Fetal and post-natal outcomes in offspring after intrauterine metformin exposure: A systematic review and meta-analysis of animal experiments.

AIMS: The impact of maternal metformin use during pregnancy on fetal, infant, childhood and adolescent growth, development, and health remains unclear. Our objective was to systematically review the available evidence from animal experiments on the effects of intrauterine metformin exposure on offspring's anthropometric, cardiovascular and metabolic outcomes. METHODS: A systematic search was conducted in PUBMED and EMBASE from inception (searched on 12th April 2023). We extracted original, controlled animal studies that investigated the effects of maternal metformin use during pregnancy on offspring anthropometric, cardiovascular and metabolic measurements. Subsequently, risk of bias was assessed and meta-analyses using the standardized mean difference and a random effects model were conducted for all outcomes containing data from 3 or more studies. Subgroup analyses were planned for species, strain, sex and type of model in the case of 10 comparisons or more per subgroup. RESULTS: We included 37 articles (n = 3133 offspring from n = 716 litters, containing n = 51 comparisons) in this review, mostly (95%) on rodent models and 5% pig models. Follow-up of offspring ranged from birth to 2 years of age. Thirty four of the included articles could be included in the meta-analysis. No significant effects in the overall meta-analysis of metformin on any of the anthropometric, cardiovascular and metabolic offspring outcome measures were identified. Between-studies heterogeneity was high, and risk of bias was unclear in most studies as a consequence of poor reporting of essential methodological details. CONCLUSION: This systematic review was unable to establish effects of metformin treatment during pregnancy on anthropometric, cardiovascular and metabolic outcomes in non-human offspring. Heterogeneity between studies was high and reporting of methodological details often limited. This highlights a need for additional high-quality research both in humans and model systems to allow firm conclusions to be established. Future research should include focus on the effects of metformin in older offspring age groups, and on outcomes which have gone uninvestigated to date.

Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTION: Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER: Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY: Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS: Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE: The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228-338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84-117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with 'male factor' as treatment indication (compared to 'tubal factor'). LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS: Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.

The long-term effect of prenatal progesterone treatment on child development, behaviour and health: a systematic review.

BACKGROUND: Progesterone is widely used in prenatal care. However, long-term effects of prenatal progesterone treatment on child development are unclear. OBJECTIVES: To evaluate long-term outcomes in children after prenatal progesterone treatment. SEARCH STRATEGY: MEDLINE, Embase and Cochrane Central Register of Controlled Trials from inception to 24 May 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) reporting outcomes in children born to women who received progesterone treatment (compared with placebo or another intervention) during any trimester in pregnancy. DATA COLLECTION AND ANALYSIS: Two authors independently selected and extracted data. We used the Cochrane Risk of Bias tool for randomised trials and Quality In Prognosis Studies. MAIN RESULTS: Of 388 papers, we included seven articles based on five RCTs, comprising 4222 measurements of children aged 6 months to 8 years. All studies compared progesterone to placebo in second and/or third trimester for the prevention of preterm birth. Meta-analysis (two studies, n = 890 children) showed no difference in neurodevelopment as assessed by the Bayley-III Cognitive Composite score at 2 years between children exposed to progesterone versus placebo (Standardised Mean Difference -0.04, 95% Confidence Interval -0.26 to 0.19), I2  = 22%. Heterogeneity prohibited additional meta-analyses. Other long-term outcomes showed no differences. CONCLUSIONS: Our systematic review comprising a multitude of developmental measurements with a broad age range did not find evidence of benefit or harm in offspring prenatally exposed to progesterone treatment for the prevention of preterm birth. We identified an urgent need for follow-up studies of prenatal progesterone administration in early pregnancy and effects in offspring beyond early childhood. TWEETABLE ABSTRACT: Progesterone to prevent preterm birth: no effect on child development. Outcomes after first trimester progesterone are unclear.

A core outcome set for hyperemesis gravidarum research: an international consensus study.

