clinical pearls in management of high risk pregnancy

1. Dr. Meenakshi Sharma
MBBS, MD (AIIMS), FICMCH
Specialist Obs & Gynae
Dr. Hedgewar Arogya Sansthan
2013

2.  Prepares endometrium for blastocyst implantation
 Maintenance of early pregnancy
 Immunomodulating effect of progesterone prevents
fetal rejection
 Progesterone induced blocking factor (PIBF) induces
Th2- dominant cytokine response which favours
pregnancy
 Regulates HLA-G expression and NK cell activity
promote normal gestation
Role of Progesterone in
pathophysiology

3. Progesterone – preparation, route
and dosage
 Natural progesterone preferred
 Parentral
 17 alpha-hydroxyprogesterone caproate (Wkly IM inj 25-
1000 mg)
 IM Progesterone
 Vaginal
 Intravaginal progesterone gel 90–100 mg
 Natural micronised progesterone -Vaginal pessary 200-
400 mg daily - bypass first pass effect
 Oral – not well investigated, poor bioavailability

5. Recurrent Miscarriage
 10-15% of all clinically recognized pregnancies end in
miscarriage
Regan 1989
 1% to 2% of couples suffering recurrent early losses
Coulam 1991
 True incidence of early spontaneous miscarriage may
be much higher
 Grudzinskas 1995, Howie 1995, Simpson 1991
 Miscarriage is an important cause of morbidity and
mortality, especially in low-income countries
Neilson 2006

6. Progesterone in preventing
miscarriage
 15 trials, 2118 women
 Metaanalysis of all women irrespective of
gravidity/ parity or no. of prev miscarriage
 No significant difference in risk of miscarriage
b/w progesterone and placebo or no treatment-
OR 0.98, 95% CI 0.78-1.24
 No diff in incidence of adverse effect
Haas DM, Cochrane, 2008

7. Progesterone in preventing
miscarriage
 Subgroup analysis – 3 trials of women with
recurrent miscarriage
 statistically significant decrease in miscarriage
rate with progesterone compared to placebo or
no treatment (OR 0.38, 95% CI 0.20-0.70)
 No difference in route of Progesterone
oral/IM/vaginal vs placebo or no treatment
Haas DM, Cochrane, 2008

8. Progesterone for preventing
Miscarriage
 WHO Update Review of Cochrane 2008 with new data
from a trial (EL-Zibdeh, 2005)
 180 women with RM were randomized to receive oral
dydrogesterone, I/M hCG or no treatment
 No statistically significant difference in the risk of
miscarriage between groups receiving a progestogen or a
placebo/no treatment [Peto odds ratio (Peto OR) 0.98; 95%
confidence interval (CI) 0.78–1.24].
 The route of administration of progestogen (oral,
intramuscular, or vaginal) appeared not to be associated
with a statistically significant difference in miscarriage
rates.
Thach TS, WHO 2009

9.  There is insufficient evidence to evaluate the
effect of progesterone supplementation in
pregnancy to prevent a miscarriage in
women with recurrent miscarriage. Level B
RCOG, 2011
 Insufficient evidence to recommend
progesterone for treatment of recurrent
miscarriage
ACOG, 2002
Progesterone treatment of RM

10. Progesterone for treatment of
Threatened Miscarriage
 4 RCT (n-421) included in metaanalysis
 Reduction in the rate of spontaneous miscarriage with the
use of progestogens compared to placebo or no treatment
(RR 0.53; 95% CI 0.35 to 0.79).
 No increase in the rate of APH (RR 0.76; 95% CI 0.30 to
1.94), or PIH (RR 1.00; 95% CI 0.54 to 1.88) for the mother.
 The rate of congenital abnormalities was not increased RR
0.70; 95% CI 0.10 to 4.82).
 Conclusion- Scarce Data, Methodological poor trials limit
power of metaanalysis
Wahabi HA,Cochrane, 2011

12. Burden of preterm pregnancy
 3 million newborns die each year due to complications
related to pregnancy and childbirth
 Preterm birth is a leading cause of neonatal and infant
mortality as well as short- and long-term disability.
 Rates for preterm birth range between 6% and 12% in
developed countries and are generally higher in
developing countries.
 About 40% of all preterm births occur before 34 weeks
and 20% before 32 weeks.
 The contribution of these preterm births to overall
perinatal morbidity and mortality is more than 50%
World Health Organization 2007

