PRETERM LABOR: RISK FACTORS,

IDENTIFICATION, MANAGEMENT & PREVENTION

29/07/23 1
PRETERM LABOUR

 Cause-Uncertain
 Diagnosis-Elusive
 Methods-Debatable
 Results-Unpredictable
 Cost- Enormous
 definition
• Preterm infants are born before 37 weeks’
gestation . Neonates born before 32 weeks
have the greatest risk for poor
health outcome and death. Those born
between 32 and 36 weeks are still at higher
risk for health
and developmental problems than those
born full term.
EPIDEMIOLOGY
&
RISK FACTORS

4
15 million born early each year:
highest rates in Africa
Number of Preterm Preterm
Births Birth Rates
%
World Total 14,870,000 9.6

Africa 5,047,000 11.9

North America (US & Canada)* 480,000 10.6
Asia 7,907,000 9.1
Latin America & the Caribbean 933,000 8.1
Oceania (Australia/New Zealand) 20,000 6.4
Europe 466,000 6.2

March of Dimes Oct 2009

 The 10 countries with the greatest
number of preterm births:
• India: 3 519 100
• China: 1 172 300
• Nigeria: 773 600
• Pakistan 748 100
• Indonesia: 675 700
• United States of America: 517 400
• Bangladesh: 424 100
• The Philippines: 348 900
• Democratic Republic of the Congo: 341 400
• Brazil: 279 300

29/07/23 WHO,2012 6
>8 MILLION PRETERM BABIES
DIE EACH YEAR

WHO 2009
 TRENDS
Spontaneous preterm birth is increasing

Spontaneous preterm delivery in primiparous women at low risk in

Denmark: population based study
Jens Langhoff-Roos et al. BMJ 2006.
29/07/23 10
latimesblogs.latimes.com
Late preterm birth 34-36+6 week

wn.com
 Risk factors
• A Sociodemographic factors
• B Maternal medical and obstetric conditions
• C Infection

29/07/23 13
RISK FACTORS

Goffinet et al. BJOG 2005

RISK FACTORS

Goffinet et al. BJOG 2005

 LIFESTYLE

socioeconomic work BMI

standard

smoking addiction alcohol 16

 Preterm Birth and
Family History

• Data from linked database of birth certificates of two

generational cohorts
• Risk of PTD for preterm mothers was higher than those
that had been born at term (OR 1.18)
• If preterm mother delivered <30 weeks OR increased to
2.38
 Employment-related physical
activity
• Tiring postures
• Industrial machines
• Physical exertion (prolonged standing,
heavy lifting, physically strenuous, long
working hours)
• Mentally unstimulating tasks
• Physically unconfortable environment
• Work-related psychological stress
 Bacterial colonization in SPT
B

Watts DH, et all, The association of occult amniotic fluid infection with gestational age and neonatal outcome
among women in preterm labor. Obstet Gynecol 1992;79:351-357
 infection
Systemic infections
a. Pyelonephritis; Pneumonia
Local infections
a. Bacterial vaginosis
b. Subclinical and clinical intra-amniotic infections
c. Sexually transmitted diseases (STDs) (very poorly defined relationship with preterm labor)

29/07/23 20
 IDENTIFICATION
OF TRUE PRETERM LABOUR

Since preterm labour is not a disease,

but rather an “event”, it may be more appropriate
to replace the term “diagnosis” with the term
“identification” in this context
 PREMISES

In most countries the identification

of preterm labour is based only on
clinical subjective data

Excessive: Costs increase

Hospitalisation Increase of unuseful
Tocolisis and potentially
Corticosteroids harmful interventions
29/07/23 22
 Prediction of spontaneous preterm birth
Cervix or vagina
Bacterial vaginosis
Amniotic fluid Saliva
IL-6 calgranulins oestriol
IL-8 defensins
IL1 IL-6
IL-8
fetal fibronectin (fFN)
ferritin
α-fetoprotein
human chorionic gonadotropin Serum
prolactin G-CSF
C-terminal propeptide of ferritin
procollagen defensins
pIGFBP-1 calgranulins
IGF BP-1 fragment
Cervical length (TVUS) relaxin
EMG
Vitamins and micronutrients
Maternal BMI
CRP, CD163
Previous History
23
Changes in Cervical Morphology