OBJECTIVE: To develop a core outcome set for trials on the treatment of hyperemesis gravidarum (HG). DESIGN: Identification of outcomes is followed by a modified Delphi survey combined with a consensus development meeting and a consultation round. SETTING: An international web-based survey combined with a consensus development meeting. POPULATION: Stakeholders including researchers; women with lived experience of HG and their families; obstetric health professionals; and other health professionals. METHODS: We used systematic review, semi-structured patient interviews, closed group sessions and Steering Committee input to identify potential core outcomes. We conducted two web-based survey rounds, followed by a face-to-face consensus development meeting and a web-based consultation round. MAIN OUTCOME MEASURES: A core outcome set for research on HG. RESULTS: Fifty-six potential outcomes were identified. The modified Delphi process was completed by 125 stakeholders, the consensus development meeting by 20 stakeholders and the consultation round by 96 stakeholders. Consensus was reached in ten domains on 24 outcomes: nausea; vomiting; inability to tolerate oral fluids or food; dehydration; weight difference; electrolyte imbalance; intravenous fluid treatment; use of medication for hyperemesis gravidarum; hospital treatment; treatment compliance; patient satisfaction; daily functioning; maternal physical or mental or emotional wellbeing; short- and long-term adverse effects of treatment; maternal death; pregnancy complications; considering or actually terminating a wanted pregnancy; preterm birth; small for gestational age; congenital anomalies; neonatal morbidity and offspring death). CONCLUSIONS: This core outcome set will help standardise outcome reporting in HG trials. TWEETABLE ABSTRACT: A core outcome set for treatment of hyperemesis gravidarum in order to create high-quality evidence.

Variation in hyperemesis gravidarum definition and outcome reporting in randomised clinical trials: a systematic review.

BACKGROUND: Hyperemesis gravidarum (HG) is a common cause of hospital admission in early pregnancy. There is no international consensus on the definition of HG, or on outcomes that should be reported in trials. Consistency in definition and outcome reporting is important for the interpretation and synthesis of data in meta-analyses. OBJECTIVE: To identify which HG definitions and outcomes are currently in use in trials. SEARCH STRATEGY: We searched the following sources: (1) Cochrane Central Register of Controlled Trials, (2) Embase and (3) Medline for published trials and the WHO-ICTRP database for ongoing trials (27 October 2017). SELECTION CRITERIA: All randomised clinical trials reporting on any intervention for HG were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and extracted data on HG definition and outcomes. MAIN RESULTS: We included 31 published trials reporting data from 2511 women and three ongoing trials with a planned sample size of 360 participants. We identified 11 definition items. Most commonly used definition items were vomiting (34 trials) and nausea (30 trials). We identified 34 distinct outcomes. Most commonly reported outcomes were vomiting (29 trials), nausea (26 trials), need for hospital treatment (14 trials) and duration of hospital (re)admission(s) (14 trials). CONCLUSION: There is substantial variation of HG definition and outcome reporting in trials. This hampers meaningful aggregation of trial results in meta-analysis and implementation of evidence in guidelines. To overcome this, international consensus on a definition and a core outcome set for HG trials should be developed. TWEETABLE ABSTRACT: There is a wide variation of definitions and outcomes reported in trials on hyperemesis gravidarum.

Hyperemesis gravidarum and cardiometabolic risk factors in adolescents: a follow-up of the Northern Finland Birth Cohort 1986.

OBJECTIVE: To investigate the long-term consequences of prenatal exposure to maternal hyperemesis gravidarum upon offspring cardiometabolic risk factors. DESIGN: This study is part of the prospective follow-up of the Northern Finland Birth Cohort 1986. SETTING: Between 1 July 1985 and 30 June 1986 all pregnant women in two provinces of Finland were recruited at first antenatal visit (99% of eligible participated). POPULATION: A total of 8953 women with liveborn singleton offspring who consented to having their children followed-up were included. METHODS: Hyperemesis gravidarum (HG) was defined as hospitalisation during pregnancy for HG based on the International Classification of Disease (ICD) code. Women who were not hospitalised for HG during pregnancy were used as a reference group. Data on pregnancy and birth outcomes were obtained via medical records and questionnaires; 6462 adolescents, aged 16 years, underwent anthropometric measurements (HG n = 42, reference n = 6420) and 5648 adolescents had a fasting blood sample taken (HG n = 36, reference n = 5612). MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, fasting glucose, and lipid levels in offspring. RESULTS: Multivariate regression analyses showed no differences in offspring BMI (kg/m2 ; adjusted percentage difference HG versus reference, 2.2; 95% CI -0.1, 4.6), systolic blood pressure (adjusted difference 2.1 mmHg; 95% CI -1.5, 5.6), and fasting blood glucose (mmol/l; adjusted percentage difference, 2.3; 95% CI -0.6, 5.4), between adolescents born to mothers with and without HG. CONCLUSIONS: We found no evidence that prenatal exposure to HG has negative consequences for cardiometabolic health of offspring at the age of 16 years. TWEETABLE ABSTRACT: Hyperemesis gravidarum does not affect cardiometabolic health in adolescent offspring.

