Prenatal exposures and birth indices, and subsequent risk of polycystic ovary syndrome: a national registry-based cohort study.

OBJECTIVE: To study the associations between prenatal exposures and risk of developing polycystic ovary syndrome (PCOS). DESIGN: National registry-based cohort study. SETTING: Sweden. POPULATION: Girls born in Sweden during the years 1982-1995 (n = 681 123). METHODS: The girls were followed until the year 2010 for a diagnosis of PCOS. We estimated the associations between maternal body mass index (BMI), smoking, and size at birth with the risk of developing a PCOS diagnosis. Risks were calculated by adjusted hazard ratio (aHR) and 95% confidence intervals (95% CIs). MAIN OUTCOME MEASURES: A diagnosis of PCOS at 15 years of age or later. RESULTS: During the follow-up period 3738 girls were diagnosed with PCOS (0.54%). Girls with mothers who were overweight or obese had 1.5-2.0 times higher risk of PCOS (aHR 1.52, 95% CI 1.36-1.70; aHR 1.97, 95% CI 1.61-2.41, respectively), compared with girls born to mothers of normal weight. The risk of PCOS was increased if the mother smoked during pregnancy (1-9 cigarettes/day, aHR 1.31, 95% CI 1.18-1.47; ≥10 cigarettes/day, aHR 1.44, 95% CI 1.27-1.64). Being born small for gestational age (SGA) was associated with a later diagnosis of PCOS in crude estimates, but the association was not significant after adjusting for maternal factors. CONCLUSIONS: Maternal smoking and increased BMI appear to increase the risk of PCOS in offspring. The association between SGA and the development of PCOS appears to be mediated by maternal factors. TWEETABLE ABSTRACT: Smoking during pregnancy and high maternal BMI are associated with PCOS diagnosis in the offspring.

Breastfeeding and long-term maternal metabolic health in the HUNT Study: a longitudinal population-based cohort study.

OBJECTIVE: Breastfeeding (BF) has been reported to improve long-term maternal metabolic health in observational studies, but not in the randomised controlled PROBIT study. Research also suggests that maternal pre-pregnant metabolic health may affect BF. We aimed to disentangle effects of BF on long-term maternal metabolic health from effects of pre-pregnant metabolic health on BF duration and long-term metabolic health. DESIGN: Longitudinal population-based cohort study. SETTING: Nord-Trøndelag county, Norway. POPULATION: Women with a first live-born baby (1987-2008) participating in the Nord-Trøndelag Health Study (HUNT). METHODS: Odds ratios (ORs) for short BF duration (<3 months) by pre-pregnant body mass index (BMI), waist circumference (WCF), blood pressures (BPs), and heart rate (HR) were adjusted for age and smoking using logistic regression. Mixed linear models were used to estimate effects of BF duration (<3, 3-6, >6 months) on mean values of metabolic health parameters from baseline to follow-up. MAIN OUTCOME MEASURES: Mean change in BMI, WCF, BPs, HR, serum-glucose, and serum-lipids from baseline to follow-up by BF duration categories. RESULTS: We analysed 1403 women with a median follow-up of 12 years (interquartile range 11-22). Pre-pregnant WCF and HR correlated inversely with BF duration. Pre-pregnant BMI had a u-shaped correlation-pattern with BF duration. We observed similar between-group differences in metabolic health parameters at baseline and at follow-up, which implies that mean change in metabolic health parameters was similar across BF groups. Those women who started out with the best health had the longest BF duration and ended up with the best health, and those women who started out with the poorest health had shortest BF duration and ended up with the poorest health. CONCLUSIONS: Our results do not support a causal relationship between long BF duration and improved metabolic health. It is more likely that pre-pregnant metabolic health affects both BF duration and long-term metabolic health. Reverse causality can explain previously observed improved long-term metabolic health after BF. TWEETABLE ABSTRACT: Breastfeeding seems not to affect long-term maternal metabolic health, but good pre-pregnant metabolic health does.

Pharmacokinetics after a single dose of naloxone administered as a nasal spray in healthy volunteers.

