med J http://emedicine.medscape.com/article/242008
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29. Cunningham G, et al. Williams Obstetrics 23 rd Edition. 2010.
Lymphangiomyomatosis Originating in the Uterus*
STEPHANIE F. PILI , MD AND CARLA V ICTORIA ESPINA-CASTRO, MD, FPOGS
Department of Obstetrics and Gynecology, Makati Medical Center
J.R. is a 47 year old, nulligravid, who presented with a two with passage of blood clots lasting for up to 14 days
year history of prolonged and profuse menstrual episodes per cycle. The patient denied constitutional symptoms
consuming up to 10 pads a day, lasting up to 2 weeks. like fever and weight loss. There were no associated
Ultrasound was done revealing a huge pelvo-abdominal symptoms of headache, dizziness, chest pain,
mass, to consider a uterine primary lesion, most probably a dyspnea, abdominal pain, or changes in urinary and
myoma with cystic degeneration. Exploratory laparotomy bowel habits.
was done revealing a well- delineated multi-cystic mass in She is hypertensive with controlled blood
the posterior myometrial wall approximately measuring pressure, on Metoprolol 50mg/tab twice a day. She
12cm x 10cm x 6cm with straw-colored fluid upon rupture
was diagnosed with bipolar disorder in 2001 and
of each cyst. The mass was sent for histopath revealing
was on Carbamazepine 200mg/tab once a day and
lymphangiomyomatosis of the uterus.
Lithium Carbamate once a day. She is allergic to
Key words: lymphangiomyomatosis, lymphangioleiomyo- shrimp and shellfish. Her previous surgeries include
matosis rhinoplasty in 1982.
The patient is a nulligravid, who has been
regularly menstruating since 13 years of age. She used
to consume 3-4 pads per day, 7 days duration and
does not experience dysmenorrhea. She has not used
L ymphangiomyomatosis is a rare disease that is
characterized by proliferation of abnormal
smooth muscle-like cells. The majority of cases
hormonal contraceptive. No previous pap smear was
done. She is unemployed, previously a banker, denies
primarily occur in the lungs, but extrapulmonary smoking, alcoholic beverage drinking and illicit drug
regions such as the pelvis and retroperitoneal spaces use.
are occasionally primary sites. We offer in this report On examination, her vital signs were stable, not
information that lymphangiomyomatosis which is in cardiorespiratory distress. She has no pallor, and
known as a rare pulmonary disease can develop in cervicolymphadenopathy. Upon chest examination,
the pelvic cavity, particularly in the uterus. breath sounds were clear. She has a normal cardiac
rate, regular rhythm, no murmur. Abdomen was
soft, had normoactive bowel sounds, with a firm,
THE CASE non-tender mass spanning the hypogastric area up
to the level of the umbilicus. On rectal examination,
J.R., is a 47 year old, nulligravid who presented sphincteric tone was intact, empty rectal vault, no
with a two year history of prolonged and profuse nodularities, uterus enlarged to 20 weeks size, solid,
menstrual episodes consuming up to 10 pads a day firm, movable, non-tender. There were no adnexal
masses and tenderness.
Transabdominal and transrectal sonology were
done. The uterus was anteverted, midline, with
_______________ heterogenous echopattern and smooth contour. It
* 3rd Place Winner, 2013 Midyear Residents' Interesting Case Paper was enlarged and measured 15.2cm x 13.0cm x
Presentation Contest last 11 April 2013, Ballroom 2, The Oriental Hotel, 13.2cm (Figure 1). From the posterior wall appears
Legaspi City.
Lymphangiomyomatosis Originating in the Uterus / Pili and Castro
to be a multiloculated cystic mass filled with lithium level which revealed values within normal.
anechoic fluid. The septa measured 0.12 cm, and is Chest X-ray was done revealing a clear chest. She
not vascular by color flow. The cystic portion also had 12L ECG, 2D echo and treadmill stress test
measured 13.3cm x 10.2cm x 10.7cm (Figure 2). The for her hypertensive work-up which also revealed
endometrium measured 0.7cm, is hyperechoic, with normal results.
irregular borders. The subendometrial halo was not Our initial impression was, Gravida 0, Uterine
seen. The cervix measured 2.1cm x 2.4cm x 2.4cm. mass probably myoma with cystic degeneration.
Both ovaries were not visualized due to the large The patient underwent exploratory laparotomy,
pelvic mass occupying almost the whole pelvis. The total abdominal hysterectomy, bilateral salpingo-
cul-de-sac was smooth without free fluid. Impression oophorectomy with frozen section. Upon opening,
on ultrasound was a huge pelvo-abdominal mass, the uterus was globularly enlarged which measured
to consider a uterine lesion probably a myoma with 16cm x 15cm x 10.5cm with a smooth surface
cystic degeneration. (Figure 3). The cervix measured 4cm x 3cm x 4cm.
The right and left ovaries appeared normal. On
cut section of the uterus, the endometrium was
0.4cm thick, smooth and devoid of masses. The
anterior myometrial wall was 3cm thick while the
posterior myometrial wall was 2cm thick. There
was a well- delineated multi-cystic mass in the
posterior myometrial wall approximately
measuring 12cm x 10cm x 6cm with straw colored
fluid upon rupture of each cyst. The cyst wall was
smooth (Figure 4).
The uter us was sent for histopatholog y.
Microscopic examination revealed that the tumor
was composed of atypical smooth muscle cells (LAM
cells) arranged in short fascicles around dilated
Figure 1. Sonographic picture shows an anteverted uterus with lymphatics and a ramifying network of endothelium-
heterogenous echopattern and smooth contour. It was enlarged and lined spaces (Figures 5 & 6). Immunohistochemical
measured 15.2cm x 13.0cm x 13.2cm. staining showed that the tumor cells were diffusely
Figure 2. From the posterior wall appears to be a multiloculated

