Childbirth experiences in women with polycystic ovary syndrome: A cohort study.

INTRODUCTION: Women with polycystic ovary syndrome (PCOS) have more pregnancy complications like gestational diabetes, hypertension, and preterm labor than other women. Metformin has been used in an attempt to improve pregnancy outcomes. Our study aims to explore childbirth experiences in women with PCOS compared with a reference population. It also explores the potential influence of metformin, obesity, pregnancy complications, and the duration and mode of birth on childbirth experiences. MATERIAL AND METHODS: This study is a cohort study combining data from two randomized trials conducted in Norway, Sweden and Iceland. The PregMet2 study (ClinicalTrials.gov, NCT01587378) investigated the use of metformin vs. placebo in pregnant women with PCOS. The Labour Progression Study (ClinicalTrials.gov, NCT02221427) compared the WHO partograph to Zhang's guidelines for progression of labor and were used as the reference population. A total of 365 women with PCOS and 3604 reference women were included. Both studies used the Childbirth Experience Questionnaire (CEQ). Main outcome measures were total CEQ score and four domain scores. The CEQ scores were compared using Mann-Whitney U test for women in Robson group 1 with PCOS (n = 131) and reference women (n = 3604). CEQ scores were also compared between metformin-treated (n = 180) and placebo-treated (n = 185) women with PCOS, and for different subgroups of women with PCOS. RESULTS: There was no difference in total CEQ score between women with PCOS and reference women-Wilcoxon-Mann-Whitney (WMW)-odds 0.96 (95% confidence interval [CI] 0.78-1.17). We detected no difference in CEQ scores between the metformin- and placebo-treated women with PCOS (WMW-odds 1.13, 95% CI 0.89-1.43). Complications in pregnancy did not affect CEQ (WMW-odds 1, 95% CI 0.76-1.31). Higher body mass index (WMW-odds 0.75, 95% CI 0.58-0.96), longer duration of labor (WMW-odds 0.69, 95% CI 0.49-0.96), and cesarean section (WMW-odds 0.29, 95% CI 0.2-0.42) were associated with lower CEQ scores in women with PCOS. CONCLUSIONS: Women with PCOS experience childbirth similarly to the reference women. Metformin did not influence childbirth experience in women with PCOS, neither did pregnancy complications. Obesity, long duration of labor or cesarean section had a negative impact on childbirth experience.

Neonatal outcome following metformin-treated gestational diabetes mellitus: A population-based cohort study.

INTRODUCTION: Neonatal hypoglycemia is a common complication associated with gestational diabetes and therefore relevant to consider in evaluations of maternal treatment. We aimed to investigate the risk of neonatal hypoglycemia in offspring exposed to metformin treatment alone (MT) or combined with insulin (MIT) in comparison with nutrition therapy alone (NT), and insulin treatment alone (IT). In addition, we investigated MT in comparison with MIT. Secondary outcomes included neonatal anthropometrics, respiratory morbidity, hyperbilirubinemia, 5-min Apgar score, and preterm birth. MATERIAL AND METHODS: This Swedish population-based cohort included 16 181 women diagnosed with gestational diabetes, and their singleton offspring born in 2019-2021. We estimated risk as adjusted odds ratio (aOR) with 95% confidence interval (CI), using individual-level, linkage register-data in multivariable logistic regression models. RESULTS: In the main analysis, MT was associated with a lower risk of neonatal hypoglycemia vs NT (aOR 0.85, 95% CI: 0.74-0.96), vs MIT (0.74 [0.64-0.87]), and vs IT (0.47 [0.40-0.55]), whereas MIT was associated with a similar risk of neonatal hypoglycemia vs NT (1.14 [0.99-1.30]) and with lower risk vs IT (0.63 [0.53-0.75]). However, supplemental feeding rates were lower for NT vs pharmacological treatments (p < 0.001). In post hoc subgroup analyses including only exclusively breastfed offspring, the risk of neonatal hypoglycemia was modified and similar among MT and NT, and higher in MIT vs NT. Insulin exposure, alone or combined with metformin, was associated with increased risk of being large for gestational age. Compared with NT, exposure to any pharmacological treatment was associated with significantly lower risk of 5-min Apgar score < 4. All other secondary outcomes were comparable among the treatment categories. CONCLUSIONS: The risk of neonatal hypoglycemia appears to be comparable among offspring exposed to single metformin treatment and nutrition therapy alone, and the lower risk that we observed in favor of metformin is probably explained by a difference in supplemental feeding practices rather than metformin per se. By contrast, the lower risk favoring metformin exposure over insulin exposure was not explained by supplemental feeding. However, further investigations are required to determine whether the difference is an effect of metformin per se or mediated by other external factors.

