Solhild Stridsklev

Metformin Versus Placebo from First Trimester to Delivery in Polycystic Ovary Syndrome: A Randomized, Controlled Multicenter Study

CONTEXT Metformin is widely prescribed to pregnant women with polycystic ovary syndrome (PCOS) in an attempt to reduce pregnancy complications. Metformin is not approved for this indication, and evidence for this practice is lacking. OBJECTIVES Our objective was to test the hypothesis that metformin, from first trimester to delivery, reduces pregnancy complications in women with PCOS. DESIGN AND SETTING We conducted a randomized, placebo-controlled, double-blind, multicenter study at 11 secondary care centers. PARTICIPANTS The participants were 257 women with PCOS, in the first trimester of pregnancy, aged 18-42 yr. INTERVENTION We randomly assigned 274 singleton pregnancies (in 257 women) to receive metformin or placebo, from first trimester to delivery. MAIN OUTCOME MEASURES The prevalence of preeclampsia, gestational diabetes mellitus, preterm delivery, and a composite of these three outcomes is reported. RESULTS Preeclampsia prevalence was 7.4% in the metformin group and 3.7% in the placebo group (3.7%; 95% CI, -1.7-9.2) (P=0.18). Preterm delivery prevalence was 3.7% in the metformin group and 8.2% in the placebo group (-4.4%; 95%, CI, -10.1-1.2) (P=0.12). Gestational diabetes mellitus prevalence was 17.6% in the metformin group and 16.9% in the placebo group (0.8%; 95% CI, -8.6-10.2) (P=0.87). The composite primary endpoint prevalence was 25.9 and 24.4%, respectively (1.5%; 95% CI, -8.9-11.3) (P=0.78). Women in the metformin group gained less weight during pregnancy compared with those in the placebo group. There was no difference in fetal birth weight between the groups. CONCLUSIONS Metformin treatment from first trimester to delivery did not reduce pregnancy complications in PCOS.

Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs

Context Metformin is used in pregnancy in women with gestational diabetes mellitus, polycystic ovary syndrome (PCOS), and obesity. Metformin passes the placenta. Objective To explore the effects of metformin use in PCOS pregnancies on offspring growth to 4 years of age. Design Follow-up study of two randomized, double-blind, placebo-controlled trials. Setting Secondary care centers. Eleven public hospitals in Norway. Participants One hundred eighty-two children of mothers with PCOS who participated in two randomized controlled trials. Intervention Metformin 1700 or 2000 mg/d or placebo from first trimester to delivery in the original studies. No intervention in the current study. Main Outcome Measures Height, weight, body mass index (BMI), and overweight/obesity at 4 years of age and head circumference at 1 year of age, converted to z scores. Results The difference in height z score means between the groups at 4 years of age was nonsignificant (0.07 [95% confidence interval (CI): -0.22 to 0.36]; P = 0.651). At 4 years of age, the metformin group had higher weight z score than the placebo group [difference in means: 0.38 (0.07 to 0.69); P = 0.017] and higher BMI z score [difference in means: 0.45 (0.11 to 0.78); P = 0.010]. There were more overweight/obese children in the metformin group [26 (32%)] than in the placebo group [14 (18%)] at 4 years of age [odds ratio: 2.17 (1.04 to 4.61); P = 0.038]. The difference in mean head circumference z score at 1 year of age was 0.27 (-0.04 to 0.58; P = 0.093). Conclusion Metformin-exposed children had higher BMI and increased prevalence of overweight/obesity at 4 years of age.

Placental STAT3 signaling is activated in women with polycystic ovary syndrome

STUDY QUESTION Does polycystic ovary syndrome (PCOS) in women without pregnancy complications affect placental signal transducer and activator of transcription 3 (STAT3) and mechanistic target of rapamycin (mTOR) signaling? SUMMARY ANSWER Placental STAT3 signaling is activated but mTOR signaling is unaffected in PCOS. WHAT IS KNOWN ALREADY Women with PCOS have increased risk of poor pregnancy outcomes (e.g. restricted or accelerated fetal growth), indicating placental dysfunction. Placental STAT3 and mTOR pathways regulate placental function and indirectly affect fetal growth. STUDY DESIGN, SIZE, DURATION In a case-control study, placental tissue and maternal blood were collected at delivery from 40 control pregnant women and 38 PCOS women with uncomplicated pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS were recruited at two medical centers and pregnant controls were recruited at one of these centers. Placental mRNA expression of genes encoding proteins related to steroid action, metabolic pathways and cytokines was analyzed by quantitative RT-PCR. Phosphorylated placental STAT3 (P-STAT3) and mTOR targets was measured by western blot. Levels of sex steroids in serum were determined by mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE Placental P-STAT3 (Tyr-705) was increased in women with PCOS (P < 0.05) versus controls. Placental mTOR signaling was not affected in PCOS women when compared with controls. Circulating levels of androstenedione, androst-5-ene-3β, 17β-diol, testosterone, 5α-dihydrotestosterone and etiocholanolone glucuronide were higher and estradiol lower in women with PCOS than in controls (all P < 0.05). No correlation between sex steroid levels in serum and P-STAT3 was observed. LIMITATIONS, REASONS FOR CAUTION Women with PCOS and pregnancy complications were excluded to avoid the confounding effects of placental pathologies, which could modify STAT3 and mTOR signaling. Moreover, 97.4% of women with PCOS in the study displayed oligoamenorrhea at diagnosis. Thus, the current findings could be restricted to PCOS women with the oligo-anovulatory phenotype without pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS Phosphorylation of STAT3 is increased in the placenta from women with PCOS and uncomplicated pregnancies, indicating that specific metabolic placental pathways are activated in the absence of obstetric and perinatal complications. STUDY FUNDING/COMPETING INTERESTS The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrenss Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests.