BACKGROUND: There is increasing interest in the use of intranasal naloxone to reverse adverse opioid effects during management of procedural pain in children and in adults after overdose. There are limited data on the pharmacokinetics of intranasal naloxone so in this study we aimed to detail the pharmacokinetic profile of the commercially marketed injectable solution of naloxone 0.4 mg/ml when administered as an intranasal spray. METHODS: Twenty healthy volunteers received naloxone as an intranasal spray at a dose of 10 µg/kg. Venous blood sampling was carried out for 90 min after administration to determine the time profile of the plasma concentrations of using tandem mass spectrometry. Pharmacokinetic parameters were calculated using a one-compartment model. RESULTS: Median time to maximum naloxone concentration (Tmax) was 14.5 (95% CI: 9.0-16.5) min, mean maximum naloxone concentration (Cmax) was 1.09 ± 0.56 ng/ml and mean AUC0-90 min was 37.1 ± 15.0 ng*min/ml. Elimination half-life estimated from the median concentration data was 28.2 min. CONCLUSION: Our results show a faster uptake of intranasal naloxone to maximum concentration compared with previous studies although with a marked variation in maximum concentration. The findings are consistent with our clinical experience of the time profile for reversing the effects of sufentanil sedation in children.

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-3ß, 17ß-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 Lundgrens's 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.

Pregnancy and perinatal outcomes in women with polycystic ovary syndrome and twin births: a population-based cohort study.

OBJECTIVE: To investigate pregnancy and perinatal outcomes in twin births among women with and without polycystic ovary syndrome (PCOS) diagnosis. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: We identified 20,965 women with twin births between 1995 and 2009 of whom 226 had a PCOS diagnosis through linkage between the Swedish Medical Birth Register and the Swedish National Patient Register. METHODS: Calculating risk ratios (RR) with 95% confidence intervals (CI) using a log-binomial regression model and hazard ratios (HR) with 95% CI for preterm birth. MAIN OUTCOME MEASURES: Preterm birth, low birthweight, caesarean section, pre-eclampsia, Apgar score <7 at 5 minutes and perinatal mortality. RESULTS: PCOS diagnosis in twin pregnancy was associated with increased risk of preterm delivery (51% versus 43%, RR 1.18 [95% CI 1.03-1.37]), particularly spontaneous preterm delivery (37% versus 28%; RR 1.30 [95% CI 1.09-1.55]) and very preterm birth (<32 weeks) (14% versus 8%, RR 1.62 [95% CI 1.10-2.37]). Twins of PCOS mothers had more often low birthweight (48% versus 39%, adjusted RR 1.40 [95% CI 1.09-1.80]). This difference disappeared when adjusting for gestational age. No risk difference was found for caesarean section, pre-eclampsia, low 5-minute Apgar score or perinatal mortality. CONCLUSIONS: The risk of preterm delivery in twin pregnancies is increased by having a PCOS diagnosis. This should be considered in risk estimation and antenatal follow-up of twin pregnancies.

Increased prevalence of diabetes and polycystic ovary syndrome in women with a history of preterm birth: a case-control study.

OBJECTIVE: To test the hypothesis that endocrine and metabolic factors predispose to preterm birth. DESIGN: A cross-sectional, case-control study. SETTING: Namsos Hospital district (Namsos, Norway). POPULATION: Women from the Namsos Hospital district with previous preterm births (n = 114) were compared with matched controls with term births (n = 127). METHODS: A clinical examination including transvaginal ultrasound was performed. Fasting blood samples were collected and an oral glucose tolerance test was performed. MAIN OUTCOME MEASURES: The prevalence of polycystic ovary syndrome (PCOS) diagnosis (Rotterdam criteria) and serum levels of androgens, glucose and insulin. RESULTS: Twenty-nine of 114 women (25.4%) met the PCOS criteria among women with preterm birth, compared with 18 of 127 (14.2%) among controls (P = 0.03). Eight (7.1%) women with preterm birth were diagnosed with diabetes compared with none in the control group (P < 0.01). Hirsutism was present in 34 (29.8%) women with preterm birth versus 12 (9.4%) in the control group (P < 0.01). CONCLUSIONS: The prevalences of PCOS, diabetes and hirsutism are increased among women with a history of preterm birth. This indicates that endocrine and/or metabolic factors may be involved in the pathogenesis of preterm birth. Women experiencing preterm delivery may have an increased risk of developing diabetes and PCOS later in life.