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero.

INTRODUCTION: Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. MATERIAL AND METHODS: Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. RESULTS: Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11- 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = -0.04, 95% CI = -0.05 to -0.03), but head circumference and birthweight were similar. CONCLUSIONS: Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.

International evidence-based guideline on assessment and management of PCOS-A Nordic perspective.

Polycystic ovary syndrome (PCOS) affects about 12% of women of reproductive age. In 2018, the first evidence-based guideline on assessment and management of PCOS was published, and an updated extended guideline was released in August 2023. These guidelines followed best practice and are endorsed by 39 organizations worldwide, making them the most robust source of evidence to guide clinical practice. In the 2023 guideline, diagnostic criteria have been further refined as polycystic ovary morphology can now be assessed with gynecological ultrasound or elevated anti-Müllerian hormone levels. A healthy lifestyle should be at the focus of care for all women with PCOS; however, with no specific diet or physical exercise recommended. The latest evidence on medical treatments and fertility management are reviewed, including special considerations regarding long-term follow-up of metabolic and psychiatric comorbidities and pregnancy in women with PCOS. Here we summarize the recommendations from a Nordic perspective.

Polycystic ovary syndrome and risk of pre-eclampsia: A national register-based cohort study.

OBJECTIVE: To explore whether the association between polycystic ovary syndrome (PCOS) and pre-eclampsia depends on treated clinical hyperandrogenism and whether PCOS is associated with different subtypes of pre-eclampsia. DESIGN: Nationwide register-based cohort study. SETTING: Sweden. POPULATION: Nulliparous women with PCOS (n = 22 947) and non-PCOS controls (n = 115 272) giving singleton birth at ≥22 gestational weeks during 1997-2015. Treated clinical hyperandrogenism was defined as filled prescriptions of anti-androgenic drugs during 2005-2017 (n = 2301 among PCOS women). METHODS: The risk of pre-eclampsia was estimated with conditional logistic regression, expressed as adjusted odds ratio (OR) with 95% confidence interval (CI). Adjustments were performed individually for confounders and predictors. MAIN OUTCOME MEASURES: Overall pre-eclampsia. Early/late (delivery <34/≥34 weeks) pre-eclampsia. Pre-eclampsia with or without a small-for-gestational-age (SGA) infant. RESULTS: Compared with controls, women with PCOS had a 29% increased risk of pre-eclampsia (predictor adjusted OR 1.29, 95% CI 1.20-1.39), with similar risk estimates for PCOS women with and without treated clinical hyperandrogenism. The association between PCOS and early pre-eclampsia seemed stronger than its association with late pre-eclampsia (predictor adjusted OR 1.64 (95% CI 1.33-2.02) and 1.26 (95% CI 1.17-1.37). Additionally, the association seemed slightly stronger between PCOS and pre-eclampsia in women with an SGA infant than without. CONCLUSIONS: Women with PCOS face an increased risk for pre-eclampsia, especially early pre-eclampsia and pre-eclampsia with an SGA infant. We were unable to determine on the basis of available data, whether hyperandrogenism is associated with pre-eclampsia.

Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.