Normal Cervix Short and Funneled Cervix

24
 Abnormal Cervix
Preterm Labour : Cervical Shortening
Cervical Length as a Marker for Risk
Assessment in Asymptomatic Women
• What is "short"?
– In the medical literature, defined as 1.5 to 3.0 cm
– ≤ 2.5 cm seems to have the best predictive accuracy

• For SPTB before 35 weeks, cervical length

of less than 2.5 cm from 16 to 24 weeks:
– Sensitivity 69%
– Specificity 80%
– PPV 55%
– NPV 88%
CERVICAL LENGTH IN SYMPTOMATIC PATIENTS

• CL >2.5 cm Not true labor

• CL <1.5 cm May be true labor

Biochemical
markers
Biochemical markers and prediction of prematurity in symptomatic patients

Marker Test Sensitivity (%) Specificity (%) PPV (%) NPV (%)

Fibronectin Cervical or 69 to 93 72 to 86 23 to 83 85 to 99a

vaginal

Cytokine Serum 50 73 to 85 47 to 57 67 to 86
(Interleukin-6)
Amniotic fluid 52 100 100 79

Estradiol-17ß Serum 12 71 to 76 12 to 14 --

Estriol Salivary 71 77 27 77

Progesterone Serum 6 to 35 67 to 69 7 to 32 --

(Cochrane Library)
 Fetal Fibronectin:
Key Biochemical Marker for Risk Assessment

• Adhesive
glycoprotein “glue”
at the maternal-fetal
interface
• Presence in
cervicovaginal
secretions highly
associated with risk
of preterm delivery
 Cervicovaginal Presence of Fetal Fibronectin
from 22 to 35 Weeks Is Abnormal

4500
Fetal Fibronectin (ng/mL)

4000
3500 Clinically Relevant Time Frame
3000 (22 to 35 weeks)
2500
2000
1500
1000
500 50 ng/mL
0 Cutoff Level
0 5 10 15 20 25 30 35 40
Gestational Age (Weeks)

31
 Comparison of Risk Factors

16
Spontaneous Preterm Birth < 32 Weeks
14.1
14
12
Relative Risk

10
8 7,7
7,1
6
4
2,6 2,7
2 1,5
0
African BMI <19.8 (+) BV Previous CL ≤25 mm (+) fFN
American SPTB

Cervical length measurement and fFN testing were performed at 22 to 24 weeks

32
 fFN Helps Target Steroid Administration
fFN Testing Allows the Healthcare Provider to:
• Choose the patients most likely to benefit from treatment with antenatal steroids
• Avoid unnecessary intervention

NNT with steroids to

fFN Test Status prevent 1 case
RDS
fFN testing negative 509
No fFN testing 109
33
fFN testing positive 17
 Differences in Management According
to fFN Test Results
(+) fFN (-) fFN
(n=28) (n=136)
Received antenatal
96.4% 4.7%
corticosteroids
Admitted to
96.4% 54.4%
hospital
Received tocolysis 71.4% 2.4%
Mean cost of
treatment (New $967.47 $335.27
Zealand dollars)
Retrospective case review.

