Updates in Preterm Birth Prevention

Check out reading for this episode: PB 234

Our last podcast on preterm birth prevention was 2 years ago in November 2019, right after the PROLONG trial was published… and there have been some major guideline changes! We’ll do prevention of preterm birth redux today, going over everything once again to provide the most up-to-date summarization of ACOG’s recommendations..

Also important: we still have podcasts on assessing/managing preterm labor where nothing has really changed! Be sure to check that out as an important CREOG topic!

Why care about preterm birth?

• Exceedingly common: 10.2% of newborns in the USA are born prematurely.

  • PTB accounts for 75% of perinatal mortality and >50% of long-term neonatal morbidity (and associated costs)

• Preterm birth rates are actually increasing in the USA:

  • Had decreased from 2007-2014, but as of 2019 had increased back to 10.2%

    • Driven primarily by increase in late preterm birth (34-36 wks)

    • Rates of early preterm birth  (less than 34wk)  largely unchanged since 2014 (2.8%)

• Preterm birth rates are disparate amongst racial/ethnic groups:

  • White women: 9.3% rate of PTB, vs Hispanic 10%, non-Hispanic Black 14.4%, AI/AN 11.5%, Hawaiian/PI 11.8%. 

    • Non-Hispanic Black women also have a disproportionately higher rate of < 34wk PTB (4.9% vs 2.7% overall rate)

• Preterm birth is not just spontaneous preterm birth:

  • 50% follow preterm labor

  • 25% follow PPROM

  • 25% are intentional, medically-indicated PTB for maternal or fetal indications

Risk factors for PTB

• Clinical

  • Prior history: prior spontaneous preterm birth <34 weeks has about a 35% recurrence risk!

    • Number of prior PTBs (more) and degree of prematurity (earlier) significantly affect this risk

    • Preterm birth followed by term birth → risk lowers

    • Twin preterm birth → still higher risk for preterm birth in subsequent singleton gestation, and as high as 40% if twins born before 30 weeks!

  • Bacterial vaginosis: 2x increased risk of spontaneous PTB, more strongly associated in early pregnancy. 

    • Treatment has not been demonstrated consistently to reduce PTB risk though.

  • UTIs in pregnancy: conflicting results based on Cochrane reviews examining risk with asymptomatic bacteriuria or symptomatic UTIs and preterm birth risk

    • However still prudent to treat - risk of pyelonephritis → sepsis, which definitely increases risk.

  • Periodontal disease: conflicting results of risk and association

  • History of prior D&C: slightly increased risk in 21-study meta-analysis of 2 million women (OR 1.29), though mechanism is uncertain. Risk slightly increased with history of multiple D&C (OR 1.74).

  • Multiple gestation: Preterm birth rate in twins of 60.3%, with 19.5% born before 34 weeks.

    • Triplets born preterm 98.3% of time, with 82.6% born before 34 weeks.

  • Short cervical length: a transvaginal short cervical length under 25mm between 16-24 weeks is associated with higher risk of PTB in a variety of screened populations.

  • History of cervical conization: inconsistent data regarding risk, though likely pronounced risk if short interval from conization-to-conception or excision greater than 15mm deep. 

• Other modifiable risks:

  • Tobacco use: likely due to vasoconstriction, hypoxic-ischemic pathways

  • Low maternal pre-pregnancy weight: BMI < 18.5

  • Interpregnancy interval < 18 months: some association in observational studies

  • Unintended pregnancy

    • Importantly for these last two, some observational data points to increased access to LARC and family planning services is associated with lower rate of preterm birth.

• What about race?

  • As we’ve discussed on the show before: race as a risk factor needs to be studied further -- a social, not a biological construct

  • Chronic stress related to exposure to racism is a potential explanation

  • Social and economic disadvantage are persistently associated with increased risk of preterm birth, with some factors including:

    • Lower educational attainment

    • Residence in ZIP code/region/states with economic disadvantage

    • Lack of access to prenatal care

  • More work is needed in evaluating and exploring these mechanisms, and more work is desperately needed in evaluating ways to correct inequity 

Screening Strategies: Identifying Patients who may Benefit from Interventions:

• Lots of things that have been tried:

  • Fetal fibronectin assay: in asymptomatic patient, has not been shown to be helpful given low PPV.