cystic mass filled with anechoic fluid. The septa measures 0.12cm,
and is not vascular by color flow. The cystic portion measures
13.3cm x 10.2cm x 10.7cm.
Other laboratory exams done were CBC, Figure 3. The uterus is globularly enlarged which measured 16cm
urinalysis, FBS, ASL, ALT, Na, K, creatinine, serum x 15cm x 10.5cm with a smooth surface.
positive for smooth muscle actin and positive for is characterized by abnormal proliferation of
human melanin black-45 (HMB-45). Final smooth muscle-like cells (LAM cells). It is an
histopathologic diagnosis was lymphangiomyo- autosomal dominant syndrome characterized by
matosis of the uterus. hamartoma-like tumor growths in various organs.
The disease is very rare with a prevalence of 1 per
million in the general population of France, UK,
and the USA. 1 It predominantly affects the lungs,
comprising 87% of cases. 2 The clinical course of
pulmonary LAM is characterized by progressive
dyspnea on exertion, recurrent pneumothorax, and
chylous fluid collections. Lung function declines
up to 3 fold. CT scan findings demonstrate thin-
walled cystic changes. On work-up of this patient,
there was no lung involvement seen. Chest x-ray
was clear.
Uterine involvement of lymphangiomyomatosis
is extremely rare, and only 8 cases of pathologically
proven uterine LAM have currently been reported.3
Based on researches from POGS and PGH, there
were no cases reported in the Philippines.
LAM occurs mainly in women, usually during
Figure 4. There was a well- delineated multi-cystic mass in the their reproductive ages. The exact pathogenesis of
posterior myometrial wall approximately measuring 12cm x 10cm lymphangiomyomatosis is still unclear. According
x 6cm with straw colored fluid upon rupture of each cyst. The cyst
wall was smooth. to literature, steroid receptors for estrogen and
progesterone have been identified in tissues affected
by LAM. Therefore, a hormonal cause has been
Her postoperative course was unremarkable and suggested.2
the patient was discharged on the 5th postoperative Lymphangiomyomatosis was also found out to
day without complications. occur in about 40% of woman with the tuberous
sclerosis complex, a genetic disorder of highly
DISCUSSION variable penetrance associated with seizure, brain
tumors and cognitive impairment. 3 LAM may be
Lymphangiomyomatosis (LAM), is a rare classified as a tuberous sclerosis associated form or
idiopathic disease affecting primarily women that a sporadic form. Both are associated with mutations
Figure 5. LAM cells in low power view. Figure 6. LAM cells in high power view.
Figures 5 and 6. Both pictures show atypical smooth muscle cells (LAM cells) arranged in short fascicles around dilated
lymphatics and a ramifying network of endothelium-lined spaces.
in the tuberous sclerosis gene, TSC1, TSC2.6 LAM diagnostic chest X-ray every 6 months for the initial
is also seen in association with a variety of 2 years and yearly thereafter.
neoplasms, including renal angiolipomas, soft tissue Recorded patients with uterine lymphangiomyo-
tumors and endocrine tumors. Our patient however, matosis were usually diagnosed postoperatively upon
showed none of the other manifestations of tuberous histopathology of uterine specimens. It is difficult to
sclerosis. obtain a correct preoperative diagnosis. In this case,
Figure 1 shows a model of effect of LAM on our preoperative diagnosis was a degenerative
lymphatics. The figure shows a normal lymphatic myoma uteri. Although smooth muscle proliferation
vessel with unidirectional valve and normal direction in LAM is considered benign, it causes considerable
of lymph flow (A), then there is proliferation of morbidity and mortality once there is lung
abnormal smooth-muscle cells (LAM cells) causing involvement due to prog ressive respir ator y
mural thickening and luminal narrowing (B), until insufficiency. Although LAM is a rare uterine
there is obstruction of the lymph flow that results in condition, it must be distinguished from a variety of
the dilatation of lymphatic proximal to obstruction, uterine tumors.
creating lymphangiomyoma (C).10
Clinical and radiologic presentations may suggest SUMMARY AND CONCLUSION
the diagnosis of LAM. Classical feature on
ultrasound of LAM is a finding of multiple thin- Recorded patients with uterine lymphangiomyo-
walled cysts distributed evenly through the affected matosis were usually diagnosed postoperatively upon
organ, with normal intervening parenchyma. histopathology of uterine specimens. It is difficult to
However, such presentation would not solely obtain a correct preoperative diagnosis. In this case,
differentiate the case from other large cystic uterine our preoperative diagnosis was a degenerative
lesions such as cystic degeneration of uterine myoma uteri. Although smooth muscle proliferation
leiomyoma, cystic adenomyosis, congenital uterine in LAM is considered benign, it causes considerable
cysts, cervical nabothian cysts, echinococcal cysts, morbidity and mortality due to progressive
intramyometrial hydrosalpinx, and cystic metastasis respiratory insufficiency. It is often seen in association
from an occult tumor. Thus, final diagnosis of LAM with tuberous sclerosis and a variety of neoplasms,
is confirmed by histopathology. including renal angiolipomas, soft tissue tumors, and
The effective treatment mode for endocrine tumors. Although LAM is a rare uterine
lymphangiomyomatosis is still obscure. Earlier condition, it must be distinguished from a variety of
management of LAM consisted of symptomatic uterine tumors.
treatment. The current treatment modality is
primarily based on the antagonism of estrogen action.
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Carbetocin Versus Oxytocin For The Prevention of Postpartum Hemorrhage Following Elective Cesarean Section: Rizal Medical Center Experience

