Middle East Fertility Society Journal (2015) 20, 43–47

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.org
www.sciencedirect.com

ORIGINAL ARTICLE

Pattern of glucose intolerance among

pregnant women with unexplained IUFD
Maher S. Mohamed a, Kamal M. Zahran a,*, Hazem Saad Eldin Mohamed a,
Hanan Galal b, Ahmed Mohamed Mustafa a

a
Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University, Assiut, Egypt
b
Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt

Received 22 November 2013; revised 9 April 2014; accepted 10 April 2014

Available online 21 May 2014

KEYWORDS Abstract Purpose: To determine the possible causes for IUFD and to investigate for the pattern
Unexplained IUFD; of glucose intolerance as a cause of unexplained IUFD among pregnant women.
Glucose intolerance; Methods: For one year, 420 pregnant women with IUFD at or after the 28th week of pregnancy
HbA1c; and another 200 women carrying normal looking fetuses were recruited as a control group.
Diabetes mellitus Random venous samples and HbA1c were tested to assess the glucose control in the studied
women.
Results: Of the studied women, 68.09% had unexplained cause for their IUFD. Other causes for
IUFD included Hypertensive disease with pregnancy (6.9%), accidental hemorrhage (5.5%), and
small for gestational age (11.4%). Overt DM was diagnosed at 1.7%. Women who had unexplained
IUFD showed higher HbA1c and Random Blood Sugar (RBS) than control group. 18% of women
carrying unexplained IUFD and had normal RBS showed abnormally high HbA1c level.
Conclusions: Unexplained IUFD represented the major category of IUFD (68.09%). Labora-
tory indices of diabetes mellitus are more prevalent in this category of patients. Accordingly, screen-
ing for diabetes is recommended for these women. However, the use of RBS alone is not sufficient
to exclude poor metabolic control. HbA1c may be a better alternative.
Ó 2014 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.

1. Introduction

* Corresponding author. Address: Department of Obstetrics and
Gynecology, Faculty of Medicine, Assiut University, P.O. 71116
Assiut, Egypt. Tel.: +20 882 41 4616, +20 882325840 (Private),
mobile: +20 1227432270; fax: +20 882 368377.
E-mail address: drzahranmk@gmail.com (K.M. Zahran).
Peer review under responsibility of Middle East Fertility Society.
Production and hosting by Elsevier
Gestational diabetes mellitus (GDM) is currently defined as
any degree of glucose intolerance with onset or first recogni-
tion during pregnancy. This definition does not exclude
glucose intolerance that may have antedated pregnancy (1).
Gestational diabetes generally has few symptoms and it is
most commonly diagnosed by screening during pregnancy.
Diagnostic tests detect inappropriately high levels of glucose
in blood samples. It affects 3–10% of pregnancies, depending
on the population studied (2).