Groom KM, Liu E, Allenby K. The impact of fetal fibronectin testing for women with symptoms of preterm labour in routine clinical
34
practice within a New Zealand population. Aust N Z J Obstet Gynaecol. 2006;46:440-445.
 fFN & US cervicometry trial
for detection of true preterm
labor
 fFN test result

positive negative

UC > 2.5 UC < 2.5 UC > 2.5 UC < 2.5

cm cm cm cm

admit,monitor administer no treatment

and potentially tocolysis and no treatment, but monitor
administer steroids monitor (<32 wks
steroids (antibiotics ?) admission and
re-evalutation;
> 32 wks
outpatient)
 MAIN POINTS
• Bearing in mind the excellent
negative predictive value of such
tests (when fibronectin is negative
and cervical length by ultrasound is
> 2.5 cm) we recommend that
tocolytic therapy and steroid
prophylaxis should be withheld
 Benefits to the hospital
• Reduces unnecessary
admissions and transfer to
NICU
• Cost savings to the hospital
• Reduction in administering
medical management
• Availability of beds
Benefits to the patient
• Unnecessary medical
intervention
• Piece of mind
• Uninterrupted travel plans
• Employment
• Less burden on spouse and
family
 PRETERM BIRTH
How do we identify who is at risk?

Risk Fetal Cervical Symptoms

Factors Fibronectin Length of PTL

39
PREVENTION

40
 PROGESTERONE
&
PREGNANCY
MAINTENANCE

29/07/23 41
Immune tolerance

Successful mammalian
pregnancy depends upon
tolerance of a genetically
incompatible fetus by the
maternal immune system.

42
 Balance between Th1 & Th 2 responses

TH1 TH2
INHIBITED
PROLIFERATION
IL - 10

INHIBITED
PRODUCTION

IL – 4
IFN Y
IL - 5

EOSINOPHYLE
B CELL
ACTIVATION PLASMATIC
CELL

MACROPHAGE HUMORAL RESPONSE

IMMUNOGLOBULINS
 Progesterone
Immunomodulation
FETAL ALLOANTIGENS
INDUCTION

P
PR PROGESTERONE
PR INDUCED

P
BLOCKING
PR FACTOR
P
“PIBF”

LYMPHOCYTE PROGESTERONE-
ACTIVATION PR COMPLEX
 Progesterone
Immunomodulation

Arachidonic Acid
Phospholipase A2
Phospholipase C Prostaglandins
PROGESTERONE
INDUCED IL -2; 12 ; IFN gamma; IFN alfa
CYTOKINE
BLOCKING
BALANCE
FACTOR IL - 4; 5; 10
“PIBF”
NK cells
Activity
 Progesterone-induced Blocking Factor (PIBF)
Link between the Endocrine and Immune System

Progesterone
Normally
PIBF Th2 Progressing
Pregnancy

Progesterone
Miscarriage
PIBF Th1
Ru 486

Progesterone
Miscarriage
PIBF Th1
+anti-PIBF

47
 PREGNANCY OUTCOME
FETUS/TROPHOBLAST
50% PATERNAL/50% MATERNAL

ALLOGENIC IMMUNE REACTION

Progesterone induced blocking factor (PIBF) at decidual (CD56+) and PBMC level

Progesterone level sufficient to Progesterone level insufficient to

form PIBF form PIBF

Asymmetric antibodies Th2 Symmetric antibodies Th1

NK cells LAK cells

Fetal protection Cytotoxic, inflammatory

Abortogenic reaction

Pregnancy continuation Abortion

(PBMC= Peripheral blood mononuclear cells; NK= Natural killer cells; LAK cells= Lymphokine activated
killer cell) DI RENZO ET AL GYN ENDOCR 2012
 Endocrino-immune Interaction
Progesterone modulates the mother-to-be’s immune response from

Rejection Protection

29/07/23 49
“that if progesterone is
indispensable in normal
pregnancy maintenance, then
progesterone withdrawal has to
be a prerequisite of pregnancy
termination”
 Progesterone Withdrawal
is Signal for Parturition (Csapo)
 CLINICAL USE OF PROGESTERONE

ANTAGONISTS
PROGESTERONE
(Mifepristone, Onapristone)

