Vaginal Progesterone in Twins: No Neurodevelopmental Signal at 6-9 Years
A blinded follow-up of a three-arm randomized trial found no effect of 200 or 400 mg/day vaginal progesterone on behavior or cognition in 206 dichorionic twins aged 6 to 9.
Click the figure to open it full size.
Summary
Vaginal progesterone reduces preterm birth in twin gestations with a short cervix, but its long-term effects on child neurodevelopment have rarely been studied beyond early childhood. Perales and colleagues re-examined the surviving children of a multicenter, double-blind randomized trial that had compared placebo with vaginal progesterone 200 mg/day and 400 mg/day, administered from 20 to 34 weeks. At ages 6 to 9, behavior was assessed with the Child Behavior Checklist (CBCL/6-18) and non-verbal reasoning with Raven's Colored Progressive Matrices, by a psychiatrist blinded to the original allocation.
The follow-up included 206 children of 104 mothers (35.4% of the original 294 women): 75 exposed to 200 mg/day, 63 to 400 mg/day, and 68 to placebo. There were no significant differences from placebo in any of the 11 CBCL syndrome scales or the CBCL total score (34.6 placebo vs 31.1 at 200 mg/day, P=0.38, and 37.5 at 400 mg/day, P=0.54). Raven percentiles were marginally, non-significantly higher in the progesterone arms (59.4 placebo vs 63.1 and 60.4; P=0.44 and 0.85). No dose-response was detected and results did not differ by child sex.
The clinically significant behavior rate (CBCL T-score >=64) was similar for placebo and 200 mg/day (16.2% vs 14.7%) but numerically higher at 400 mg/day (23.8%, P=0.28 vs placebo) - not significant, though the sample is too small to exclude it. The 200 mg/day subgroup also showed a lower gestational age at birth than placebo (35.3 vs 36.5 weeks, P=0.002). The authors acknowledge the study may be underpowered and frame the result as reassuring rather than definitive.
Clinical bottom line
- This is a follow-up of a randomized trial, not a fresh RCT, and retained only 35.4% of the original cohort (104 of 294 mothers); the authors explicitly note possible inadequate statistical power.
- The primary outcomes were null: no significant placebo-versus-progesterone difference in CBCL behavior scores or Raven cognitive percentiles at either dose, in both sexes, with no dose-response.
- A non-significant numerical excess of clinically significant behavior scores at 400 mg/day (23.8% vs 16.2%) cannot be excluded at this sample size and warrants cautious interpretation rather than dismissal.
- Behavior was parent-reported (CBCL) and paternal age, parental psychopathology, and socioeconomic status were unmeasured confounders; findings apply only to dichorionic twins at these doses and timing.
- The result is consistent with two prior twin follow-ups (STOPPIT and PREDICT), and is best read as no evidence of neurodevelopmental harm to age 9 rather than proof of none.
Key references
- Perales A, Avino J, Diaz-Martinez A, Conde-Agudelo A, Romero R, Rojo L, et al. Prenatal exposure to vaginal progesterone for the prevention of preterm birth is not associated with abnormal psychopathological and cognitive profiles in dichorionic twins at 6 to 9 years of age: a follow-up study of a randomized controlled trial. Am J Obstet Gynecol. 2025;233(4):313.e1-313.e12.Primary source. All figures in this infographic are taken from this paper.doi:10.1016/j.ajog.2025.04.056 →
- Serra V, Perales A, Meseguer J, et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial. BJOG. 2013;120(1):50-7.The original three-arm randomized trial that this study follows up.doi:10.1111/j.1471-0528.2012.03448.x →
- McNamara HC, Wood R, Chalmers J, et al. STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome. PLoS One. 2015;10(4):e0122341.Prior twin follow-up (STOPPIT) with concordant no-harm findings at 3-6 years.doi:10.1371/journal.pone.0122341 →
- Vedel C, Larsen H, Holmskov A, et al. Long-term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age. Ultrasound Obstet Gynecol. 2016;48(3):382-9.Prior twin follow-up (PREDICT) reporting no developmental harm.doi:10.1002/uog.15948 →
Related infographics
Placental Volume: 2D EPV vs 3D VOCAL™
A 30-second handheld measurement, checked against the gold standard in 58 paired scans.
Bot or Not: Readers Preferred the AI Story and Could Not Identify It
Three studies, 2,587 US adults, and a bias that points the opposite way from the blindness it accompanies.
Clinical AI Competence in Obstetrics and Gynecology
Adoption has outrun training: 81% of physicians report awareness or use of AI, while fewer than 15% report formal expertise in its clinical application.