Objective
To explore mechanisms that modulate gestational weight gain (GWG) in women with polycystic ovary syndrome (PCOS) and healthy controls.
Design
Sub‐sample of randomised controlled trials ...(PCOS) combined with a prospective cohort (controls).
Setting
Eleven Norwegian, Swedish, and Icelandic hospitals.
Population
Pregnant women with PCOS treated with metformin (PCOS‐M, n = 36) or placebo (PCOS‐P, n = 37), and healthy pregnant women (HC, n = 15).
Methods
Serum levels of the appetite regulating hormones leptin, ghrelin, allopregnanolone, and soluble leptin receptor (sOB‐R) were determined in the first and third trimesters.
Main Outcome Measures
Excessive GWG (eGWG) relative to body mass index according to Institute of Medicine (IOM) guideline. Serum leptin/sOB‐R ratio, or free‐leptin‐index (FLI), as biomarker of leptin sensitivity. Serum ghrelin and allopregnanolone levels.
Results
The overall prevalence of eGWG was 44% (38/86). Women with eGWG had higher first and third trimester FLI (P < 0.001), and lower third trimester allopregnanolone levels (P = 0.003) versus women with non‐eGWG. The prevalence of eGWG was lower in PCOS‐M versus PCOS‐P (28% versus 62%, odds ratio = 0.4, 95% CI 0.2–0.8, P = 0.005). FLI decreased during pregnancy in PCOS‐M (P = 0.01), but remained unaltered in PCOS‐P and HC. Ghrelin and allopregnanolone levels were comparable in PCOS‐M, PCOS‐P and HC throughout pregnancy.
Conclusion
Excessive GWG is associated with enhanced leptin resistance, and attenuated physiological increase in serum allopregnanolone levels during pregnancy. Metformin reduces the risk for eGWG and improves leptin sensitivity in pregnant women with PCOS.
Tweetable
Metformin counteracts excessive weight gain and leptin resistance in pregnant women with polycystic ovary syndrome.
Tweetable
Metformin counteracts excessive weight gain and leptin resistance in pregnant women with polycystic ovary syndrome.
Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during ...pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS.
PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1:1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials.gov, number NCT01587378, and EudraCT, number 2011-002203-15.
The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio OR 0·50, 95% CI 0·22-1·08; p=0·08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 25% of 238 women in the metformin group vs 57 24% of 240 women in the placebo group; OR 1·09, 95% CI 0·69-1·66; p=0·75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group compared with 40 (10%) of 399 women in the placebo group (OR 0·43, 95% CI 0·23-0·79; p=0·004).
In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes.
Research Council of Norway, Novo Nordisk Foundation, St Olav's University Hospital, and Norwegian University of Science and Technology.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune ...system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy.
This work aimed to determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS.
A post hoc analysis was conducted of longitudinal serum samples from 2 randomized, placebo-controlled multicenter studies of pregnant women with PCOS and 2 studies of pregnant women without PCOS. Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from 4 time points in pregnancy (weeks 10, 19, 32, and 36). Main outcome measures included maternal serum levels of 22 cytokines and C-reactive protein (CRP) at 4 time points in pregnancy.
Women with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal body mass index, smoking, and fetal sex.
Pregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications.
Background and objectives
Metformin is used to treat gestational diabetes. It is also used to treat women with polycystic ovary syndrome and has been shown to prevent late miscarriage and preterm ...birth. However, increased renal clearance during pregnancy causes a decline in serum concentrations of metformin. The aim of this study was to explore the time course of the pregnancy‐related changes in metformin pharmacokinetics and the return to the non‐pregnant state.
Method
A subgroup of women in the PregMet2 study (n = 73) agreed to provide serum samples at three time‐points in pregnancy (gestational weeks 19, 28 and 32) and once in post partum, (either 2, 4 or 8 weeks after delivery). Serum metformin concentrations were compared using a four‐parameter logistic model.
Findings
The mean steady‐state serum concentration of metformin during pregnancy was 9.39 μmoL/L, whereas the post partum concentration was 12.36 μmoL/L, an increase of 32% (p = 0,019). This change took place already during the first 2 weeks post partum.
Conclusion
Clinicians who treat pregnant women with metformin should be aware of the significant decrease in metformin concentration mediated by pregnancy, and the rapid increase after delivery, as it may impact both the therapeutic efficacy and the risk of adverse drug reactions.
IMPORTANCE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, characterized by subfertility, increased risk of metabolic diseases, and pregnancy complications. Previous studies diverge ...regarding the association between maternal PCOS and newborn anthropometrics. OBJECTIVE: To explore the association between maternal PCOS and newborn anthropometrics and the modifying effects of maternal body mass index, PCOS phenotype, and gestational diabetes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study followed up women from the first half of pregnancy to birth and combined data from 3 clinical trials of pregnant women with PCOS and a reference population consisting of participants in the Norwegian Mother, Father, and Child Cohort (MoBa) Study, with data from the Medical Birth Registry of Norway. The recruitment period for the clinical trials was between October 1, 2000, and August 31, 2017, and for MoBa, between July 1, 1999, and December 31, 2008. Participants included women with singleton pregnancies and live-born children. Data were analyzed from January 1 to June 15, 2023. EXPOSURE: Maternal PCOS status. MAIN OUTCOMES AND MEASURES: Newborn birth weight, birth length, and head circumference as continuous variables and z scores, and ponderal index (calculated as the birth weight in grams × 100 divided by the birth length in centimeters cubed), placenta weight, and ratio of birth weight to placenta weight (BWPW). RESULTS: The cohort included 390 pregnant women with PCOS (mean SD age, 29.6 4.2 years) and 68 708 women in the reference group (mean SD age, 30.4 4.5 years). Offspring in the PCOS group had lower birth weight, birth length, and head circumference than in the reference group offspring. The estimated mean differences in z scores were −0.26 (95% CI, −0.38 to −0.14) for birth weight, −0.19 (95% CI, −0.33 to −0.05) for birth length, and −0.13 (95% CI, −0.26 to −0.01) for head circumference. The PCOS group also had a lower ponderal index (−0.04 95% CI, −0.07 to −0.004 g × 100/cm3) and placenta weight (−24 95% CI, −43 to −5) g), and higher BWPW ratio (0.4 95% CI, 0.3 to 0.5). The association between growth restriction and PCOS was more apparent when additionally adjusting for body mass index. Neither PCOS phenotype nor gestational diabetes diagnosis was associated with neonatal anthropometry in women with PCOS. CONCLUSIONS AND RELEVANCE: In this cohort of mother-infant pairs, maternal PCOS status was associated with lower birth weight, shorter birth length, and smaller head circumference in the offspring. This growth restriction was more pronounced when adjusting for BMI, providing insight into the association between PCOS and body mass index. The study contributed to the understanding of how PCOS affects the offspring.