OBJECTIVE: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously. DESIGN: This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials. SETTING: Pregnant women with PCOS were included from 11 study centres in Norway. PARTICIPANTS: From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples. INTERVENTION: Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism. RESULTS: Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS. CONCLUSIONS: Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes. TRIAL REGISTRATION NUMBER: NCT03259919 and NCT00159536.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Immunomodulatory Effects of Metformin Treatment in Pregnant Women With PCOS.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade systemic inflammation and increased risk of pregnancy complications. Metformin treatment reduces the risk of late miscarriage and preterm birth in pregnant women with PCOS. Whether the protective effect of metformin involves immunological changes has not been determined. OBJECTIVE: To investigate the effect of metformin on the maternal immunological status in women with PCOS. METHODS: A post-hoc analysis was performed of two randomized controlled trials, PregMet and PregMet2, including longitudinal maternal serum samples from 615 women with PCOS. Women were randomized to metformin or placebo from first trimester to delivery. Twenty-two cytokines and C-reactive protein were measured in serum sampled at gestational weeks 5 to 12, 19, 32, and 36. RESULTS: Metformin treatment was associated with higher serum levels of several multifunctional cytokines throughout pregnancy, with the strongest effect on eotaxin (P < .001), interleukin-17 (P = .03), and basic fibroblast growth factor (P = .04). Assessment of the combined cytokine development confirmed the impact of metformin on half of the 22 cytokines. The immunomodulating effect of metformin was more potent in normal weight and overweight women than in obese women. Moreover, normoandrogenic women had the strongest effect of metformin in early pregnancy, whereas hyperandrogenic women presented increasing effect throughout pregnancy. CONCLUSION: It appears that metformin has immunomodulating rather than anti-inflammatory properties in pregnancy. Its effect on the serum levels of many multifunctional cytokines demonstrates robust, persisting, and body mass-dependent immune mobilization in pregnant women with PCOS.

Cardiovascular Health Does Not Change Following High-Intensity Interval Training in Women with Polycystic Ovary Syndrome.

INTRODUCTION: polycystic ovary syndrome (PCOS) is associated with cardiovascular disease (CVD) risk factors. First-line therapy for PCOS is lifestyle changes including exercise. We compared CVD risk factors between women with and without PCOS and examined the responses to high-intensity interval training (HIIT). METHODS: women with PCOS were randomized to HIIT (n = 41) or a non-exercise control group (n = 23) for 16 weeks. Women without PCOS (n = 15) were age- and BMI-matched to participants with PCOS and completed 16 weeks of HIIT. CVD markers included blood pressure, heart rate, flow mediated dilatation (FMD), carotid intima-media thickness (IMT), and circulating concentrations of lipids, glucose, insulin, and matrix metalloproteinase-9 (MMP-9). RESULTS: resting heart rate was higher in women with PCOS than without PCOS (p =0.011) and was reduced after HIIT in women with PCOS (-2.8 beats/min, 95% CI: -5.4, -0.2, p = 0.037). FMD was not significantly different between women with PCOS (5.5%, SD 4.1) and those without PCOS (8.2%, SD 3.9) at baseline. HIIT reduced time-to-peak dilatation of the brachial artery in women with PCOS compared with women without PCOS (-55 s, 95% CI: -96, -13, p = 0.012). CONCLUSIONS: we found little difference in CVD risk factors between women with and without PCOS at baseline, but some indications of endothelial dysfunction in women with PCOS.

Thyroid Status During Pregnancy in Women With Polycystic Ovary Syndrome and the Effect of Metformin.

Objective: Polycystic ovary syndrome (PCOS) and hypothyroidism are related conditions, and both are associated with adverse pregnancy outcomes. Knowledge is lacking about the complex interaction between thyroid status and PCOS during pregnancy. We investigated the thyroid status and its association with pregnancy complications in PCOS, and in relation to metformin treatment. Design: Post-hoc analyses of two randomized, double-blind, placebo-controlled trials. Methods: 288 pregnant women with PCOS were randomized to treatment with metformin or placebo from first trimester to delivery. We measured serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) at gestational week (gw) 5-12, 19, 32 and 36 and related to metformin treatment and pregnancy complications. Thyroid peroxidase antibodies (TPO-ab) were analyzed at inclusion and at gw 36. Results: The overall prevalence of subclinical and overt hypothyroidism was 1.5% and 0%, respectively. The TSH level was not affected by metformin, whereas fT4 was significantly higher in the metformin group with less decrease throughout pregnancy compared to placebo, p<0.001. A lower decrease in fT4 during pregnancy correlated to less weight gain (r= -0.17, p=0.020) and tended to be associated with reduced odds ratio for gestational diabetes (OR 0.85 per 1 pmol/L, 95% CI 0.71;1.02). Conclusions: In women with PCOS, metformin treatment during pregnancy was associated with less decrease in fT4 compared to placebo, while it did not affect TSH. A smaller decrease in fT4 correlated to less weight gain and tended to be associated with a lower risk of gestational diabetes. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00159536 (The PregMet study); identifier NCT03259919 (The pilot study).