Vitamin B12 and folate status in early pregnancy and cardiometabolic risk factors in the offspring at age 5-6 years: findings from the ABCD multi-ethnic birth cohort.

OBJECTIVE: To explore whether maternal vitamin B12 and folate status during early pregnancy are associated with cardiometabolic risk factors in the offspring at age 5-6. DESIGN: Prospective multi-ethnic birth cohort, the Amsterdam Born Children and their Development study (ABCD). SETTING: 12,373 pregnant women living in Amsterdam were approached between 2003 and 2004 for participation in the study. POPULATION: Mother-child pairs for whom information on maternal vitamin B12 or folate status in early gestation and health at age 5-6 years was available (n = 1950). METHODS: Vitamin B12 and folate concentrations were determined in maternal serum at intake in early pregnancy (median 13 weeks' gestation). Anthropometric measurements, blood pressure and fasting blood samples were collected during a health check of children aged 5-6 years. Multiple linear regression was performed to investigate the association between maternal serum concentrations and children's outcomes, corrected for confounders. MAIN OUTCOME MEASURES: Gestational age at birth, birthweight, body mass index (BMI), glucose levels, triglyceride levels, blood pressure and heart rate of the offspring at age 5-6. RESULTS: Low maternal folate levels during early pregnancy were associated with slightly higher BMI in the offspring [decrease per 10 units: ß 0.07 kg/m(2), 95% confidence interval (CI) 0.01, 0.13]. Low maternal vitamin B12 concentrations were associated with higher heart rates (decrease per 100 units: ß 0.49 beats/min, 95% CI 0.11, 0.87). CONCLUSION: This study provides further evidence that maternal nutrition in early pregnancy may possibly program cardiometabolic health of the offspring. TWEETABLE ABSTRACT: Low folate and vitamin B12 levels during pregnancy are associated with higher BMI and heart rate in offspring.

Weight loss in pregnancy and cardiometabolic profile in childhood: findings from a longitudinal birth cohort.

OBJECTIVE: To investigate the consequences of weight loss in pregnancy on pregnancy outcomes and cardiometabolic profile in childhood. DESIGN: Prospective birth cohort (ABCD study). SETTING: Between 2003 and 2004, all pregnant women in Amsterdam were approached for study participation. POPULATION: 7818 pregnant women were included, of which 3165 consented to having their children examined at 5-6 years of age. In 1956 children fasting capillary blood samples were also taken. METHODS: At antenatal booking, women answered questions about their pregnancy and whether they suffered from severe weight loss (SWL; >5 kg). Pregnancy details and outcomes were available through the obstetric caregiver. MAIN OUTCOME MEASURES: At birth main outcome measures were prematurity (<37 weeks) and birthweight. At follow-up, body mass index (BMI), blood pressure, glucose and lipids were assessed. RESULTS: SWL occurred in 6.8% of cases. Women with SWL had similar preterm birth rates compared with women without these complaints (adjusted OR 1.1, 95%CI 0.7, 1.7). Birthweight (adjusted difference - 31 g, 95%CI -76, 15) and BMI at 5-6 years of age (adjusted difference 0.2 kg/m(2) , 95%CI 0.0, 0.5) were similar in children born to mothers with SWL and without SWL, but blood pressure was increased. For diastolic blood pressure this association was independent of confounders (adjusted difference 1.4 mmHg, 95%CI 0.4, 2.4). Lipid and glucose levels were not significantly different between these groups. CONCLUSION: Early pregnancy weight loss, usually occurring as a manifestation of hyperemesis gravidarum, could have long-term consequences for offspring health.

The interrelation between microbial immunoglobulin coating, vaginal microbiota, ethnicity, and preterm birth.