Breast size increment during pregnancy and breastfeeding in mothers with polycystic ovary syndrome: a follow-up study of a randomised controlled trial on metformin versus placebo.

OBJECTIVE: To study the significance of breast size increment in pregnancy, and the impact of metformin during pregnancy on breastfeeding in women with polycystic ovary syndrome (PCOS). DESIGN: A follow-up study of a randomised controlled trial (the PregMet study). SETTING: Eleven secondary care centres. POPULATION: Women with PCOS during pregnancy and postpartum. METHODS: Women with PCOS were randomised to treatment with metformin or placebo from the first trimester to delivery. Questionnaires were sent to 240 participants 1 year postpartum: 186 responded. MAIN OUTCOME MEASURES: Pre-pregnancy and late-pregnancy brassiere size and breastfeeding patterns were registered, and androgen levels were measured in the mothers. RESULTS: No difference in breast size increment and breastfeeding were found between the placebo and metformin groups. Breast size increment correlated positively with the duration of both exclusive and partial breastfeeding, whereas body mass index (BMI) correlated negatively with the duration of partial breastfeeding. Dehydroepiandrostenedione-sulphate (DHEAS), testosterone and free testosterone index (FTI) in pregnancy did not correlate with breast size increment or duration of breastfeeding. Women with no change in breast size were more obese, had higher blood pressure, serum triglycerides and fasting insulin levels, and had a shorter duration of breastfeeding compared with those with breast size increment. CONCLUSIONS: Metformin and androgens had no impact on breastfeeding. Women with PCOS who had no breast size increment in pregnancy seem to be more metabolically disturbed and less able to breastfeed.

Metformin influence on hormone levels at birth, in PCOS mothers and their newborns.

BACKGROUND: Polycystic ovary syndrome (PCOS) tends to run in families and excess intrauterine androgen exposure has been suggested as one possible cause of PCOS. We wanted to study the relationship between maternal and offspring sex hormone levels and the possible effects of metformin treatment in PCOS pregnancies. METHODS: We performed a post hoc analysis of a trial in which 40 pregnant women with PCOS were randomized in the first trimester, to use either metformin 850 mg twice daily or placebo until delivery. Maternal venous blood and umbilical arterial and venous blood samples were collected at delivery. Outcome measures were levels of androgens, estrogens and sex hormone binding globulin (SHBG). RESULTS: (i) In newborns, SHBG levels were higher in the metformin group. All other hormones, both in mothers and offspring, were unaffected by metformin treatment. (ii) Mothers, who gave birth to boys, had higher estrone and estradiol levels compared with those who gave birth to girls. (iii) Male newborns had higher levels of testosterone, androstanediol glucuronide and estradiol compared with females. (iv) Positive correlations were found between maternal and newborn levels of androstenedione, dihydrotestosterone and estradiol. CONCLUSIONS: Intrauterine metformin exposure seems to result in elevated SHBG levels in newborns. However, at birth, maternal and newborn androgen and estrogen levels are unaffected by metformin use in pregnancy. Although androgen and estrogen levels are higher in male newborns compared with females, maternal and newborn androgen and estrogen levels are highly correlated at birth.

Anti-Müllerian hormone concentrations in androgen-suppressed women with polycystic ovary syndrome.

BACKGROUND: Current data suggest that excessive androgen exposure can lead to the development of polycystic ovaries and polycystic ovary syndrome (PCOS). Anti-Müllerian hormone (AMH) levels reflect the number of small antral follicles in the ovaries and are elevated in PCOS. We hypothesized that protracted reduction of circulating androgens and/or insulin resistance would reduce circulating AMH concentrations in women with PCOS. METHODS: A prospective, randomized, double-blind 26 week long study was undertaken in 50 women with PCOS. They all received diet and lifestyle counselling, and metformin 850 mg three times daily. Concomitantly, they were randomized to either dexamethasone 0.25 mg daily (n = 25) or placebo (n = 25). Thirty-eight women completed the study. AMH (primary outcome) and other hormone levels were measured at inclusion and after 8 and 26 weeks of treatment. RESULTS: At baseline in univariate regression analyses, AMH levels associated positively with testosterone levels (P = 0.041) and ovarian volume (P = 0.002). In multivariate regression analyses, AMH associated positively with testosterone P = 0.004), and negatively with dehydroepiandrosterone sulphate (DHEAS) (P = 0.001) and C-peptide levels (P = 0.020). Circulating AMH concentrations were unaffected by 6 months of lifestyle counselling with metformin and placebo treatment. AMH levels were also unaffected by 6 months of androgen suppression with dexamethasone in addition. CONCLUSIONS: AMH levels in untreated PCOS women associated positively with testosterone, and negatively with DHEAS and C-peptide levels. Six months of androgen suppression by either metformin or low-dose dexamethasone treatment failed to influence circulating AMH levels.

Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. STUDY DESIGN SIZE DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. A (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. The guideline was peer-reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE II criteria and underwent methodological review. This guideline was approved by all members of the GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low (n = 1), low (n = 9) and moderate (n = 4) quality with no EBRs based on high-quality evidence. The guideline provides 14 EBRs, 10 clinical consensus recommendations (CCRs) and 20 clinical practice points on the assessment and management of infertility in PCOS. Key changes in this guideline include emphasizing evidence-based fertility therapy, including cheaper and safer fertility management. LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTERESTS: The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine (ASRM). GDG members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

Association of size at birth with adolescent hormone levels, body size and age at menarche: relevance for breast cancer risk.

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7-15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life.

Metformin has no major effects on glucose homeostasis in pregnant women with PCOS: results of a randomized double-blind study.

OBJECTIVE: Previous non-randomized and uncontrolled studies indicate major metformin effects on glucose homeostasis in pregnant women with polycystic ovary syndrome (PCOS). We investigated metformin effects on glucose homeostasis in a prospective controlled study. MATERIAL AND METHODS: Forty pregnant women with PCOS and without known diabetes mellitus were included in the first trimester and randomized to either metformin 850 mg twice daily or placebo. Outcome measures were fasting glucose and insulin at inclusion and changes to pregnancy weeks 19, 32 and 36 and 2 h glucose levels during a 75 g oral glucose tolerance test (OGTT) carried out at inclusion and pregnancy weeks 19 and 32. Insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta) were calculated using the homeostasis assessment model. RESULTS: At inclusion, 2 h glucose levels during OGTT were higher in the placebo group (7.14 versus 6.03 mmol/L; p = 0.012). Accordingly, 6 out of 22 in the metformin group versus 2 out of 18 women in the placebo group (p = 0.21) had gestational diabetes mellitus at inclusion. At gestational weeks 19 and 32, 2-h plasma glucose levels were equal between the groups. The total proportion of women with gestational diabetes did not differ between the groups, nor did any of the other indices of glucose metabolism and insulin resistance. CONCLUSIONS: Metformin seems to be without major effects on glucose homeostasis in pregnant women with PCOS.

Androgens and hyperemesis gravidarum: a case-control study.

OBJECTIVE: The pathogenesis of hyperemesis gravidarum (HG) is probably multifactorial, involving several hormones. Androgen concentrations are reported to correlate positively with emesis gravidarum. Hypothesizing a continuum between emesis gravidarum and HG, we investigated androgen concentrations in women with HG. STUDY DESIGN: In a case-control study, 32 women hospitalized for HG were compared with 29 control women scheduled for elective surgical abortion. Control women were matched for age, gestational length, body mass index (BMI) and parity. Patient characteristics and concentrations of dehydroepiandrosterone sulphate (DHEAS), androstenedione, testosterone, sex hormone binding globulin (SHBG), free testosterone index (FTI), androstanediol glucuronide (ADG), progesterone, TSH, free T3 and T4, beta-hCG, ferritin, insulin, estradiol and estriol were compared using Mann-Whitney tests and multivariate linear regression analyses. RESULTS: Women with HG had higher concentrations of ADG (8.49±4.19 vs. 6.19±1.77pmol/L; p=0.015), estradiol (2.39±1.36 vs. 1.60±9.30nmol/L; p=0.009) and ferritin (186±138 vs. 117±94pmol/L; p=0.040) compared with control women. Androstenedione (5.34±2.82 vs. 6.86±2.67; p=0.004) and insulin (63.7±35.0 vs. 75.3±25.8; p=0.050) concentrations were lower in women with HG. DHEAS, testosterone, FTI, SHBG, estriol, progesterone, beta-hCG, TSH, free T3 and free T4 concentrations did not differ between the groups. In multivariate regression analyses HG was associated with high concentrations of ADG (p=0.026) and low concentrations of androstenedione (p=0.018). CONCLUSION: Steroid hormone homeostasis may be altered in women with HG. HG may be associated with high ADG and low androstenedione concentrations.