- +

UTERINE CONTRACTILITY

THREATENED
PRETERM
ABORTION
DELIVERY

RECURRENT ABORTION LABOR

ABORTION INDUCTION INDUCTION
PROGESTERONE ACTIVITIES IN PREGNANCY
PROGESTERONE
&
PRETERM BIRTH

54
55
PREVENTION OF PRETERM
BIRTH
• Intramuscular progesterone 17 alpha-
hydroxyprogesterone caproate (17P
• for the prevention of spontaneous
preterm birth in women with singleton
pregnancies and a history of a prior spontaneous
preterm birth. As compared to placebo, weekly
intramuscular injections of 17P reduced the rate of
preterm birth by approximately one-third

56
 ACOG
• The American College of Obstetricians and
Gynecologists (ACOG) recommends the use of
17P in patients with a prior spontaneous singleton
(not medically indicated) preterm birth that
occurred between 20 to 36 and 6/7 weeks, starting
with weekly intramuscular injections of 250 mg
between 16 and 20 weeks of gestation.

57
 . Cerclage
• The use of cerclage to prevent recurrent preterm birth
in women who had a prior spontaneous preterm at less
than 34 weeks’ gestation was investigated in a
multicenter randomized trial.
• the American College of
Obstetrics & Gynecology has not made a formal
statement on the use of transvaginal cervical
length ultrasound in the decision-making process for
cerclage placement.

58
 Vaginal progesterone
• The majority of preterm births in the United States
do not occur in
women with a history of preterm birth. The use of
progestational agents to prevent preterm birth
• vaginal progesterone
significantly reduced the frequency of preterm
birth before 34 weeks of gestation among
asymptomatic women with a short cervix (less
than 15 mm) as seen on ultrasonography.

59
 Is there scientific evidence for
progesterone?

Preterm delivery

Preterm labour

Low birth weight (2,500gr)

0.1 0.3 0.5 1 2 3 4

Émile Papiernik

Keirse, M. Progestogen administration in pregnancy may prevent

preterm delivery?, Br. J. Obstet. Gynaecol., 97: 149-54, 1990.
 Short cervical
length
RCT: Micronized progesterone
(200mg/night) at 24-34 wks

30,517 pregnancies
at 20-25 wks

82%

Accepted
25,050 pregnancies

1.7% Outcome Placeb P4

o
414 short cervix
Delivery before 34 wks
(<15 mm) PTD <34wks: 34% vs 19%
Spontaneous 34.4% 19.2% *
60% All 44% reduction
36.0% 20.8% *
07/29/23 250 randomized 61
Fonseca et al. N Engl J Med. 2007
Effect of Vaginal progesterone & preterm
birth before 33 weeks of gestation

CONCLUSION: Vaginal progesterone administration to

asymptomatic women with a sonographic short cervix
reduces the risk of preterm birth and neonatal morbidity and
mortality.
Romero R et al. Am J Obstet Gynecol 2012
07/29/23 62
07/29/23 63
 management
• A Tocolysis Treatment with tocolytic medications
may not reduce the rate of preterm birth, but it
may delay delivery for 48 hours and reduce the
associated complications. The time gained allows
for transfer to a tertiary center or corticosteroid
administration. Women diagnosed with preterm
labor at less than 34 weeks of gestation should be
hospitalized and consideration given to the use of
tocolytic medications.

07/29/23 64
 The aim of treatment
reduce contractility of uterus with:
• Magnesium sulfate
•Mimetics
• Indomethacin
• Calcium channel blockers -nifedipine
Nifedipine is administered orally, 10 to 20
mg every 8 hours.

07/29/23 65
• Magnesium sulfate for cerebral palsy
prevention. A recent study investigated
the use of magnesium sulfate to prevent
cerebral palsy in women between 24 and
32 weeks’ gestation at imminent
risk for preterm delivery..