  • Home uterine contraction monitors

  • Ongoing research into biomarkers, microbiome research, cervical texture, genetic associations…

• Best and most important screening strategy we have: transvaginal cervical length screening in the 2nd trimester (16-24 weeks)

  • TVCL beyond 24 weeks is less predictive overall.

• Recommendation for universal assessment of cervix at the time of anatomy ultrasound, with TVUS then performed if suspicious:

  • TAUS under 36mm identifies 96% of patients with TVCL under 25mm, and 100% of patients with TVCL of 20mm or less.

    • This universal assessment of length outright with TVCL is debated, though the cervix should at least be visualized to assess for previa, and a TACL is a reasonable 1st screen.

• What cervical lengths are important to remember?

  • Compared to old guidelines, ACOG simplifies things in this document. There are two primary lengths to remember (both transvaginally assessed):

    • 25mm 

    • 10mm

  • Then, there are a few major interventions that can be considered:

    • Progesterone, either vaginal or intramuscular (17-OHP)

    • Cerclage

    • Pessary

  • The recommendations and intervention options vary by the history/clinical scenario of the patient (summarized in the table from the PB), so let’s review from there!

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ACOG PB 234

Singleton Pregnancy with No Prior History of Preterm Birth:

• Shortened cervix under 25 mm:

  • Vaginal progesterone

    • Dosing: 200mg micronized, from time of dx until 34-37 weeks gestation (Varies by trial)

    • Effects:

      • Multiple trials demonstrating lowered risk of early preterm birth (less than 34 weeks) by approximately 50%.

      • OPPTIMUM meta-analysis of progesterone demonstrated vagP reduced risk of spontaneous preterm birth prior to 34 weeks by about 40%, with an NNT of 14 patients to prevent one sPTB before 34 weeks.

  • Intramuscular progesterone

    • Dosing: 500mg weekly IM

    • Effects:

      • Very few trials on this in this population (singleton, no PTB history)

      • The few direct trials of this that exist generally have not found benefit

      • Not recommended in this population.

  • Exam-indicated cerclage

    • Identified painless cervical dilation prior to 24 weeks

    • Effects:

      • Associated with pregnancy prolongation by approximately 34 days and increased neonatal survival in a meta-analysis of multiple study types → thus recommended practice if truly painless cervical dilation.

    • Technique notes:

      • Amniocentesis to assess for infection pre-procedure: 

        • limited data, no RCT described in bulletin. Retrospective data colored by amnio-performance was tied to more severe cases. 

      • Antibiotic and tocolytic use:

        • RCT of periop abx + indomethacin demonstrated improved pregnancy lengths in rescue cerclages receiving medications, but no difference in neonatal outcomes overall (good or bad) → reasonable to consider

    • Contraindications:

      • PPROM

      • Suspected infection

      • Preterm labor or active bleeding

      • Fetal demise or anomaly incompatible with life

  • Ultrasound-indicated cerclage

    • Cervical shortening without dilation prior to 24 weeks.

    • Prior ACOG recommendation: cerclage not indicated in this population (only rescue cerclage was indicated without history of PTB)

    • NEW ACOG recommendation: possibly of benefit with extreme cervical shortening < 10mm

      • Based on a subgroup analysis of 126 patients in a meta-analysis of 5 RCTs. 

        • CL < 25mm - cerclage did not reduce risk of PTB <34wk

        • CL < 10mm - cerclage reduced risk of PTB <35 weeks (39.5% vs 58%). 

      • Importantly -- none of these patients were on vaginal progesterone, nor are there trials comparing vagP to cerclage in this population, or their combined effect.

  • Pessary

    • Cervical pessaries can compress, elevate, and posteriorly rotate the cervix.