PCOS – what matters in early pregnancy?– data from a cross-sectional, multicenter study

Objective. To describe patient characteristics according to different diagnostic criteria in early pregnancy, in women with polycystic ovary syndrome (PCOS). Design. Descriptive, cross‐sectional study of 257 women with PCOS in the first trimester of pregnancy. Setting. Data from a multicenter trial at the time of inclusion. Population. 257 PCOS women with singleton pregnancies. Methods. Investigator‐administrated questionnaires were filled out. Clinical examination was performed by the investigators. Fasting blood samples were collected. Main outcome measures. Biometric data, androgens, glucose and insulin levels. Results. Women who met the National Institutes of Health (NIH) criteria for PCOS had higher body mass index (BMI), testosterone, dehydroepiandrostenedione, free testosterone index (FTI) and insulin levels compared with those who only met the Rotterdam consensus criteria. Adjusted for age and BMI, only testosterone and FTI were higher in those who met the NIH criteria. BMI was a strong, independent predictor of both systolic and diastolic blood pressure in early PCOS pregnancy, while both FTI and fasting insulin were independent predictors of systolic blood pressure. Twenty‐two (9%) of the participants had gestational diabetes mellitus in the first trimester of pregnancy. Conclusions. In the first trimester, PCOS women diagnosed according to NIH criteria were more metabolically and endocrinologically abnormal compared with those who only met the Rotterdam consensus criteria. BMI and FTI were independent predictive factors for blood pressure. There was a high prevalence of gestational diabetes mellitus in early PCOS pregnancies.

Midpregnancy Doppler Ultrasound of the Uterine Artery in Metformin- Versus Placebo-Treated PCOS Women: A Randomized Trial

CONTEXT Metformin is used to reduce pregnancy complications in women with polycystic ovary syndrome (PCOS), although it is not approved for this indication and solid evidence is lacking. Midpregnancy Doppler ultrasound is one of the best methods for prediction of adverse pregnancy outcome. OBJECTIVE The objectives of the study were to investigate the following: 1) whether metformin treatment influenced the midpregnancy pulsatility index (PI) of the uterine artery; 2) whether metabolic or endocrine factors affect the PI of the uterine artery of PCOS women; and 3) whether PI predicted adverse pregnancy outcome in PCOS woman. DESIGN This is a substudy of a randomized, placebo-controlled, double-blind, multicenter study conducted at 11 secondary care centers. We randomly assigned 273 pregnancies to receive metformin or placebo, from the first trimester of pregnancy to delivery. In the present substudy, 231 pregnancies are included, ie, those who completed the ultrasound examinations. MAIN OUTCOME MEASURES Midpregnancy PI in the uterine artery related to metformin use, androgen levels, an oral glucose tolerance test, and insulin levels was measured. We found no difference in the PI between the metformin and placebo groups. In multivariate analyses, fasting serum glucose of the first and second trimester correlated positively to the midpregnancy PI. Only in univariate analyses a weak correlation between androstenedione and PI was seen. CONCLUSIONS Metformin treatment did not affect uterine artery blood flow, measured by PI. High fasting blood glucose correlated inversely to uterine artery blood flow. The midpregnancy PI correlated positively to preeclampsia, hypertension, and gestational diabetes mellitus in PCOS pregnancies. Androgen levels correlated only to PI in univariate analyses.

Maternal and fetal insulin levels at birth in women with polycystic ovary syndrome: data from a randomized controlled study on metformin.