1110-5690 Ó 2014 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
http://dx.doi.org/10.1016/j.mefs.2014.04.004
44
GDM is associated with increased incidence of maternal
hypertension, pre-eclampsia, obstetric intervention and risk
of developing diabetes mellitus (DM) in later life (3).
The major morbidities associated with infants of diabetic
mothers include respiratory distress, growth restrictions,
polycythemia, hypoglycemia, congenital malformations, hypo-
calcemia and hypomagnesemia (4). Perinatal outcome associ-
ated with poor glycemic control in mothers is associated
with as high as 42.9% mortality (5). Appropriate diagnosis
and management of GDM can improve maternal and perinatal
outcome.
An improved outcome of pregnancy complicated by diabe-
tes mellitus has been reported in recent studies. However, this
achievement is not shared in full by African countries where
the Perinatal morbidity and mortality is still high, although
reports are scarce (6).
Unfortunately, there are no national figures about the mag-
nitude of gestational diabetes among pregnant women in
Upper Egypt, especially those with IUFD. The aim of this
study was to determine the possible causes for IUFD and to
investigate for impaired glucose tolerance as a possible cause
of death among pregnant women with unexplained IUFD pre-
sented to the women’s health Hospital of Assiut University.
2. Materials and methods
This hospital based case control study was conducted in the
Women’s Health hospital, Assiut University, Egypt. For one
year, starting from the 1st of July 2012 through the 30th of
June 2013. Four hundred and twenty pregnant women who
attended antenatal care clinic with IUFD at or after the 28th
weeks of pregnancy or with estimated fetal weight of 1 kg or
more by ultrasound were recruited for the study. Another
two hundred women with normal looking fetuses at or after
the 28th week of pregnancy were recruited as a control group.
Patients meeting the inclusion criteria were counseled about
participating in the study. A written informed consent was
taken. The institutional Review Board approved the study.
Clinical work-up of the mothers included: entry history tak-
ing, with special emphasis on symptoms and signs suggestive
of DM, date of IUFD, evidence of fetal anomalies by US, his-
tory of previous IUFD, fetal macrosomia, difficult labor, past
history of gestational DM or family history of DM, history of
genetic or herido-familial disease or medical disease of acute or
chronic illness and the Pattern of antenatal care or obstetric
problems in the investigated pregnancy. Clinical examination
and ultrasound ****evaluation (detailed ultrasound evaluation
especially on evidence of congenital anomalies, evidence of
fetal macrosomia). Gestational age was determined on the
basis of the last menstrual period, confirmed by ultrasound
evaluation and calculated in menstrual weeks.
Clinical work-up of the newborns included: clinical exami-
nation at birth, photography, and report of anomalies, macer-
ation, fatal weight and sex or other abnormalities.
Random venous samples were withdrawn from mothers
carrying IUFD and control group mothers to test for blood
sugar.
The first 200 mothers carrying IUFD of unspecified causes
were selected and tested with HbA1c in addition to the control
group mothers to assess the previous glucose control in the last
few months.
M.S. Mohamed et al.
The primary outcome measure was to determine the possi-
ble causes for IUFD and to investigate for impaired glucose
tolerance as a cause of death among pregnant women with
unexplained IUFD. Secondary outcomes included the validity
of RBS as a screening test for gestational DM as a possible
cause of IUFD, the role of HbA1c in the detection of previous
glucose control in the last few months.
Statistical analysis was performed using SPSS computer
package (SPSS, Inc., Chicago, IL) version 17.0. and has been
revised by statistician. Student’s t test was used for mean
and standard deviation. Fisher’s exact test was used to com-
pare continuous data. A significance level of 5% was adopted.
Risk ratio (RR) and 95% confidence interval (CI 95%) were
calculated to assess the magnitude of the association between
outcomes.
3. Results
Out of 20,887 deliveries in that year, 420 mothers carrying
IUFD were recruited for the study.
Table 1 shows the demographic data of study group and
control groups. There was no statistically significant difference
between groups in the mean age, parity, gestational age,
working status and education (P > 0.05). But there was a sta-
tistically significant difference in the abortion rate (P < 0.05).
Table 2 shows causes of fetal death in the study group.
68.09% of women had unexplained cause for their IUFD,
6.9% had hypertensive disease with pregnancy (Preeclamp-
sia–eclampsia, chronic hypertension, Gestational hyperten-
sion), 5.5% had accidental hemorrhage and 11.4% were
small gestational age. Overt DM was diagnosed in 7 cases only
(1.7%).
Table 3 shows some different features in unexplained and
explained groups. Women with unexplained IUFD showed
tendency toward higher mean R.B.S level of more than 2 m
mole than women with explained causes, this difference was
statistically significant. There was a statistically significant dif-
ference between both group as regards parity, history of previ-
ous abortions and the mode of delivery with tendency toward
low parity, more number of previous abortions and more
women who achieved vaginal delivery in unexplained group.
There was no statistically significant difference between both
groups as regards fetal weight, sex and mother age (P > 0.05).
Table 4 shows HbA1c and Random blood sugar in study
and control groups.
200 women were randomly selected from the group of unex-
plained IUFD in the study group to be compared for HbA1c
and Random blood sugar with the control groups.
Women who had unexplained IUFD in the study group
showed tendency toward higher HbA1c and RBS than the con-
trol group but this difference was statistically significant only
in HbA1c.
Table 5 shows the relation between demographic data and
the level of HbA1c in women with unexplained IUFD. Out of
the two hundred women with unexplained IUFD who had
normal RBS, 36 women (18%) showed high level of HbA1c.
Women with unexplained IUFD who had elevated HbA1c
level showed tendency toward older maternal age, prolonged
labor duration, higher parity and more previous abortion,
these differences were statistically significant. They also
showed bigger fetal weight (more than 350 gm), than women
Glucose Intolerance in Women with IUFD 45

Table 1 Demographic data of study and control groups.