BACKGROUND: Vaginal microbiota composition is associated with spontaneous preterm birth (sPTB), depending on ethnicity. Host-microbiota interactions are thought to play an important underlying role in this association between ethnicity, vaginal microbiota and sPTB. METHODS: In a prospective cohort of nulliparous pregnant women, we assessed vaginal microbiota composition, vaginal immunoglobulins (Igs), and local inflammatory markers. We performed a nested case-control study with 19 sPTB cases, matched based on ethnicity and midwifery practice to 19 term controls. RESULTS: Of the 294 included participants, 23 pregnancies ended in sPTB. We demonstrated that Lactobacillus iners-dominated microbiota, diverse microbiota, and ethnicity were all independently associated with sPTB. Microbial Ig coating was associated with both microbiota composition and ethnicity, but a direct association with sPTB was lacking. Microbial IgA and IgG coating were lowest in diverse microbiota, especially in women of any ethnic minority. When correcting for microbiota composition, increased microbial Ig coating correlated with increased inflammation. CONCLUSION: In these nulliparous pregnant women, vaginal microbiota composition is strongly associated with sPTB. Our results support that vaginal mucosal Igs might play a pivotal role in microbiota composition, microbiota-related inflammation, and vaginal community disparity within and between ethnicities. This study provides insight in host-microbe interaction, suggesting that vaginal mucosal Igs play an immunomodulatory role similar to that in the intestinal tract. Video Abstract.

The WHO 2013 oral glucose tolerance test: The utility of isolated glucose measurements - A retrospective cohort study.

OBJECTIVE: The WHO 2013 guidelines recommend screening for gestational diabetes mellitus (GDM) by 3-point oral glucose tolerance test (OGTT). The objective of this retrospective cohort study was to evaluate GDM diagnosed by an isolated high glucose. STUDY DESIGN: We included pregnant women deemed at risk for GDM were offered GDM screening. We examined the records of 1939 consecutively screened pregnancies at two teaching hospitals in Amsterdam during 2016-2020. Using the WHO 2013 diagnostic criteria, we calculated the proportion of GDM cases diagnosed by isolated abnormal glucose values. RESULTS: Among those screened in our high risk cohort, GDM incidence was 31.5%. Of the GDM diagnoses, 57.0% were based on an isolated fasting glucose value, 30.9% based on multiple raised glucose measurements, 7.4% on an isolated raised 2-hour glucose and 4.7% on an isolated raised 1-hour glucose. For 1-hour glucose, the number needed to screen was 67 persons for one additional GDM case. CONCLUSION: The 1-hour glucose in the 3 point OGTT, as suggested by the WHO 2013 guidelines for GDM, contributes only small numbers of GDM cases and a high number needed to screen (67 for 1 additional case in a selective high risk GDM screening strategy), and is likely even less effective in universally screened populations.

Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine.

OBJECTIVE: We previously showed that maternal under-nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren. DESIGN: Historical cohort study. SETTING: Web-based questionnaire. POPULATION: The adult offspring (F2) of a cohort of men and women (F1) born around the time of the 1944-45 Dutch famine. METHODS: We approached the F2 adults through their parents. Participating F2 adults (n = 360, mean age 37 years) completed an online questionnaire. MAIN OUTCOME MEASURES: Weight, body mass index (BMI), and health in F2 adults, according to F1 prenatal famine exposure. RESULTS: Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers (+4.9 kg, P = 0.03; +1.6 kg/m(2), P = 0.006). No such effect was found for the F2 offspring of prenatally exposed F1 mothers. We observed no differences in adult health between the F2 generation groups. CONCLUSIONS: Offspring of prenatally undernourished fathers, but not mothers, were heavier and more obese than offspring of fathers and mothers who had not been undernourished prenatally. We found no evidence of transgenerational effects of grandmaternal under-nutrition during gestation on the health of this relatively young group, but the increased adiposity in the offspring of prenatally undernourished fathers may lead to increased chronic disease rates in the future.

The barriers and needs of transgender men in pregnancy and childbirth: A qualitative interview study.