07/29/23 66
 Contraindications to tocolitycs
• Severe preeclampsia and eclampsia
• Nonreassuring fetal heart rate
• Significant antepartum bleed
• Clinical chorioamnionitis
Relative contraindications
a. Major fetal anomaly
b. Mild preeclampsia
c. Maternal cardiac disease
07/29/23 67
 Tocolytics and progesterone
Progesterone enhances the tocolytic effect of ritodrine
in isolated pregnant human myometrium

Cumulative effect of natural progesterone Association progesterone and ritodrine

- Natural progesterone reduces the myometrial oxytocin-induced contraction

- Overnight incubation with progesterone significantly inhibited contractility
- Natural progesterone enhances the relaxant action of ritodrine

Source: Chanrachakul et al. Am J Obstet Gynecol. 2005; 192, 350-9

 Combined use of beta-
mimetics & progesterone
• 47 ( -mimetics )
• Gest.age: 30,5 (3,2)
• Ritodrine (100 mg in saline
0,1-0.3 mg/min)
• Del. after 48 h: 87%
• Del. After 7 d: 65%
• 42 (-mimetics + P)
• Gest. age: 30,3 (2,7)
• Ritodrine (50 mg in
saline 0.1-0.3 mg/min) +
P (200 mg die)
• Del. After 48 h: 85%
• Del.after 7 d: 68%
Di Renzo et al., BJOG 2005
 Combined use of beta-
mimetics & progesterone
• -mimetics • -mimetics + P
• Mat. tachicardia : 97% • Mat tachicardia: 42%
• Nausea & vomiting: 28% • Nausea & vomiting: 6%
• Tremblings: 26% • Tremblings: 12%
• Palpitations: 32% • Palpitations: 12%
• Chest pain: 15% • Chest pain: 8%
• Hyperglycemia: 47% • Hyperglycemia: 28%
• Hypokaliemia: 92% • Hypokaliemia: 23%

Di Renzo et al.,BJOG 2005

HARMS?
 Stillbirth / fetal death
• Increased embryolethality noted in animal studies
with 10x the human dose (progesterone) and 1x
the human dose (17 OHP caproate)

• Trend to more antepartum and intrapartum fetal

deaths in the 17 OHP caproate group, in the Meis
study although not significant
– 2% v. 1.3% RR 1.5 (0.31 – 7.34)

• Trend to increased risk of miscarriage before 20

weeks in the 17OHP group 1.5% v 0
 Increased incidence of GDM in women
receiving IM 17 OHP compared with controls

P value OR (95% CI)

Obese BMI ( 30) < 0.001 6.91 (2.93 – 16.28)

Overweight BMI (≥ 25) <0.004 3.70 (1.53 – 8.92)

17 OHP < 0.001 3.09 (2.17 - 4.40)

Rebarber A et al 2007 Diabetes Care 30: 2277

CONCLUSIONS

74
 European Association of Perinatal Medicine
“Study Group on “Preterm birth”

Guidelines for the management

of spontaneous preterm labour
G. C. Di Renzo (Italy)
L. Cabero Roura (Spain)
F. Facchinetti ( Italy)
A. Antsaklis (Greece), C. Sen (Turkey), R. Lamont (UK),
G. Breborowicz (Poland), S.C. Robson (UK), M. Robson (Ireland), A. Shennan (UK), F.
Stamatian ( Romania), A. Mikhailov (Russia), N. Montenegro (Portugal),
E. Gratacos ( Spain) P. Husslein (Austria),Y. Ville (France)
J Perinat Med 2006
75
J Mat Fet Neon Med 2011
 Efficacy of Progesterone in
PREVENTING
Spontaneous Preterm Delivery

Poor Obstetric Hystory

-Previous PTD Socio-demographic
-Recurrent abortion Low education
Poor income
Actual Risk Predictors Teen Age
-Threatened -TVU Cx length Familial hystory
preterm labour -Fibronectin Psycho social stress
-Multiple pregnancy
 Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

NNT: Number Needed to Treat

 Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

Magnesium sulfate Cerebral palsy 0.69 (0.55-0.88) 52 (31-154)