    • Trials overall have not demonstrated effectiveness of pessary in those with short cervix without prior history of PTB, alone or in combination with vaginal progesterone.

Singleton Pregnancy in Patient with Prior Spontaneous Preterm Birth

• Cervical Length Screening

  • In addition to the usual screen, in patients with prior PTB history, serial cervical length assessment has been studied:

    • A TVCL under 25mm before 24 weeks had a sensitivity of 65% for PTB under 35 weeks; PPV 33%, NPV 92%. However, sensitivity and PPV is similar for just risk factor of prior PTB.

    • Many studies have assessed utility of cervical length screening, without definitive data to guide frequency/schedule of assessment.

    • Most protocols will perform screening starting at 16 weeks and repeat q1-4 weeks through 24 weeks.

      • Because treatment is available for short cervix (US-indicated cerclage, we’ll get to that in a minute!), even with absence of superb data, serial screening is reasonable to perform.

• IM Progesterone

  • We talked about this controversy on our previous podcast with the Meis trial and the PROLONG trial. 

    • Meis trial: RCT 463 patients, IM progesterone vs placebo. Reduced risk of PTB before 35 weeks by about 33% (20.6% vs 30.7%). Overall considered to be a higher risk population than the PROLONG trial, which came later.

    • PROLONG trial: RCT 1740 patients, no difference in PTB before 35 wks (11% vs 11.5%) or neonatal outcomes.

  • SQ progesterone is also available, but there is no direct evidence to support its efficacy vs IM or other formulations. 

  • In the interim, ACOG and SMFM have released statements supporting shared decision-making and patient preference in using progesterone supplementation (IM or vaginal), given the mixed evidence.

• Vaginal Progesterone

  • Vs placebo:

    • 3 blinded RCTs demonstrate no benefit in reducing recurrent PTB.

    • 5 trial meta-analysis lookig at vagP for use in short cervix with sPTB history demonstrated a reduction of preterm birth by about 40%. 

  • Vs 17-P:

    • Meta-analysis of 3 trials comparing 17-P to vag P demonstrated patients receiving vagP had lower risk of PTB before 34 weeks, though the trials were not blinded and excluded patients with short cervix. 

    • Meta-analysis of multiple progesterone supplementation strategies suggested more robust evidence for BagP in preventing PTB prior to 34 weeks

      • Including largely heterogenous trials with a variety of risk factors present, somewhat limiting outright applicability.

• History-Indicated Cerclage

  • Indicated in those with prior spontaneous preterm birth due to painless cervical dilation in the 2nd trimester without identified etiology (i.e., abruption), or in those who have had cerclages in prior pregnancy

  • Can be placed in early 2nd trimester with good effect.

• Ultrasound-Indicated cerclage

  • Five-trial meta-analysis demonstrates that in those with prior sPTB and TVCL <25mm prior to 24 weeks, cerclage reduces the rate of PTB by about 35% (28% vs 41%). 

    • Unknown if progesterone supplementation may augment this effect at all, and there are no trials comparing cerclage to vaginal progesterone vs cerclage in this population.

    • There are ways to do indirect comparisons between trials, and when this is performed the effect size observed seemed to be similar between vagP and cerclage. 

      • Thus, ACOG states that cerclage or vagP are acceptable options in those with prior sPTB and short cervix, and states that cerclage may be offered in addition to continuation of progesterone.

• Pessary

  • Evidence has not demonstrated any efficacy of pessary alone.

Multifetal Gestations

• Cervical Length Screening

  • Multifetal pregnancies will generally have a shorter cervical length in the 2nd trimester, but the short cervix remains an effective predictor of early preterm birth:

    • TVUS < 25 mm at 20-24wks had PPV of 75.5% for delivery prior to 37 weeks, and 25.8% for delivery before 28 weeks. 

    • TVUS < 20 mm had PPV of 61.9% before 34 weeks in a separate analysis. 