OBJECTIVE: Transgender and gender diverse individuals are individuals whose gender identity differs from their sex assigned at birth. The discordance between gender identity and sex assignment may cause significant psychological distress: gender dysphoria. Transgender individuals may choose to undergo gender-affirming hormone treatment or surgery, but some decide to (temporarily) refrain from surgery and gender affirming hormone treatment and hence retain the possibility to become pregnant. Pregnancy may enhance feelings of gender dysphoria and isolation. To improve perinatal care for transgender individuals and their health care providers, we conducted interviews to explore the needs and barriers of transgender men in family planning, pregnancy, childbirth, puerperium and perinatal care. DESIGN: In this qualitative study five in-depth semi-structured interviews were conducted with Dutch transgender men who had given birth while identifying on the transmasculine spectrum. The interviews were conducted online through a video remote-conferencing software program (n=4) or live (n=1). Interviews were transcribed verbatim. An inductive approach was used to find patterns and collect data from the participants' narratives and constant comparative method was adapted in analysing the interviews. MEASUREMENTS AND FINDINGS: The experiences of transgender men regarding the preconception period, pregnancy and puerperium and with perinatal care varied widely. Though all participants expressed overall positive experiences, their narratives emphasized they had to overcome substantial hurdles pursuing pregnancy. For instance the necessity to prioritise becoming pregnant over gender transitioning, lack of support by healthcare providers and increased gender dysphoria and isolation during pregnancy KEY CONCLUSIONS: Since pregnancy in transgender men enhances feelings of gender dysphoria, transgender men comprise a vulnerable group in perinatal care. Health care providers are perceived as feeling unaccustomed for the care of transgender patients, as they are perceived to often lack the right tools and knowledge to provide adequate care. Our findings help strengthen the foundation of insight in the needs and hurdles of transgender men pursuing pregnancy and therefore may guide health care providers to provide equitable perinatal care, and emphasize the necessity of patient-centred gender-inclusive perinatal care. A guideline including the option for consultation of an expertise center is advised to facilitate patient-centered gender-inclusive perinatal care.

Blood pressure in ICSI-conceived adolescents.

STUDY QUESTION: Do young adolescents conceived by ICSI display a higher blood pressure than spontaneously conceived (SC) adolescents? SUMMARY ANSWER: In our study, 14-year-old male and female ICSI teenagers were not found to have increased blood pressure at rest. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Only limited data are available regarding the cardiovascular risk of children born after assisted conception and up till now, no data on the cardiovascular health in pubertal children conceived by ICSI have been published. In this study, resting blood pressure and blood pressure response to a psychological stressor were measured in a cohort of 14-year-old teenagers conceived by ICSI and compared the results with those of a group of SC peers. DESIGN: In this cross-sectional study, resting blood pressure measurements were available from 217 singleton ICSI children (116 boys, 101 girls) and 223 singleton control children born after spontaneous conception (115 boys, 108 girls). Continuous blood pressure measurements, performed during a psychological stress test, were available for only 67 ICSI and 38 SC children. PARTICIPANTS AND SETTING: The study group comprised adolescents conceived by ICSI predominantly because of male factor infertility and they were part of a previously published cohort followed since birth; controls were a cross-sectional sample of peers born to fertile parents and recruited from comparable schools as those attended by the ICSI teenagers. Response rates were 56% (tested/reached) in the ICSI group and 50% (agreed/eligible) in the SC group, but information regarding health could be obtained in 63 and 72% of the ICSI and SC children, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: ICSI girls had a comparable resting systolic (109 ± 9 mmHg) and diastolic (64 ± 6 mmHg) blood pressure in comparison with girls in the SC group (111 ± 9 mmHg, P = 0.2 and 66 ± 7 mmHg, P = 0.05), even after adjustment for age and height. After adjustment for current body characteristics, early life and parental background factors, systolic and diastolic blood pressure remained comparable in both groups. In ICSI boys, a slightly lower systolic (113 ± 10 mmHg), but comparable diastolic (64 ± 6 mmHg) resting blood pressure was found in comparison with the SC group (116 ± 9 mmHg; P = 0.04 and 65 ± 5 mmHg; P = 0.1). After adjustment for height and age, systolic and diastolic blood pressure were comparable in both groups (P = 0.7 and P = 0.6). After correction for current body characteristics, early life and parental factors, ICSI and SC boys still had comparable systolic (difference in ICSI versus SC: -1.1 mmHg; 95% CI: -3.8-1.6; P = 0.4) and diastolic (difference in ICSI versus SC: -1.2 mmHg; 95% CI: -3.2-0.7; P = 0.2) blood pressure measurements. In the small subsample of girls and boys with continuous blood pressure readings, the systolic and diastolic blood pressure response to the stress test was not significantly different between the ICSI and SC groups even after taking into account the baseline values. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Despite the rather low response rate in the ICSI group and the fact that no information on current health status could be obtained from more than a quarter of the eligible comparison group, the non-participating analysis in the ICSI as well in the SC group did not reveal differences between participating and non-participating children regarding clinical characteristics. The negative results for the sub-analysis on blood pressure response to stress should be interpreted with caution, because these data were available for only a small number of children, and the analysis may be underpowered. This result can only rule out a large effect on blood pressure responsiveness to a psychological stressor. Although our sample size appears to be appropriate, our results need confirmation by others and in larger cohorts when more data become available. GENERALIZABILITY TO OTHER POPULATIONS: Our results are the first described ever in ICSI offspring, born to parents suffering from predominantly male factor infertility. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Onderzoeksraad Vrije Universiteit Brussel and Wetenschappelijk Fonds Willy Gepts. Unconditional grants from MSD Belgium, Merck International, IBSA Institut Biochimique and Ferring International Center are kindly acknowledged.