NNT: Number Needed to Treat

 Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

Magnesium sulfate Cerebral palsy 0.69 (0.55-0.88) 52 (31-154)

RDS 0.66 (0.59-0.73) 11 (9-14)

Antenatal
corticosteroids
Neonatal death 0.69 (0.58-0.81) 22 (16-36)

NNT: Number Needed to Treat

 Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

Magnesium sulfate Cerebral palsy 0.69 (0.55-0.88) 52 (31-154)

RDS 0.66 (0.59-0.73) 11 (9-14)

Antenatal
corticosteroids
Neonatal death 0.69 (0.58-0.81) 22 (16-36)

Vaginal progesterone in Preterm birth <33

0.55 (0.33-0.92) 14 (8-87)
short cervix weeks

NNT: Number Needed to Treat

 Comparison with other Interventions in
Perinatal Medicine/Obstetrics

Intervention To prevent: RR (95% CI) NNT (95% CI)

Magnesium sulfate Eclampsia 0.41 (0.29-0.58) 100 (50-100)

Magnesium sulfate Cerebral palsy 0.69 (0.55-0.88) 52 (31-154)

RDS 0.66 (0.59-0.73) 11 (9-14)

Antenatal
corticosteroids
Neonatal death 0.69 (0.58-0.81) 22 (16-36)

Preterm birth <33

0.55 (0.33-0.92) 14 (8-87)
Vaginal progesterone in weeks
short cervix
RDS 0.39 (0.17-0.92) 22 (12-186)

NNT: Number Needed to Treat

 Implications

• Universal risk assessment for preterm

birth with cervical ultrasound

• Vaginal progesterone for women with a

short cervix
– All singleton gestations
– Cervical length < 25 mm
– Low Risk and Prior preterm birth
 Estimated Reduction in Preterm Births
< 35 weeks as a Function
of Cervical Length

short Efficacy
Reduction in
Total births cervix PTB rate** (reduction) with
PTBs < 35 weeks
rate* treatment***
Cx Length

<20mm 4,100,000 5% 0.3 ~0.35 ~21,525

<25mm 4,100,000 10% 0.23 ~0.33 ~31,119

Preliminary estimates based on published work; additional pharmacoeconomic

analyses are required in light of new findings

* Iams et al, New Eng J Med 1996

** Berghella et al, Ob Gyn 2007
*** Romero et al, Am J Obstet Gynecol 2011, and Hassan et al, UOG 2011
MESSAGES

84
 TAKE HOME MESSAGES
• Preterm birth is representing more than
12% of worldwide births
• Rates are increasing due to better
diagnosis, late preterm and new risk
factors
• The continued increase in premature birth
rates is a problem with long term
implications that needs to be addressed
worldwide
 TAKE HOME MESSAGES
• Proper identification of patients at risk
for preterm birth is essential
• Take into consideration new risk factors
( age, PMA, fetal sex, psychosocial
stress, previous cesarean section etc)
• fFN and cervical US measurement are
best tests for identifying the patient at
real risk
 TAKE HOME MESSAGES
• The physio-pharmachologic activities of P4
may explain the preventive actions on
preterm birth in different high risk settings
• In asymptomatic women with previous PTB,
or with short cervical length at mid gestation
or after an acute episode of threatened
preterm labor, natural Progesterone ( and
also 17 OHP but with concerns on safety)
may reduce by 50% the chance of PTB
• Born too soon is the latest contribution to the
UN Secretary General’s Global Strategy for
Women’s and Children’s Health, which aims to
save 16 million lives by 2015.

29/07/23 88
• We know what to do. And we all have a role to
play. Let us act on the findings and
recommendations of this report. Let us change
the future for millions of babies born too soon,
for their mothers and families, and indeed for
entire countries. Enabling infants to survive
and thrive is an imperative for building the
future we want.

Ban Ki-moon, UN, 2012

29/07/23 89
29/07/23 90
Thank you!