Item Study group ‘‘n = 420’’ Control group ‘‘n = 200’’ P-value
1 – Age (years)
Mean ± SD 23.42 ± 3.51 27.34 ± 6.53 0.375
Range (20–41) (19–42)
2 – Parity
Mean ± SD 2.34 ± 1.47 2.05 ± 1.06 0.416
Range (0–7) (0–4)
3 – Abortion
Mean ± SD 3.71 ± 1.71 1.34 ± 0.97 P < 0.02*
Range (0–6) (0–7)
4 – Gestational age ’’weeks’’
Mean ± SD 37.24 ± 1.47 38.01 ± 0.98 0.371
Range (28–39) (29–40)
5 – Education
Illiterate 130 (30.95%) 47 (43.5%)
Primary education 143 (34.0%) 84 (42.0%) 0.571
Secondary education 127 (30.2%) 60 (30.0%)
Higher education 20 (4.76%) 9 (4.5%)
6 – Working status
House wife 389 (92.6%) 175 (87.5%) 0.482
Working 31 (7.3%) 25 (12.5%)
*
Statistically significant.

systemic lupus erythematosus, chronic renal disease and

Table 2 Causes of fetal death in study group ‘‘n = 420’’.
thyroid disorders with pregnancy (8,9).
Item Descriptive Rates of stillbirth in low income countries are substantially
Causes of death higher (9–34/1000 births) than in high income countries (3.1/
1. Unexplained IUFD 286 (68.09%) 1000). Antepartum stillbirths are often related to maternal
2. Hypertensive disease with pregnancy 29 (6.90%) infection or fetal growth restriction. An unexplained stillbirth
(PET-eclampsia, chronic HT, G.HT) is a fetal death that cannot be attributed to an identifiable
3. Antepartum hemorrhage 36 (8.6%) fetal, placental, maternal, or obstetrical etiology. It accounts
– Accidental hemorrhage 23 (5.5%)
for 25–60% of all fetal deaths. Variation in the proportion
– Placental preavia 13 (3.1%)
of stillbirths reported as unexplained generally reflects whether
4. Diabetes mellitus 7 (1.7%)
5. Severe IUGR 48 (11.4%) the stillbirth has been fully evaluated (10,11).
6. Others 14 (3.3%) In the present study, the percentage of IUFDs attributed to
clinical diabetes was 1.7%. Other causes of explained IUFD in
There is overlap of more than one cause of death.
the present study included hypertensive disorders with preg-
PET: pre-eclampsia, HT: Hypertension, GHT: Gestational hyper-
tension, IUGR: Small for gestational age. nancy (6.9%), Antepartum hemorrhage (8.6%) and intrauter-
Others: as Hydrocephalus, Anencephaly and Hydrops Fetalis. ine growth restriction (11.4%). These figures were much lower
than the figures reported in other studies, the corresponding
figures of Shankar et. al. study were 29.3%, 14% and 24.8%
respectively (12). The difference in the prevalence of docu-
with normal of HbA1c level but this difference was statistical mented causes of IUFD between the present study and data
not significant. available in the literature may be attributed to the high per-
centage of unexplained IUFD revealed in the present study
mostly because the underlying cause of many cases of IUFD
4. Discussion is missed after the occurrence of the accident if the patient is
not regularly on documented antenatal care; women with
The Perinatal Mortality Surveillance Report defined stillbirth hypertension may have their blood pressure dropped after
as ‘a baby delivered with no signs of life after 24 completed IUFD and women with gestational diabetes may have their
weeks of pregnancy’. Intrauterine fetal death refers to babies blood glucose level corrected after the accident. Causes like
with no signs of life in utero after that age. This is common, these were missed if not documented during antenatal care.
with 1 in 200 babies born dead (7). However, unexplained IUFD accounts for a large propor-
Overall, over one third of IUFD are small-for-gestational- tion of total cases of IUFD (about 27.2%) and this percentage
age fetuses with half classified as being unexplained (7). Com- have been constant over decades (13). These cases have been
monly associated antepartum conditions include congenital long investigated to provide an explanation that would help
malformation, congenital fetal infection, antepartum hemor- in the management of future pregnancy. The percentage of
rhage, pre-eclampsia and maternal disease such as diabetes unexplained IUFD in the present study was quite higher
mellitus. Overall, about 10% of all fetal deaths are related to (68.09%) and this can be attributed to the lack of advanced
maternal medical illnesses such as hypertension, diabetes, investigations including postmortem examination (for social
46 M.S. Mohamed et al.