Salivary testosterone concentrations in pubertal ICSI boys compared with spontaneously conceived boys.

BACKGROUND To date, no data exist about Leydig cell function of pubertal boys born after ICSI. To evaluate a potential risk of gonadal dysfunction in children born from fathers with compromised fertility, testicular function was assessed by the measurement of salivary testosterone. METHODS Morning salivary testosterone levels at the age of 14 years were compared between 58 ICSI teenagers who are part of the oldest ICSI cohort, and 62 boys born after spontaneous conception (SC). RESULTS Salivary testosterone levels were comparable between ICSI (113 ± 42 pg/ml) and SC (123 ± 56 pg/ml) teenagers at the age of 14 years. In the ICSI group, testosterone levels in boys from fathers with severe oligozoospermia were not different from concentrations in boys from fathers without severe oligozoospermia (115.5 ± 43 and 109 ± 41 pg/ml, respectively). CONCLUSIONS At the age of 14 years, pubertal ICSI boys show testosterone levels comparable to their peers born after SC. ICSI adolescents fathered from men with severely compromised spermatogenesis show testosterone levels comparable to those from fathers with normal spermatogenesis. This notwithstanding, further follow-up of ICSI teenagers into adulthood is mandatory to confirm a normal gonadal function.

Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis.

BACKGROUND: There is evidence that hyperemesis gravidarum (HG) is associated with a predominance of female fetuses, lower birthweights and shorter gestational ages at birth. As the adverse effects of prematurity and low birthweight on disease risk in later life have become increasingly clear, the repercussions of HG might not be limited to adverse perinatal outcomes. OBJECTIVES: To summarise the evidence on short- and long-term outcomes of pregnancies with HG. SEARCH STRATEGY: A literature search was conducted in the electronic databases Medline and Embase. SELECTION CRITERIA: Studies were included that reported on the fetal, neonatal and long-term outcome of pregnancies complicated by HG. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. Meta-analysis was performed using review manager. MAIN RESULTS: Women with HG during pregnancy were more likely to have a female child (OR 1.27; 95% CI 1.21-1.34). They were also more likely to have a baby with low birthweight (LBW, <2500 kg; OR 1.42; 95% CI 1.27-1.58) that was small for gestational age (SGA; OR 1.28; 95% CI 1.02-1.60), and to deliver prematurely (OR 1.32; 95% CI 1.04-1.68). There was no association with Apgar scores, congenital anomalies or perinatal death. One study described an association between HG and testicular cancer in the offspring. AUTHOR'S CONCLUSIONS: There is evidence that HG is associated with a higher female/male ratio of offspring and a higher incidence of LBW, SGA and premature babies. Little is known about the long-term health effects of babies born to mothers whose pregnancies were complicated by HG.

The role of PCOS in mental health and sexual function in women with obesity and a history of infertility.