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Carbetocin Versus Oxytocin For The Prevention of Postpartum Hemorrhage Following Elective Cesarean Section: Rizal Medical Center Experience

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Carbetocin Versus Oxytocin for the Prevention of

Postpartum Hemorrhage Following Elective Cesarean

Department of Obstetrics and Gynecology, Rizal Medical Center

Postpartum hemorrhage is a preventable event in abdominal

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 71

In several trials, carbetocin was associated with MATERIALS AND METHODS

72 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

Sample Size Estimation operatively and 24 hours post-operatively. Blood

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 73

Characteristics Carbetocin Oxytocin P-value

Mean age in years (SD) 30 (5.7) 31 (6.3) .55*

Indication for Cesarean Section

Repeat Cesarean Section

Duration of Cesarean Section

Mean Preoperative SBP (SD) 117.5 (6.8) 118.3 (8.3) .68*

Resident’s Year Level Doing the Operation

*No significant difference by independent T-test, ** by chi-square test

74 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 75

Outcome Carbetocin Oxytocin P-value

Need for Additional Uterotonics

Estimated Blood Loss (mL)

*Significant difference by independent T-test **Chi-square test

Uterine Tone Carbetocin Oxytocin P-value

After Delivery of Neonate

Significant difference by independent **Chi-Square Test

76 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

Uterine Tone Carbetocin Oxytocin P-value

After Delivery of Neonate

Significant difference by independent **chi-square test

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 77

78 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 79

Department of Obstetrics and Gynecology, St. Luke's Medical Center

80 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

Objectives Low gestational sac position refers to an abnormally

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June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 83

Variables Pregnancy Outcome P value

Choriodecidual appearance† ---

Gestational sac position† ---

Yolk sac size† ---

Fetal heart rate <0.001

Subchorionic hemorrhage 0.685

Laterality of the corpus luteum 0.780

Maternal Clinical Characteristics

History of previous abortion/s 0.425

84 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)

Maternal age ≥35 years 0.001 4.666 1.891 11.513

Constant 0.000 0.026

Table 5. Sonographic and maternal clinical characteristics

Variables Sig. Exp (B) 95% CI for Exp (B)

Fetal heart rate 0.001 0.974 0.960 0.989

Maternal age 0.016 1.102 1.018 1.193

Constant 0.151 0.102

Table 6. Presence or absence of fetal bradycardia according to pregnancy outcome.

Fetal Bradycardia Pregnancy Outcome P value

Absent 17 377 394

Total 29 390 419

June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2) 85

86 June, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 2)