For decades, infertility and metabolic health challenges have been the main concerns for women diagnosed with polycystic ovary syndrome (PCOS). Poorer pregnancy outcomes and obstetric complications ...have only recently been recognized as concerns for women with PCOS. Women diagnosed with PCOS are more often overweight and obese, and the prevalence of pregnancy complications in PCOS is influenced by several co-factors such as body mass index, co-morbidities, and ethnicity. The most frequently reported pregnancy complications in PCOS are gestational diabetes, miscarriage and preterm delivery, hypertension, and preeclampsia. This narrative review focuses on existing evidence and clinical practice for prepregnancy screening, antenatal care, and postpartum follow-up of women with PCOS. We also briefly review treatment options, neonatal outcomes, and breastfeeding. Our aim is to increase awareness about obstetric challenges in PCOS.
Polycystic ovary syndrome is a common endocrinopathy in reproductive-age women, and associates with insulin resistance. Exercise is advocated in this disorder, but little knowledge exists on the ...optimal exercise regimes. We assessed the effects of high intensity interval training and strength training on metabolic, cardiovascular, and hormonal outcomes in women with polycystic ovary syndrome.
Three-arm parallel randomized controlled trial. Thirty-one women with polycystic ovary syndrome (age 27.2 ± 5.5 years; body mass index 26.7 ± 6.0 kg/m2) were randomly assigned to high intensity interval training, strength training, or a control group. The exercise groups exercised three times weekly for 10 weeks.
The main outcome measure was change in homeostatic assessment of insulin resistance (HOMA-IR). HOMA-IR improved significantly only after high intensity interval training, by -0.83 (95% confidence interval CI, -1.45, -0.20), equal to 17%, with between-group difference (p = 0.014). After high intensity interval training, high-density lipoprotein cholesterol increased by 0.2 (95% CI, 0.02, 0.5) mmol/L, with between group difference (p = 0.04). Endothelial function, measured as flow-mediated dilatation of the brachial artery, increased significantly after high intensity interval training, by 2.0 (95% CI, 0.1, 4.0) %, between-group difference (p = 0.08). Fat percentage decreased significantly after both exercise regimes, without changes in body weight. After strength training, anti-Müllarian hormone was significantly reduced, by -14.8 (95% CI, -21.2, -8.4) pmol/L, between-group difference (p = 0.04). There were no significant changes in high-sensitivity C-reactive protein, adiponectin or leptin in any group.
High intensity interval training for ten weeks improved insulin resistance, without weight loss, in women with polycystic ovary syndrome. Body composition improved significantly after both strength training and high intensity interval training. This pilot study indicates that exercise training can improve the cardiometabolic profile in polycystic ovary syndrome in the absence of weight loss.
ClinicalTrial.gov NCT01919281.
Polycystic ovary syndrome (PCOS) is characterized by the presence of insulin resistance, and women with PCOS have high prevalence of gestational diabetes (GDM). Both conditions have been associated ...with increased risk for pregnancy complications such as preterm birth, preeclampsia and increased offspring birth weight. We aimed to estimate the prevalence of GDM in women with PCOS using both previous and new diagnostic criteria, and to analyse whether the risk of pregnancy complications increased with the presence of GDM. In addition, we aimed to assess the response to metformin treatment in PCOS women with GDM. We performed post-hoc analysis of three prospective, double blinded studies of altogether 791 pregnant women with PCOS randomized to either metformin or placebo treatment from first trimester to delivery. Glucose data allowing GDM classification after previous (WHO 1999) and new (WHO 2013 and Norwegian 2017) diagnostic criteria were available for 722 of the women. Complications such as preeclampsia, late miscarriage and preterm birth, birth weight and gestational age were correlated to the presence of GDM and metformin treatment. The prevalence of GDM was 28.3% (WHO 1999), 41.2% (WHO 2013) and 27.2% (Norwegian 2017). Having GDM already in first trimester associated with increased risk for late miscarriage (p<0.01). Having GDM according to newer criteria correlated to increased maternal age and BMI (p<0.001). Otherwise, having GDM (any criteria) correlated neither to the development of preeclampsia, nor to birth weight z-score or the proportion of offspring being large for gestational weight. Maternal age and BMI, parity and gestational weight gain, but not GDM or metformin treatment, were determinants for birth weight z-score. Conclusion: in pregnant women with PCOS, having GDM did not increase the risk for other pregnancy complications except for an increased risk for late miscarriage among those with GDM already in the first trimester.
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