STUDY QUESTION: Do mental health and sexual function differ between women with or without polycystic ovary syndrome (PCOS) with comparable BMI and fertility characteristics? SUMMARY ANSWER: Women with PCOS have a poorer mental quality of life than women without PCOS, but there were no differences in symptoms of depression, anxiety, physical quality of life or sexual function. WHAT IS KNOWN ALREADY: Various studies suggest that women with PCOS have poorer mental health, such as higher symptoms of anxiety and depression with a lower quality of life, and have an impaired sexual function compared to women without PCOS. However, in most studies, BMI and infertility status differ between women with and without PCOS, which may hamper comparability. STUDY DESIGN SIZE DURATION: This study is a cross-sectional analysis of a 5-year follow-up of a randomized controlled trial (RCT) among women with obesity and a history of infertility. PARTICIPANTS/MATERIALS SETTING METHODS: Participants in this follow-up study of an RCT were women with obesity and infertility randomized to a lifestyle intervention followed by infertility treatment or prompt infertility treatment (control), stratified by ovulatory status and trial centre. In total, 173 (30.0%) women of the 577 women randomized in the initial trial participated in this follow-up study, with a mean follow-up of 5.5 years (range 3.7-7.0 years); of these women 73 had been diagnosed with PCOS and 100 did not have PCOS. Participants completed questionnaires on symptoms of anxiety and depression (Hospital Anxiety and Depression scale (HADS)), quality of life (36-item Short Form Health Survey (SF-36)) and sexual function (McCoy Female Sexuality Questionnaire (MFSQ)). We also compared quality of life subscale scores in women with and without PCOS and compared them to an age-matched Dutch reference population with average BMI. Effect sizes were calculated to assess the differences. MAIN RESULTS AND THE ROLE OF CHANCE: Symptoms of anxiety and depression, physical quality of life and sexual function did not differ significantly between obese women with and without PCOS. However, women with PCOS had a worse mental quality of life summary component score (-3.60 [95% CI -6.72 to -0.56]), mainly due to a lower score on the subscale 'role limitations due to emotional problems' (-12.41 [95% CI -22.78 to -2.28]), compared to women without PCOS. However, compared to an age-matched Dutch reference population, the obese infertile women with and without PCOS both scored lower on almost all physical and mental quality of life subscales. LIMITATIONS REASONS FOR CAUTION: These are secondary analyses of the follow-up study of the RCT. No power analysis was performed for the outcomes included in this analysis and, as our study had a relatively small sample size, the null findings could be based on insufficient power to detect small differences between the groups. Our study population had a high mean BMI (average total group 34.5 [SD ± 5.1]); therefore, our results may only be generalizable to women with obesity. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that PCOS status is associated with impaired mental quality of life. Anxiety and depression, physical quality of life and sexual function in obese infertile women with PCOS seem more related to the obesity than the PCOS status. STUDY FUNDING/COMPETING INTERESTS: The initial study and follow-up were supported by grants from: ZonMw (50-50110-96-518), the Dutch Heart Foundation (2013T085) and the European Commission (633595). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands, outside the submitted work. A.H. reports consultancy for Ferring pharmaceuticals. B.W.J.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.J.M. reports consultancy for ObsEva, Merck Merck KGaA, iGenomix and Guerbet. All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: The initial trial was registered on 16 November 2008 in the Dutch trial register; clinical trial registry number NTR1530.

The windsor definition for hyperemesis gravidarum: A multistakeholder international consensus definition.

OBJECTIVE: To develop an international definition for hyperemesis gravidarum to assist in clinical diagnosis and harmonize hyperemesis gravidarum definition for study populations. STUDY DESIGN: A mixed-methods approach was used to identify potential hyperemesis gravidarum definition criteria (i.e. systematic review, semi-structured interviews and closed group sessions with patients and Project Steering Committee input). To reach consensus on the definition we used a web-based Delphi survey with two rounds, followed by a face-to-face consensus development meeting, held in Windsor UK, and a web-based consultation round, in which the provisional hyperemesis gravidarum definition was fed back to the stakeholders. Four stakeholder groups were identified 1) researchers; 2) women with lived experience of hyperemesis gravidarum and their families; 3) obstetric health professionals (obstetricians, gynecologists, midwives); and 4) other health professionals involved in care for women with hyperemesis gravidarum (general practitioners, dieticians, nurses). To reflect the opinions of the international community, stakeholders from countries in all global regions were invited to participate. RESULTS: Twenty-one identified potential criteria entered the Delphi survey. Of the 277 stakeholders invited, 178 completed round one, and 125 (70%) also completed round two. Twenty stakeholders attended the consensus development meeting, representing all stakeholder groups. The consultation round was completed by 96 (54%) stakeholders, of which 92% agreed with the definition as presented. The consensus definition for hyperemesis gravidarum consisted of: start of symptoms in early pregnancy (before 16 weeks gestational age); nausea and vomiting, at least one of which severe; inability to eat and/or drink normally; strongly limits daily living activities. Signs of dehydration were deemed contributory for the definition for hyperemesis gravidarum. CONCLUSIONS: The proposed definition for hyperemesis gravidarum will help clinical studies to achieve more uniformity, and ultimately increasing the value of evidence to inform patient care.

