Background: Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications and fetal growth restriction is reported. Increased head size has been reported in PCOS-offspring exposed to intrauterine metformin. We aimed to explore whether maternal PCOS-status, and the use of metformin, during pregnancy affect fetal cerebral and placental circulation.

Methods: The Pilot (2000-2003) and the PregMet2 (2012-2017) studies are randomized controlled trials where women with PCOS were randomized to metformin or placebo in pregnancy. Individually pooled data from Doppler examinations at gestational week 32 from these RCT's were included in a post-hoc analysis of totally 64 participants. The pulsatility index (PI) z-scores of the fetal middle cerebral artery (MCA), umbilical artery (UmbA), and the cerebroplacental ratio (CPR) were compared between the metformin and placebo treated groups with a two-sample t-test. The PI z-scores of the women with PCOS were compared to low-risk reference populations of pregnant women. The PI z-scores were correlated with maternal BMI at inclusion, androgen levels measured at gestational week 32, percentage gestational weight gain from first trimester to gestational week 32 and offspring head circumference.

Results: There was no significant difference in PI z-scores of fetal MCA, UmbA, and CPR between metformin and placebo treated women with PCOS, or between women with PCOS compared to low-risk reference populations. Maternal BMI, androgen levels, percentage gestational weight gain, and offspring head circumference did not correlate significantly with PI z-scores of fetal MCA, UmbA or CPR.

Conclusion: Maternal PCOS and metformin exposure during pregnancy had no significant impact on placental and fetal cerebral pulsatility indices. The reported fetal growth restriction in PCOS-offspring and the larger head size in metformin exposed fetuses may not be explained by altered umbilical and cerebral pulsatility indices, or their relationship. These findings support the current clinical practice that fetoplacental Doppler assessment in PCOS pregnancies should follow standard obstetric indications.

Trial registration: The Pilot study was performed before trial registrations became mandatory and the trial was retrogradely registered on the 17th of August 2017.

Clinicaltrials: gov Identifier: NCT03259919. The PregMet 2 study was registered on the 26^th of April 2012 at ClinicalTrials.gov Identifier: NCT01587378. The CircMet study was a sub-study of the PregMet 2 study.