Table 3 Comparison between groups of unexplained and explained causes of IUFD.

Item Unexplained death ‘‘n = 286’’ Explained death ‘‘n = 134’’ P-value
1 – R.B. Sugar ‘‘m mole’’
Mean ± S.D 7.55 ± 1.80 5.33 ± 3.4 P < 0.001*
Range (4–11) (3–9)
2 – Fetal weight
Mean ± S.D 2687.1 ± 892.58 2691 ± 854.83 0.258
Range (min–max) (1300–4100) (1200–4000)
3 – Age of mother
Mean ± S.D 29.16 ± 25.98 28.26 ± 5.94 0.378
Range (19–41) (18–40)
4 – Fetal sex
– Male 169(59.09%) 48(35.82%) 0.479
– Female 117 (40.90%) 86 (64.17%)
5 – Parity
Mean ± S.D 1.02 ± 0.9 3.04 ± 2.01
Range (0–4) (0–6) P < 0.000*
6 – Abortion
Mean ± S.D 5.04 ± 1.9 2.06 ± 1.03 P < 0.000*
Range (0–4) (0–3)
7 – Mode of delivery
– Vaginal 197 (68.8%) 73 (54.47%) P < 0.02*
– C.s 89 (31.1%) 61 (45.52)
*
Statistically significant.

the validity of this test in these women (7). Rarely a woman

Table 4 Comparison of HbA1c and Random blood sugar in
will have incidental type 1 diabetes mellitus, usually with
women with unexplained IUFD in the study and control
severe ketosis (7). Women with gestational diabetes mellitus
groups.
return to normal glucose tolerance within a few hours after late
Item Study group Control group P-value IUFD has occurred. Engel PJ et. al. did not find a significant
‘‘n = 200’’ ‘‘n = 200’’ difference in maternal random glucose levels among cases with
1-HbA1c IUFD and control women except when type 1 diabetes
Mean ± SD 7.8 ± 1.70 6.5 ± 1.32 P < 0.03* (pregestational) was implicated (15). This was the same conclu-
Range (4.8–11.5) (4.0–9.10) sion we found in the present study when no significant differ-
2 – R.B.S ence was found in random glucose level (7.55 ± 1.80 mmol/L
Mean ± SD 7.55 ± 1.80 6.50 ± 1.58 0.388 versus 6.50 ± 1.58) in women with IUFD who are not known
Range (4.0–10.0) (4.0–9.10)
to be diabetic and control group. However, perinatal outcomes
*
Statistically significant. in women diagnosed with GDM differ by racial/ethnic group.
Such variation can be used to individually counsel women with
GDM (16).
and cultural reasons) and laboratory tests (e.g. thrombophi- Accordingly, another alternative is to use maternal HbA1c
lias). The high abortion rate in the group of unexplained to avoid the drawbacks of random glucose level mentioned
IUFD may suggest common etiological factors e.g. anti- earlier. HbA1c monitors glycaemia over the previous 3 months
phospholipid syndrome (APS) (14). This should be suggested by reflecting the average glucose concentration over the life of
when evaluating IUFD. the red cells and therefore may provide information to aid in
Assessment of unexplained IUFD for possible diabetes has the consideration of the contribution of diabetes to the fetal
been suggested in several studies. Maternal random blood death. If the HbA1c level is raised, fasting blood glucose
glucose was used to screen women with IUFD to identify should be undertaken and if abnormal a Glucose Tolerance
occult diabetes. However, there were 2 problems that reduce Test performed 6–8 weeks postnatally. HbA1c may be