Serum inhibin B concentrations in pubertal boys conceived by ICSI: first results.

BACKGROUND: Currently, no published data exist about the gonadal function of children born after ICSI. To evaluate potential risk of testicular seminal dysfunction in boys born to fathers with compromised spermatogenesis, serum inhibin B (as a marker for spermatogenesis) was assessed. METHODS: We recruited 50 pubertal adolescents from the oldest cohort of infants born following ICSI. Cross-sectional serum inhibin B levels of all 50 ICSI adolescents, and longitudinal serum inhibin B (assessed at 8 and 14 years) in 25 boys, are reported. RESULTS: A statistically significant increase in inhibin B levels was observed between 8 (mean 69 ng/l, SD ± 35) and 14 years (mean 145 ng/l, SD ± 41; P < 0.001). In three quarters of the ICSI boys an increase in serum inhibin B levels of at least 30% between 8 and 14 years was observed. In all but 4 of the 14-year-old ICSI boys serum inhibin B was normal. Serum inhibin B levels in boys from fathers with severe oligozoospermia did not differ from concentrations in boys from fathers without severe oligozoospermia (154 ± 51 and 142 ± 47 ng/l, respectively; P = 0.4). CONCLUSIONS: The majority of ICSI boys have a significant increase in serum inhibin B, attaining normal values for pubertal status at the age of 14 years. ICSI adolescents from fathers with severely compromised spermatogenesis do not have lower inhibin B levels than those with fathers with normal spermatograms. Further follow-up of the spermatogenic potential of ICSI teenagers up to young adulthood is mandatory to confirm a normal reproductive capacity.

Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE: Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS: We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case-control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle-Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES: Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: -2.45 95% CI -4.51 to -0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI -4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI -0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS: Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity.

Gestational diabetes mellitus among Sub-Saharan African and Surinamese women in the Netherlands.

AIM: We assessed the association between ethnicity and the risk of gestational diabetes mellitus (GDM) in the Netherlands. METHODS: A cohort of 7815 women with known GDM status and ethnicity, including women of Sub-Saharan African ethnicity who are currently not identified as high-risk in guidelines. We compared GDM rates among participants of ethnicity to those of ethnic Dutch participants. We employed multivariable regression to correct for possible confounders, including maternal age, pre-pregnancy body mass index (BMI), and education. GDM prevalence and odds ratios based on ethnicity were the main outcome measures. RESULTS: The prevalence rates of GDM according to ethnicity were: Dutch 0.6%, South-Asian Surinamese 6.9%, African-Surinamese 3.5%, Antillean 1.0%, Turkish 1.0%, Moroccan 1.4%, Ghanaian 6.8%, Sub-Saharan African 3.5%, other Western 0.5% and other non-Western 2.8%. After adjustment for age, pre-pregnancy BMI, and education duration, compared with the reference Dutch-ethnicity population, adjusted odds ratios (aOR) for GDM were statistically significantly higher in South-Asian Surinamese (aOR 10.9; 95% Confidence Interval (CI), 4.7-25.0), African-Surinamese (4.3; 2.0-9.2), Ghanaian (6.5; 3.0-14.5), Sub-Saharan African (5.7; 2.0-16.0), and other non-Western women (4.5; 2.2-9.0). GDM was not significantly increased among Antillean (1.4; 0.2-10.3), Turkish (1.4; 0.4-4.2), Moroccan (1.8; 0.8-4.0), and other Western women (0.8; 0.3-2.2). CONCLUSIONS: This study shows for the first time in the Netherlands that women of Ghanaian or other Sub-Saharan African ethnicity have an increased risk of developing GDM than the Dutch. This calls for adaptation of the Dutch guidelines of screening high-risk groups for GDM and more awareness amongst obstetric caregivers.