13. Progesterone and preterm delivery
 P suppresses the myometrial contraction by inibibiting
estrogen in myometrium by replacement of cytosolic
estrogen receptors.
 Progesterone antagonises nuclear factors activation of
COX-2 induced contractility in uterus
 It also has direct action of myometrial receptors
 Modulate gene expression in cervix both in presence
and absence of inflammation
 Blocks type 1 collagen degradation in dilated cervix
Xu H, AJOG, 2008

14. Prenatal administration of progesterone for preventing
preterm birth in women considered to be at risk of preterm
birth Cochrane, 2013
 36, RCT- 8523 women and 12,515 infants
 Objective
 To assess the benefits and harms of progesterone for the
prevention of preterm birth for women considered to be
at increased risk of preterm birth and their infants.
 Two review authors independently evaluated trials for
methodological quality and extracted data.
Dodd JM, Cochrane, 2013

15. Use of progesterone in women with a history of
prior spontaneous preterm birth(Cochrane 2013)
 11 studies- 1936 women with a past history of
spontaneous preterm birth
 4 studies - weekly im inj with placebo
 5 studies - daily vaginal progesterone, 3 with
placebo and 2 with routine care
 2 studies - daily oral progesterone with placebo
Dodd JM, Cochrane, 2013

16. Use of progesterone in women with a history of
prior spontaneous preterm birth(Cochrane 2013)
 Statistically significant reduction in
 preterm birth less than 34 weeks (5 studies; 602 women;
RR 0.31, 95% CI 0.14 to 0.69)
 preterm birth less than 37 weeks (10 studies; 1750
women; average RR 0.55, 95% CI 0.42 to 0.74)
 perinatal mortality (6 studies; 1453 women; RR 0.50,
95% CI 0.33 to 0.75)
 Infant birthweight less than 2500 g (4 studies; 692
infants; RR 0.58, 95% CI 0.42 to 0.79)
Dodd JM, Cochrane, 2013

17. Progesterone use in women with a short
cervix on vaginal ultrasound
 Systematic review and metaanalysis of 5 trials -775 women and 827
infants
 Treatment with vaginal progesterone- significant reduction in the rate
of preterm birth
 <33 weeks (RR 0.58; 95% CI 0.42-0.80),
 <35 weeks (RR, 0.69; 95% CI, 0.55-0.88),
 <28 weeks (RR, 0.50; 95% CI, 0.30-0.81)
 Significant reduction in RDS, composite neonatal morbidity and
mortality, birthweight <1500 g, admission to NICU, requirement for
mechanical ventilation
 There were no significant differences between the vaginal
progesterone and placebo groups in the rate of adverse maternal
events or congenital anomalies.
Romero R, AJOG 2012

18. Progesterone v/s placebo for women with
a short cervix identified on ultrasound
 4 studies- 1560 women
 2 studies -i/m progesterone wkly/ biwkly,
 2 studies – daily vaginal progesterone
 Statistically significant reduction in the risk of
 Preterm birth less than 34 weeks (2 studies; 438 women; RR 0.64,
95% CI 0.45 to 0.90),
 Preterm birth at less than 28 weeks’ gestation (2 studies; 1115
women; RR 0.59, 95% CI 0.37 to 0.93)
 Increased risk of urticaria in women when compared with placebo
(one study; 654 women; RR 5.03, 95% CI 1.11 to 22.78)
 It was not possible to assess the effect of route of progesterone
administration, gestational age at commencing therapy, or total
cumulative dose of medication.
Dodd JM, Cochrane, 2013

19. Progesterone in women with threatened preterm
labour (cochrane 2009)
 Two studies, 130 pregnant women between 24 -35
weeks with Th PTL
 Progesterone 400 mg daily intravaginal pessary v/s
placebo, or 300 mg every 4 days until 36 weeks or
until delivery.
 Progesterone was associated with a significant
reduction in
 Preterm birth at <37 weeks (RR 0.29; 95% CI 0.12–0.69)
 Low birth weight <2500 g (RR 0.52; 95% CI 0.28–0.98)
 Respiratory distress syndrome (RR 0.30; 95% CI 0.11–0.83)

20. Progesterone versus no treatment/placebo for
women following presentation with threatened
preterm labour
 5 small studies- 384 women
 No statistically significant differences identified when
compared with placebo in preterm birth before 34 wks
and perinatal death
 Progesterone, was associated with a statistically
significant reduction in the risk of infant birthweight
less than 2500 g (1 study; 70 infants; RR 0.52, 95% CI
0.28 to 0.98).
Dodd JM, Cochrane, 2013

21. Progesterone in women at risk of preterm birth
for other reasons (cochrane 2009)
 Two studies,267 patients
 Inclusion criteria:
 A high preterm risk score or a condition of an active
military service
 250 mg or 1000 mg of 17 alpha-hydroxyprogesterone
caproate x3 per week or weekly IM were compared with
placebo between 20 wks to 36 wks.
 Progesterone was not associated with significant
differences for the outcomes