High-Intensity Interval Training in Polycystic Ovary Syndrome: A Two-Center, Three-Armed Randomized Controlled Trial.

PURPOSE: Exercise training is recommended to improve cardiometabolic health and fertility in women with polycystic ovary syndrome (PCOS), yet there are few randomized controlled trials on the effects of different exercise protocols on clinical reproductive outcomes. Our aim was to determine the effect of high-intensity interval training (HIT) on menstrual frequency, as a proxy of reproductive function, in women with PCOS. METHODS: The IMPROV-IT study was a two-center randomized controlled trial undertaken in Norway and Australia. Women with PCOS were eligible for inclusion. After stratification for body mass index <27 or ≥27 kg·m-2 and study center, participants were randomly allocated (1:1:1) to high-volume HIT (HV-HIT), low-volume HIT (LV-HIT), or a control group. Measurements were assessed at baseline, after the 16-wk exercise intervention, and at 12-month follow-up. The primary outcome was menstrual frequency after 12 months. Secondary outcomes included markers of cardiometabolic and reproductive health, quality of life, and adherence to and enjoyment of HIT. RESULTS: We randomly allocated 64 participants to the HV-HIT (n = 20), LV-HIT (n = 21), or control group (n = 23). There were no differences in menstrual frequency at 12 months between the LV-HIT and control groups (frequency ratio, 1.02; 95% confidence interval [CI], 0.73-1.42), the HV-HIT and control groups (frequency ratio, 0.93; 95% CI, 0.67-1.29), or the LV-HIT and HV-HIT groups (frequency ratio, 1.09; 95% CI, 0.77-1.56). Menstrual frequency increased in all groups from baseline to 12 months. More participants became pregnant in the LV-HIT group (n = 5) than in the control group (n = 0, P = 0.02). CONCLUSIONS: A semisupervised HIT intervention did not increase menstrual frequency in women with PCOS.Clinical Trial Registration Number:ClinicalTrials.gov (NCT02419482).

Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study.

BACKGROUND: Metformin is prescribed to women with polycystic ovary syndrome (PCOS) to prevent pregnancy complications. Children exposed to metformin vs. placebo in utero, have increased head circumference at birth and are more overweight and obese at 8 years of age. Also, maternal PCOS-status seems to alter the long-term cardio-metabolic health of offspring. We hypothesized that the long-term effects of metformin-exposure and/or maternal PCOS may be mediated by circulatory adaptations during fetal life. MATERIAL AND METHODS: This is a sub-study of a larger double-blinded, placebo-controlled trial, where women with PCOS were randomized to metformin (2g/day) or placebo in pregnancy, a total of 487 women. A sub-group of participants (N = 58) took part in this sub-study and had an extended ultrasound examination at gestational week 32, including blood flow velocity and diameter measurements of the umbilical vein (UV), the ductus venosus (DV) and the portal vein (PV). Blood flow volume was calculated and adjusted for estimated fetal weight (EFW) (normalized flow). Metformin exposed fetuses were compared to placebo exposed fetuses. Fetuses of mothers with PCOS (metformin [n = 30] and placebo [n = 28]) were compared to a low-risk reference population (N = 160) by z-score statistics. RESULTS: There was no difference in fetal liver flow between metformin vs. placebo-exposed fetuses. Fetuses of mothers with PCOS had higher EFW (0.63 [95% CI 0.44-0.83] p<0.001), lower normalized UV, DV, PV, and lower total venous liver blood flows than the reference population. CONCLUSION: Metformin during pregnancy did not affect fetal liver blood-flow. In our population, maternal PCOS-status was associated with reduced total venous liver blood-flow, which may explain altered growth and metabolism later in life.

Changes in Serum Cytokines Throughout Pregnancy in Women With Polycystic Ovary Syndrome.

CONTEXT: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ureteric injuries during hysterectomy-A Norwegian retrospective study of occurrence and claims for compensation over an 11-year period.