The effect of exercise and metformin treatment on circulating free DNA in pregnancy.

INTRODUCTION: Some pregnancy complications are characterized by increased levels of cell-free fetal (cffDNA) and maternal DNA (cfmDNA), the latter may also be elevated during physical strain. This study aims at assessing the impact of exercise and metformin intervention in pregnancy, and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis. METHODS: Consecutive women from two previous randomized controlled trials in pregnancy were included. Women came from a trial with organized exercise vs. standard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women. Levels of cffDNA, cfmDNA and cell-free total DNA (cftDNA) were measured by qPCR. RESULTS: Training in pregnancy did not affect the levels of cffDNA, cfmDNA or cftDNA. PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 (mean ± SD: 301 ± 162 versus 570 ± 337, p = 0.012, 345 ± 173 versus 635 ± 370, p = 0.019); otherwise the levels were comparable to PCOS-controls. Metformin-treated PCOS-women had higher cffDNA at inclusion, in the 1st trimester; later on in pregnancy the levels in the metformin and placebo groups were equal. A comparison of pregnant women in the exercise study (TRIP) to placebo-treated pregnant PCOS-women, showed the levels of cffDNA, cfmDNA or cftDNA during mid-pregnancy (weeks 18-36) to be equal. DISCUSSION: Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA, but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women.

Gestational diabetes mellitus among Norwegian women with polycystic ovary syndrome: prevalence and risk factors according to the WHO and the modified IADPSG criteria.

OBJECTIVE: The consequences of the recently proposed International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria for gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) are not known. We compared the prevalence rates and risk factors for GDM in PCOS women according to both the WHO and the modified IADPSG criteria. DESIGN: Post hoc analyses from a randomized, multicenter study were used. METHODS: Fasting and 2-h plasma glucose levels were measured using a 75 g oral glucose tolerance test. GDM was diagnosed according to both the WHO and the modified IADPSG criteria. RESULTS: The prevalence rates of GDM according to the WHO and the modified IADPSG criteria were 9.2 and 15.0% at week 12, 18.7 and 18.7% at week 19, and 25.6 and 24.2% at week 32. Shorter stature and increased insulin levels were correlated with WHO-GDM, but not with modified IADPSG-GDM at weeks 12 and 19. Less weight gain in pregnancy predicted GDM according to both sets of criteria. GDM diagnosis was correlated with less maternal weight loss the first year post-partum. CONCLUSIONS: No difference was found in the prevalence of GDM between the two sets of criteria used. Less weight gain in pregnancy was associated with GDM, independent of the diagnostic criteria used. Reduced weight loss the first year post-partum in women with GDM raises the question of whether GDM diagnosis per se or the fact that these women lose less weight after pregnancy predicts later diabetes mellitus.

Metformin treatment in pregnant women with polycystic ovary syndrome--is reduced complication rate mediated by changes in the uteroplacental circulation?