22. Progesterone versus placebo for women with
‘other’ risk factors for preterm birth
 3 studies- 482 women
 1 trial-99 women with high preterm score
 1 trial- 168 women in active millitary service
 1 trial 313 women concieved after IVF/ICSI,(91 twins analysed
separately
 No statistically significant differences identified when
compared with placebo in preterm birth before 34 wks and
perinatal death
 Progesterone, was associated with a statistically significant
reduction in the risk of infant birthweight less than 2500 g
(3 studies; 482 infants; RR 0.48, 95% CI 0.25 to 0.91).
Dodd JM, Cochrane, 2013

23. Vaginal progesterone v/s Cerclage in prevention
of preterm birth in high risk pregnancy
 Systematic review and indirect comparison metaanalysis
 4trials - vaginal progesterone v/s placebo (158 patients)
 5 trials- cerclage v/s no cerclage (504 patients)
 Both result in significant reduction in the
 Risk of preterm birth <32 weeks of gestation (RR 0.47, 95% CI
0.24–0.91 for vaginal progesterone and RR 0.66, 95% CI 0.48–
0.91 for cerclage)
 Composite perinatal morbidity and mortality (RR 0.43, 95%
CI 0.20–0.94 for vaginal progesterone and RR 0.64, 95% CI
0.45–0.91 for cerclage) when compared with placebo and no
cerclage
AJOG 2013, 208(1), 42e1-42e18

24. Vaginal progesterone v/s Cerclage in prevention
of preterm birth in high risk pregnancy
 Adjusted indirect meta-analyses did not show statistically
significant differences between vaginal progesterone and
cerclage in reducing preterm birth or adverse perinatal
outcomes.
 NNT with vaginal progesterone rather than with placebo to
prevent one case of preterm birth <32 weeks of gestation or
composite perinatal morbidity/mortality was 7 (95% CI, 5–
38 for preterm birth < 32 weeks of gestation and 5–69 for
composite perinatal morbidity/mortality).
 The corresponding NNTs for cerclage were 10 (95% CI, 7–
38) and 11 (95% CI, 7–45), respectively.
AJOG 2013, 208(1), 42e1-42e18

26. Progesterone in women with a multiple pregnancy
(cochrane 2009)
 Two studies, 738 pregnant women with twin pregnancy
 Doses of progesterone were 250 mg weekly IM,
starting at 16–20 or at 28 weeks to 35–37 weeks.
 Progesterone was associated with a significant
reduction in risk of tocolysis
 RR 0.75; 95% CI 0.57, 0.97
 No significant differences were observed for primary
outcomes.

27. Progesterone for prevention of preterm birth in twin
pregnancy (STOPPIT)
 A randomized, double-blind, placebo-controlled study and
meta-analysis – 500 women with twins
 Daily use of 90 mg of a vaginal progesterone gel or placebo z
 Results: Combined proportion of IUD or delivery before 34 wks
of pregnancy
 Progesterone group 24.7% (61/247)
 Placebo group 19.4% (48/247) (OR 1.36, 95% CI 0.89-2.09; p=0.16).
 rate of adverse events: Similar in both groups
 Meta-analysis confirmed that progesterone does not prevent
early preterm birth in women with twin pregnancy (pooled OR
1.16, 95% CI 0.89-1.51
Norman J, Lancet 2009; 373: 2034-2040

28. Vaginal micronized progesterone and risk
of preterm delivery in high-risk twin
pregnancy
 Placebo-controlled randomized trial and meta-analysis
(PREDICT Group)
 72 of 677 women in PREDICT study with high-risk twin
pregnancies
 Short cervical length ≤10th centile at 20–24 weeks’ gestation
in the current pregnancy
 History of either spontaneous delivery before 34 weeks or
miscarriage after 12 weeks
 Mean gestational age at delivery did not differ significantly
between the two groups either in patients with a short
cervix (34.3 vs 34.5 weeks p 0.87) or in women with prior
preterm delivery (34.6 vs 34.5 weeks p 0.62)
K. KLEIN Ultrasound Obstet Gynecol 2011; 38: 281–287

29. Vaginal micronized progesterone and risk
of preterm delivery in high-risk twin
pregnancy
 Metaanalysis with 2 previous studies – 123 women with
high risk twin pregnancies
 No significant effect of progesterone on the risk of preterm
delivery was shown (pooled OR, 1.07 (95% CI, 0.52–2.19)
 In conclusion, prophylactic use of progesterone in highrisk
twin pregnancies does not have a significant effect on the
rate of preterm delivery, perinatal outcome or long term
development of the infants and consequently there is no
justification for such treatment.
K. KLEIN Ultrasound Obstet Gynecol 2011; 38: 281–287