INTRODUCTION: Ureteric injury is a rare but serious, iatrogenic complication of hysterectomy. The risk depends on indication for surgery, predisposing risk factors, and peroperative conditions. Our aims were to evaluate and learn from compensation claims to The Norwegian System of Patient Injury Compensation (NPE) for ureteric injury occurring during hysterectomies to predict risk factors, time of identification, symptoms, and consequences, and to relate these cases to injuries registered in The Norwegian Patient Registry. MATERIAL AND METHODS: A retrospective study of ureteric injuries occurring during hysterectomies, reported to NPE and the Norwegian Patient Registry from 2009 through 2019. RESULTS: During the study period, 53 096 hysterectomies were registered in The Norwegian Patient Registry, of which ureteric injury was documented in 643 (1.2%). More ureteric injuries were registered in large hospital trusts than in small trusts (1.3% vs. 0.7%, p < 0.05). NPE received 69 claims due to ureteric injury occurring during hysterectomy, comprising 11% of all injuries in the study period. Compensation was approved for 15%. Women who claimed compensation were younger (48.1 ± 8.9 years vs. 55.1 ± 13.6 years, p < 0.01), more likely to have had a benign diagnosis (89.9% vs. 52.1%, p < 0.01), and more likely to have had the ureteric injury recognized after discharge (58.0% vs. 33.0%, p < 0.001) compared with non-complainants. Identification of the ureters during the hysterectomy was documented in 30% of the NPE patient files. Additional information for the NPE cases included the following. The most common symptoms of unidentified injury were pain (77%), fever (12%), urinary leakage (13%), and anuria (8%). Re-operation was necessary in 77% of the cases, and 10% of the women lost one kidney. Long-term consequences after repair, such as loss of a kidney or persistent pain, were seen in 17%. No women died because of the injury. CONCLUSIONS: The incidence of ureteric injury occurring during hysterectomy in Norway was 1.2%; 11% involved a claim for compensation, and 15% of these had their case approved. Most ureteric injuries were not recognized during the hysterectomy. Documentation of peroperative identification of the ureters during hysterectomy was often missing. Vigilance to pain as a postoperative symptom of peroperative unrecognized ureteric injury may result in earlier diagnosis and treatment.

Gestational weight gain, appetite regulating hormones, and metformin treatment in polycystic ovary syndrome: A longitudinal, placebo-controlled study.

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 ABSTRACT: Metformin counteracts excessive weight gain and leptin resistance in pregnant women with polycystic ovary syndrome.

Metformin serum concentrations during pregnancy and post partum - A clinical study in patients with polycystic ovary syndrome.

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.

Cytokine Patterns in Maternal Serum From First Trimester to Term and Beyond.

Pregnancy implies delicate immunological balance between two individuals, with constant changes and adaptions in response to maternal capacity and fetal demands. We performed cytokine profiling of 1149 longitudinal serum samples from 707 pregnant women to map immunological changes from first trimester to term and beyond. The serum levels of 22 cytokines and C-reactive protein (CRP) followed diverse but characteristic trajectories throughout pregnancy, consistent with staged immunological adaptions. Eotaxin showed a particularly robust decrease throughout pregnancy. A strong surge in cytokine levels developed when pregnancies progressed beyond term and the increase was amplified as labor approached. Maternal obesity, smoking and pregnancies with large fetuses showed sustained increase in distinct cytokines throughout pregnancy. Multiparous women had increased cytokine levels in the first trimester compared to nulliparous women with higher cytokine levels in the third trimester. Fetal sex affected first trimester cytokine levels with increased levels in pregnancies with a female fetus. These findings unravel important immunological dynamics of pregnancy, demonstrate how both maternal and fetal factors influence maternal systemic cytokines, and serve as a comprehensive reference for cytokine profiles in normal pregnancies.

Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5-10 years old children from the PregMet randomized controlled study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. DESIGN: This is a follow-up study of 5-10 years old children from the PregMet-study-a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. METHODS: There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. RESULTS: Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14-1.17), p = 0.014). CONCLUSION: Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

No impact of gestational diabetes mellitus on pregnancy complications in women with PCOS, regardless of GDM criteria used.

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.