Case 1 Previous spontaneous PTD at 31 weeks
MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?
Cervical length measurement narrows in on risk
The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome7) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.8 To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.9 Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.
Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.10 Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.11 Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.12 Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.
Case 1 Continued
MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?
The value of vaginal progesterone
There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.13 Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.13
The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.14 In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,15 daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.16 It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. 17
After evaluating the data from the largest available study of vaginal progesterone,18 the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.19 At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.
Continue to: Case 1 Continued...