30. Progesterone versus placebo for women
with a multiple pregnancy (Cochrane 2013)
 10 studies -3395 women
 No statistically significant differences identified when
compared with placebo in primary outcomes perinatal
death and preterm birth less than 34 weeks’ gestation
 Progesterone was associated with no statistically
significant differences for the risk of birth before 37, or
28 weeks, infant birthweight less than 2500 g, Apgar
score less than seven at five minutes, RDS, Ventilation,
IVH
 Heterogenity of Data

31. Progesterone for Triplet pregnancy
 Placebo controlled RCT, 14 centers.
 134 Healthy women with triplets were randomized to either
 17 alpha-hydroxyprogesterone caproate (Wkly IM inj 250 mg)
(n=71
 Matching placebo, starting at 16-20 weeks and ending at
delivery or 35 weeks (n=61)
 Primary study outcome : Delivery or fetal loss before 35
weeks.
 A composite of delivery or fetal loss before 35 0/7 weeks: Similar
 83% of pregnancies in progesterone group and
 84% in the placebo group,
 Relative risk 1.0, 95% confidence interval 0.9-1.1.
 Rx with 17 alpha-OH-progesterone caproate did not reduce
the rate of preterm birth in women with triplet gestations.
Caritis et al, Obstrics and Gynecology 2009

32. American College of Obstetrics & Gynecology (2008)
 Use of antenatal progesterone to prevent preterm
birth should be restricted to
 Women with a documented history of prior
spontaneous preterm delivery at less than 37 weeks
 Women incidentally (i.e. without routine screening)
found to have a short cervix (less than 15 mm)
 Progesterone should be used with caution on a case-by-
case basis.

33. Applicability of the results
 Useful in the following situation:
 In women with a singleton pregnancy & history of
previous preterm delivery, antenatal administration of
progesterone reduces risk of preterm labour before 37 wks
and 34 weeks.
 Reduces the risk of a newborn being born with a LBW <
2500 g.
 Progesterone use can also be recommended for pregnant
women who are found incidentally to have a short cervix.
 Not useful in
 However, current data do not support the use of
progesterone in women with multiple pregnancies.

34. Future research
 To study the effectiveness of antenatal progesterone in
women in whom the symptoms (contractions) or
specific conditions (short cervix, premature rupture of
membranes) started for the first time in the current
pregnancy.
 Optimal dose, timing and route of administration of
progesterone.
 Larger randomized controlled trials are required to
determine if antenatal administration of progesterone
reduces perinatal mortality and long-term serious
neonatal and child morbidity.

36. Implications for practice (prior
spont Preterm Birth)
 The use of progesterone is associated with a reduction in
the risk of perinatal death, preterm birth before 34 wks’
and 37 wks’ gestation, infant birthweight less than 2500 g,
use of assisted ventilation, NEC, neonatal death, admission
to NICU, and prolongation of pregnancy.
 There is limited information about longer-term childhood
health.
 Further information is required as to the optimal route of
administration of progesterone, the optimal dose to be
administered, and the best time to commence therapy.

37. Implications for Practice (short
cervix)
 The use of progesterone is associated with a reduction in
the risk of preterm birth less than 34 and 28 weeks’
gestation, and a significant increase in the risk urticaria in
women receiving progesterone.
 Further information is required about other maternal,
infant and childhood health outcomes.
 No comparative data reported on long term childhood
health from trials conducted to date.
 Further information is required as to the optimal route of
administration of progesterone, the optimal dose to be
administered, and the best time to commence therapy.

38. Implications for Practice (Th
Preterm labor)
 The use of progesterone was associated with a
statistically significant reduction in the risk of infant
birthweight less than 2500 g. However, for all other
outcomes, the role of progesterone for women
presenting following symptoms or signs of threatened
preterm labour is uncertain.

39. Implications for Practice (at other
risk Preterm Labour)
 The use of progesterone was associated with a
statistically significant reduction in the risk of infant
birthweight less than 2500 g. However, for all other
outcomes, the role of progesterone in women
considered to be at risk of preterm birth for ’other
reasons’ is uncertain.

40. Implications for Practice (Multiple
Pregnancy)
 The use of progesterone in this group of women is not
associated with any statistically significant differences
in perinatal death, preterm birth and other maternal,
infant, and childhood health outcomes.