CONTEXT Metformin is suggested to reduce pregnancy complications in women with polycystic ovary syndrome (PCOS). Metformin crosses the placenta and therapeutic concentrations are measured in the fetal circulation. Whether metformin treatment in pregnant PCOS women affects maternal and fetal insulin concentrations at birth is not clarified. OBJECTIVES To investigate the possible effect of metformin on insulin concentrations in umbilical cord blood and the possible association between maternal and fetal insulin concentrations. DESIGN Post-hoc analysis of a subgroup of PCOS women participating in a double-blind randomized controlled trial. SETTING University hospital setting. PARTICIPANTS Women with PCOS (n=118), aged 19-39 years. MAIN OUTCOME MEASURES Maternal and umbilical cord insulin concentrations immediately after birth. RESULTS At delivery women randomized to metformin had lower insulin concentrations than those randomized to placebo (259±209 vs 361±261 pmol/l; P=0.020). No difference was found in insulin concentrations in umbilical venous (P=0.95) and arterial (P=0.39) blood between the metformin and placebo groups. The arteriovenous difference was also equal between the groups (P=0.38). Insulin concentrations were higher in the umbilical vein than in the umbilical artery independent of randomization (70±51 vs 45±48 pmol/l; P<0.0005). CONCLUSIONS In PCOS, metformin treatment during pregnancy resulted in lower maternal insulin concentrations at delivery. Metformin treatment did not affect fetal insulin concentrations. Higher insulin concentrations in the umbilical vein indicate that the placenta somehow secretes insulin to the fetus. The possibility of placental insulin secretion to the fetus deserves further investigations.

Uterine artery Doppler measurements during first and second trimesters of normal pregnancy

The aim of this study was to construct a reference curve based on longitudinal Doppler blood flow measurements of the uterine artery during the first and second trimesters of normal pregnancy.

Cervical Length and Androgens in Pregnant Women With Polycystic Ovary Syndrome: Has Metformin Any Effect?

CONTEXT Women with polycystic ovary syndrome (PCOS) have increased risk of preterm delivery. Shortening of the cervix is a sign of preterm delivery. OBJECTIVE This study aimed to investigate potential effect of metformin on cervical length and whether androgen levels correlate with cervical length in PCOS pregnancies. DESIGN AND SETTING This was a sub-study of a randomized, placebo-controlled, multicenter study (The PregMet study) performed at 11 secondary or tertiary centers from 2005 to 2009. PARTICIPANTS Two-hundred sixty-one pregnancies of 245 women with PCOS, age 18-42 years participated. INTERVENTIONS Participants were randomly assigned to metformin or placebo from first trimester to delivery. OUTCOME MEASUREMENTS We compared cervical length and androgen levels in metformin and placebo groups at gestational weeks 19 and 32. We also explored whether cervical length correlated with androgen levels. RESULTS We found no difference in cervical length between the metformin and the placebo groups at gestational week 19 and 32. Dehydroepiandrosterone (DHEAS) tended to be higher in the metformin group. There were no correlations between androgens and cervical length at week 19. At gestational week 32, androstenedione (P = .02) and DHEAS (P = .03) showed a trend toward negative correlation to cervical length. High androstenedione level correlated with shortening of cervical length from week 19 to 32 when adjusted for confounders (P = .003). T (P = .03), DHEAS (P = .02), and free testosterone index (P = .03) showed a similar trend. CONCLUSION Metformin in pregnancy did not affect cervical length in women with PCOS. High maternal androgen levels correlated with cervical shortening from the second to the third trimester of pregnancy, as a sign of cervical ripening.

Uterine Artery Doppler in Pregnancy: Women with PCOS Compared to Healthy Controls

The objective of this study was to investigate possible differences in uterine artery pulsatility index (UtAPI) between pregnant women with PCOS and healthy controls and to explore possible effects of metformin on UtAPI. Material and Methods. The study was conducted in a tertiary center. Forty-eight pregnant women diagnosed with PCOS before pregnancy and 124 healthy pregnant women were included. Women with PCOS were randomly assigned to metformin 2000 mg daily or a placebo. UtAPI was measured five times during 1st and 2nd trimesters of pregnancy in women with PCOS and four times in healthy controls. Results. There was no difference in UtAPI between PCOS women and healthy controls at any point in time (p = 0.34–0.77). In women with PCOS, randomly assigned to metformin 2000 mg or placebo, UtAPI was unaffected by metformin two hours after intake of the first dose of study medication (p = 0.34). All PCOS women, regardless of randomization, had higher UtAPI two hours after intake of study medication and a meal compared to before a meal (p = 0.02). Conclusions. In the first and second trimesters of pregnancy, there was no difference in UtAPI between women with PCOS and healthy controls. Metformin had no immediate effect on the UtAPI. Interestingly, blood flow decreased after a meal, suggesting that time since last meal should be taken into consideration when interpreting the results of UtAPI measurements in pregnancy. This trial is registered with ClinicalTrials.gov (NCT00466622) Metformin in Pregnant PCOS women (PregMet) (NCT00159536).