Table 5 Comparison between demographic data and the level of HbA1c in 200 women with unexplained IUFD.
Item Normal HbA1c Elevated HbA1c P-value
Frequency 164(82%) 36(18%) P < 0.001*
1 – Age 24.12 ± 3.35 35.38 ± 2.78 P < 0.001*
2 – Fetal weight 2500.0 ± 1035.24 2852.41 ± 1132.45 0.478
3 – labor duration (h) 7.67 ± 3.65 10.76 ± 4.35 P < 0.04*
4 – Parity: Mean ± S.D 2.67 ± 1.32 3.78 ± 2.89 P < 0.03*
5 – Abortion: Mean ± S.D 2.03±.97 4.23 ± 1.9 P < 0.02*
*
Statistically significant.
Glucose Intolerance in Women with IUFD
abnormal indicating higher glucose levels in the few last
months before IUFD even if maternal glucose level returns
to normal after IUFD. This also needs to be tested in future
pregnancy (17). HbA1C carries the advantage of indicating
either occult type 1 or type 2 diabetes. The drawback of this
test is that it may be normal in many cases. Keshavarz et al.
and Günter HH found that HbA1c may be a better choice
despite being normal in many cases and that glucose challenge
test is an excellent option but, like random maternal glucose, it
may yield normal results after IUFD (18,19). The present
study supports this conclusion because of the significant differ-
ence between the case and control groups in their HbA1c levels
(7.8 ± 1.70 versus 6.5 ± 1.32). Our results also revealed that
the use of HbA1c added significant information to the use of
random blood glucose; HbA1c was elevated in 18% of cases
with normal random blood glucose. this means that, random
blood sugar test is quite insufficient to screen for abnormal
diabetic control, as 18% of women who had abnormal HbA1c
would be missed if we used RBS alone for testing for diabetic
control and we suggest that the use of these tests is better to be
combined. This supports the previous conclusions regarding
the use of random glucose as a test.
In the present study, elevated HbA1c was found to be asso-
ciated with other factors including age (24.12 ± 3.35 versus
35.38 ± 2.78), parity (2.67 ± 1.32 versus 3.78 ± 2.89) and this
is consistent with a higher risk of diabetes mellitus. The present
study also concluded that elevated HbA1c was also associated
with higher risk of abortion (2.03 ± 0.97 versus 4.23 ± 1.9).
Moreover, women with unexplained IUFD who had elevated
HbA1c level showed tendency toward prolonged labor dura-
tion and bigger fetal weight.
The main conclusions from this study were that, unex-
plained IUFD represented the main category that needs to
be carefully assessed on basis of cost effectiveness particularly
in developing countries. Laboratory indices of diabetes melli-
tus are more prevalent in this category of patients. Accord-
ingly, screening for diabetes is recommended for all pregnant
women specially those women with unexplained IUFD. How-
ever, the use of random blood glucose alone, which is a com-
mon practice, is not sufficient to exclude poor metabolic
control during pregnancy. HbA1c should be considered as a
better alternative.
Women with unexplained IUFD should be scheduled for
HbA1c then GTT 6–8 weeks postnatally. RBS and HbA1c
should be an integral part of each ANC visit. Other studies
should be undertaken to assess the role of repeated RBS and
HbA1c in early diagnosis of glucose intolerance especially in
developing countries where most of ANC programs are poor
or disorganized.
Conflict of interest
The authors declare that they have no conflict of interest.
References
(1) Hillier TA, Vesco KK, Whitlock EP, et al. Diagnosis and classifi-