OBJECTIVES: To study a possible effect of metformin on the uteroplacental circulation. METHODS: Forty pregnant women with polycystic ovary syndrome (PCOS) were enrolled in a randomized, double-blind, placebo-controlled trial of metformin (1700 mg/day) during pregnancy. Doppler ultrasound examinations of the uterine arteries were performed at 12, 19, 24, 32 and 36 gestational weeks and of the umbilical artery at 19, 24, 32 and 36 gestational weeks. RESULTS: There was a greater mean bilateral uterine artery pulsatility index (PI) at 12 weeks (1.95 vs. 1.58, P = 0.02), and a greater reduction in mean PI from 12 to 19 weeks (P = 0.03) in metformin-treated women. There were no differences in mean PI values between groups at 19, 24, 32 or 36 gestational weeks. Pregnancy complications, such as preterm delivery before 32 weeks, severe pre-eclampsia or serious postpartum events, occurred only in the placebo group (7 of 22 vs. 0 of 18, P = 0.01). There were no associations between uterine artery Doppler measurements and pregnancy complications. We found no differences between groups in mean umbilical artery PI at 19, 24, 32 or 36 gestational weeks. CONCLUSIONS: In this small randomized trial, metformin treatment in pregnancy reduced uterine artery impedance between 12 and 19 weeks of gestation, and this was associated with reduced complication rate. Published by John Wiley & Sons, Ltd.

[The salpingitis diagnosis under scrutiny]. / Salpingittdiagnosen under lupen.

The rationale for the diagnosis of Pelvic Inflammatory Disease (PID) was studied among hospitalized patients at the Department of Gynaecology, Regional Hospital of Trondheim, Trondheim. From 1 January 1991 to 31 December 1993, 153 patients were discharged with a diagnosis of Pelvic Inflammatory Disease. In retrospect, the diagnoses were reconsidered applying strict criteria. All 26 patients (17%) who had a diagnosis verified by laparoscopy were classified as suffering from a "true" diagnosis, 83 (54%) patients were reconsidered as suffering from a "more likely" and 44 (29% as suffering from a "less likely" diagnosis of Pelvic Inflammatory Disease. Women who had a laparoscopy verified diagnosis of Pelvic Inflammatory Disease, had higher ESR (erythrocyte sedimentation rate), C-reactive protein and temperature when compared with women reclassified as "less likely" suffering from Pelvic Inflammatory Disease. Only 72% of the patients had microbiological sampling from the cervix. In order to increase diagnostic precision we argue for minimum criteria and a systematic clinical examination, including vaginal ultrasound, when diagnosing Pelvic Inflammatory Disease. We recommend more diagnostic use of laparoscopy especially among women with mild symptoms and few objective signs.

Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin.

BACKGROUND: The purpose of this study was to investigate the effect of low-dose dexamethasone on androgen levels in women with polycystic ovary syndrome (PCOS) treated with diet and lifestyle counselling, and metformin. METHODS: A prospective, randomized, double blind, placebo-controlled study was carried out. Thirty-eight women with PCOS were randomized to either dexamethasone 0.25 mg daily or placebo for 26 weeks. All received diet and lifestyle counselling at inclusion and metformin 850 mg three times daily during the whole study. Main outcome measures were: androgen levels, body mass index (BMI), insulin c-peptide, fasting glucose and serum lipids. Two-tailed t-tests and Pearson's statistics were used. RESULTS: Compared with the placebo, dexamethasone reduced testosterone by 27%, androstenedione by 21%, dehydroepiandrosterone sulphate by 46% and free testosterone index by 50% in women with PCOS treated with diet and lifestyle advice, and metformin. BMI, fasting glucose, insulin c-peptide and serum lipid levels were unaffected. CONCLUSIONS: Six-month, low-dose dexamethasone treatment further reduces androgen levels in metformin-treated PCOS women.

Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study.

BACKGROUND: Investigation of a possible effect of metformin on androgen levels in pregnant women with polycystic ovary syndrome (PCOS). METHODS: A prospective, randomized, double-blind, placebo-controlled pilot study was conducted. Forty pregnant women with PCOS received diet and lifestyle counselling and were randomized to either metformin 850 mg twice daily or placebo. Primary outcome measures were changes in serum levels of dehydroepiandrosterone sulphate, androstenedione, testosterone, sex hormone-binding globulin, and free testosterone index. Secondary outcome measures were pregnancy complications and outcome. Two-tailed t-tests and chi2-tests were used. RESULTS: Maternal androgen levels were unaffected by metformin treatment in pregnant women with PCOS. While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication, seven of the 22 (32%) women experienced severe complications in the placebo group (P = 0.01). CONCLUSIONS: Metformin treatment did not reduce maternal androgen levels in pregnant women with PCOS. In the metformin-treated group we observed a reduction of severe, pregnancy and post-partum complications. Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period.