  • There are not a lot of data regarding screening, and as you’ll see, less consensus regarding effectiveness of intervention in twin pregnancies; thus, serial screening is not necessarily recommended. 

  • A single screen at the anatomy scan should still be performed at minimum, as it is with singleton gestations without prior history.

• IM Progesterone

  • Trial of 661 twin pregnancies of placebo vs 17-P demonstrated no benefit; a Cochrane review of randomized trials actually found slight increase in risk of PTB before 34 weeks with 17-P (though no difference in perinatal outcomes)

  • In those with prior sPTB and subsequent twin pregnancy, 66 patient trial showed less delivery prior to 34 weeks (20.6% vs 46.9%), but mean gestational length didn’t differ, and no significant difference in neonatal outcomes.

    • Bottom line: can consider in those with prior history of sPTB, not for use in those without sPTB history (same as singletons)

• Vaginal Progesterone

  • Outright use - not recommended:

    • Cochrane review: no difference in rates of PTB before 34 weeks, perinatal death, NICU admission, or respiratory distress vs placebo.

    • Two other meta-analyses with similar conclusions, and an RCT subsequent to these meta-analyses demonstrated no difference.

  • Short cervix - could be considered, but insufficient data to make recommendation:

    • Six RCTs with different doses/compounds, but when analyzed together, demonstrates likely reduction in PTB risk prior to 33 weeks with vaginal progesterone.

    • Diffferent meta-analyses have not found a significant difference.

• Cerclage

  • Prophylactic (i.e., place in a cerclage without other risk factors than multiple gestations) -- no evidence to suggest benefit.

  • Ultrasound-indicated

    • Insufficient data to recommend at this time, though trials that exist overall are small and have not found significant benefit, though at least one meta-analysis has shown potential benefit if cervical length is <15mm. 

  • Exam-indicated/”Rescue” cerclage

    • New RCT (2020) of twin gestations with asymptomatic cervical dilation between 16’0 and 23’6 demonstrated reduced risk of PTB before a variety of cut points (24/28/32/34) in patients receiving rescue cerclage vs no cerclage

    • Small trial, but based on limited data, there may be some benefit -- so could consider! Major practice change!

• Pessary

  • Two RCTs looked at prophylactic pessary, and a third looking at pessary for short cervix, did not find benefit. 

  • Many other trials are limited by power and methodology in this space, but generally also have not found benefit.

  • Overall, pessary is not recommended in higher order gestation.

Does activity restriction reduce PTB risk?

• Super common question, and one that this update in the PB directly addresses:

  • RCT of 165 pregnant persons found no relationship between coitus and risk for recurrent PTB

  • Secondary analysis of 17-P RCT for short cervix demonstrated PTB at less than 37 weeks was more common among pts who were placed on an activity restriction, and after controlling for confounders PTB remained more common in those placed on restrictions.

    • Thus, based on available data, activity restriction is not recommended.

Summary:

• Singleton pregnancies without history of PTB:

  • CL screening: visualize at anatomy scan, TVUS if suspected to be short

  • 17-P: not indicated

  • Vag P: indicated if TVCL is <25mm

  • Cerclage: possibly indicated, more strong evidence if TVCL < 10mm; OR can be used for “rescue” with dilated cervix (painless)

• Singleton pregnancies with history of sPTB:

  • CL screening: consider serial length screening from 16-24 weeks

  • 17-P: can be considered

  • Vag P: can be considered, may be of stronger benefit if short cervix identified

  • Cerclage:

    • History-indicated: if prior cerclage, or history of painless cervical dilation leading to loss in prior pregnancy 

    • US-indicated: if TVCL < 25mm, can consider this versus vaginal P

    • Rescue: still available

• Multiples:

  • CL screening: same as singleton: at least visualize at anatomy scan

  • 17-P: Not indicated, unless prior history of sPTB

  • Vag P: not indicated, unless short cervix identified

  • Cerclage:

    • US-indicated: limited inconclusive evidence

    • Rescue: can consider → major practice change!