cation of diabetes mellitus. Diabetes Care 2006;29(Suppl 1):S43–8.
47
(2) Thomas R, Moore MD., et al. Diabetes Mellitus and Pregnancy.
med/2349 at eMedicine. Version: January 27, 2005 update.
(3) Davey RX, Hamblin PS. Selective versus universal screening for
gestational diabetes mellitus: an evaluation of predictive risk
factors. Med J Aust 2001;174:118–21.
(4) Opara PI, Jaja T, Onubogu UC. Morbidity and mortality
amongst infants of diabetic mothers admitted into a special care
baby unit in Port Harcourt, Nigeria. Ital J Pediatr 2010;36:77,
PMC free article.
(5) Otolorin EO, Famuyiwa OO, Bella AF, Dawodu AH, Adelusi B.
Reproductive performance following active management of
diabetic pregnancies at the University College Hospital, Ibadan,
Nigeria. Afr J Med Med Sci 1985;14:155–60.
(6) Challis K, Melo A, Bughalo A, Jeppsson J, Bergstrom S.
Gestational diabetes mellitus and fetal death inMozambique: an
incident case-referent study. Acta Obstet Gynecol Scand 2002;81:
560–3.
(7) Confidential Enquiry into Maternal and Child Health
(CEMACH). Perinatal Mortality 2007: United Kingdom. Lon-
don: CEMACH; 2009.
(8) Ohana O, Holcberg G, Sergienko R, Sheiner E. Risk factors for
intrauterine fetal death (1988–2009). J Matern Fetal Neonatal
Med 2011;24(9 (September)):1079–83.
(9) Al-Kadri HM, Tamim HM. Factors contributing to intra-uterine
fetal death. Arch Gynecol Obstet 2012;286(5 (November)):
1109–16.
(10) Causes of death among stillbirthsStillbirth Collaborative Research
Network Writing Group. JAMA 2011;306(22 (December)):2459–68.
(11) Magann EF, Chauhan SP, Bofill JA, Waddell D, Rust OA,
Morrison JC. Maternal morbidity and mortality associated with
intrauterine fetal demise: five-year experience in a tertiary referral
hospital. South Med J 2001;94(5 (May)):493–5.
(12) Shankar M, Navti O, Amu O, Konjel JC. Assessment of still birth
risk and associated risk factors in a tertiary hospital. J Obstet
Gynaecol 2002;22:34–8.
(13) Huang Diana Y, Usher Robert H, Kramer Michael S, Yang
Hong, Morin Lucie, Fretts Ruth C. Determinants of unex-
plained antepartum fetal deaths. Obstet Gynaecol 2000;95(2):
215–21.
(14) Helgadottir LB, Skjeldestad FE, Jacobsen AF, Sandset PM,
Jacobsen EM. The association of antiphospholipid antibodies
with intrauterine fetal death: a case-control study. Thromb Res
2012;130(1 (July)):32–7.
(15) Engel PJ, Smith R, Brinsmead MW, Bowe SJ, Clifton VL. Male
sex and pre-existing diabetes are independent risk factors for
stillbirth. Aust N Z J Obstet Gynaecol 2008;48:375–83.
(16) Esakoff TF, Caughey AB, Block-Kurbisch I, Inturrisi M, Cheng
YW. Perinatal outcomes in patients with gestational diabetes
mellitus by race/ethnicity. J Matern Fetal Neonatal Med
2011;24(3 (March)):422–6.
(17) Perinatal Clinical Practice Guidelines Working Party. Clinical
Practice Guidelines for the prevention of neonatal early onset
group B streptococcal disease. Brisbane: Queensland Health;
2003.
(18) Keshavarz M, Cheung NW, Babaee GR, Moghadam HK, Ajami
ME, Shariati M. Gestational diabetes in Iran: incidence, risk
factors and pregnancy outcomes. Diabetes Res Clin Pract
2005;69:279–86.
(19) Günter HH, Scharf A, Hertel H, Hillemanns P, Wenzlaff P, Maul
H. Perinatal morbidity in pregnancies of women with preconcep-
tional and gestational diabetes mellitus in comparison with
pregnancies of non-diabetic women. Results of the perinatal
registry of Lower Saxony, Germany. Z Geburtshilfe Neonatol
2006;210:200–7. Article in German.