Puberty disorders among ART-conceived singletons : a Nordic register study from the CoNARTaS group

STUDY QUESTION Do ART-conceived children have an increased risk for puberty disorders? SUMMARY ANSWER Both ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys. WHAT IS KNOWN ALREADY Some physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited. STUDY DESIGN, SIZE, DURATION A register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994-2014), Finland (1990-2014), Norway (2002-2015) and Sweden (1985-2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE There were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29-1.64) and late puberty (aHR 1.47, 95% CI: 1.21-1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29-1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24-1.95). LIMITATIONS, REASONS FOR CAUTION Using reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers' own puberty characteristics and BMI, as well as children's BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility. WIDER IMPLICATIONS OF THE FINDINGS This large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg oresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway's Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium 'Family Formation in Flux-Causes, Consequences and Possible Futures', funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose.Peer reviewe

International migration and adverse birth outcomes: role of ethnicity, region of origin and destination

Background: The literature on international migration and birth outcomes shows mixed results. This study examined whether low birth weight (LBW) and preterm birth differed between non-migrants and migrant subgroups, defined by race/ethnicity and world region of origin and destination. Methods: A systematic review and meta-regression analyses were conducted using three-level logistic models to account for the heterogeneity between studies and between subgroups within studies. Results: Twenty-four studies, involving more than 30 million singleton births, met the inclusion criteria. Compared with US-born black women, black migrant women were at lower odds of delivering LBW and preterm birth babies. Hispanic migrants also exhibited lower odds for these outcomes, but Asian and white migrants did not. Sub-Saharan African and Latin-American and Caribbean women were at higher odds of delivering LBW babies in Europe but not in the USA and south-central Asians were at higher odds in both continents, compared with the native-born populations. Conclusions: The association between migration and adverse birth outcomes varies by migrant subgroup and it is sensitive to the definition of the migrant and reference groups

Maternal care and birth outcomes among ethnic minority women in Finland

<p>Abstract</p> <p>Background</p> <p>Care during pregnancy and labour is of great importance in every culture. Studies show that people of migrant origin have barriers to obtaining accessible and good quality care compared to people in the host society. The aim of this study is to compare the access to and use of maternity services, and their outcomes among ethnic minority women having a singleton birth in Finland.</p> <p>Methods</p> <p>The study is based on data from the Finnish Medical Birth Register in 1999–2001 linked with the information of Statistics Finland on woman's country of birth, citizenship and mother tongue. Our study data included 6,532 women of foreign origin (3.9% of all singletons) giving singleton birth in Finland during 1999–2001 (compared to 158,469 Finnish origin singletons).</p> <p>Results</p> <p>Most women have migrated during the last fifteen years, mainly from Russia, Baltic countries, Somalia and East Europe. Migrant origin women participated substantially in prenatal care. Interventions performed or needed during pregnancy and childbirth varied between ethnic groups. Women of African and Somali origin had most health problems resulted in the highest perinatal mortality rates. Women from East Europe, the Middle East, North Africa and Somalia had a significant risk of low birth weight and small for gestational age newborns. Most premature newborns were found among women from the Middle East, North Africa and South Asia. Primiparous women from Africa, Somalia and Latin America and Caribbean had most caesarean sections while newborns of Latin American origin had more interventions after birth.</p> <p>Conclusion</p> <p>Despite good general coverage of maternal care among migrant origin women, there were clear variations in the type of treatment given to them or needed by them. African origin women had the most health problems during pregnancy and childbirth and the worst perinatal outcomes indicating the urgent need of targeted preventive and special care. These study results do not confirm either healthy migrant effect or epidemiological paradox according to which migrant origin women have considerable good birth outcomes.</p

Producing valid statistics when legislation, culture, and medical practices differ for births at or before the threshold of survival: Report of a European workshop

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Quantifying the burden of stillbirths before 28 weeks of completed gestational age in high-income countries: a population-based study of 19 European countries

Background International comparisons of stillbirth allow assessment of variations in clinical practice to reduce mortality. Currently, such comparisons include only stillbirths from 28 or more completed weeks of gestational age, which underestimates the true burden of stillbirth. With increased registration of early stillbirths in high-income countries, we assessed the reliability of including stillbirths before 28 completed weeks in such comparisons. Methods In this population-based study, we used national cohort data from 19 European countries participating in the Euro-Peristat project on livebirths and stillbirths from 22 completed weeks of gestation in 2004, 2010, and 2015. We excluded countries without national data for stillbirths by gestational age in these periods, or where data available were not comparable between 2004 and 2015. We also excluded those countries with fewer than 10 000 births per year because the proportion of stillbirths at 22 weeks to less than 28 weeks of gestation is small. We calculated pooled stillbirth rates using a random-effects model and changes in rates between 2004 and 2015 using risk ratios (RR) by gestational age and country. Findings Stillbirths at 22 weeks to less than 28 weeks of gestation accounted for 32% of all stillbirths in 2015. The pooled stillbirth rate at 24 weeks to less than 28 weeks declined from 0·97 to 0·70 per 1000 births from 2004 to 2015, a reduction of 25% (RR 0·75, 95% CI 0·65–0·85). The pooled stillbirth rate at 22 weeks to less than 24 weeks of gestation in 2015 was 0·53 per 1000 births and did not significantly changed over time (RR 0·97, 95% CI 0·80–1·16) although changes varied widely between countries (RRs 0·62–2·09). Wide variation in the percentage of all births occurring at 22 weeks to less than 24 weeks of gestation suggest international differences in ascertainment. Interpretation Present definitions used for international comparisons exclude a third of stillbirths. International consistency of reporting stillbirths at 24 weeks to less than 28 weeks suggests these deaths should be included in routinely reported comparisons. This addition would have a major impact, acknowledging the burden of perinatal death to families, and making international assessments more informative for clinical practice and policy. Ascertainment of fetal deaths at 22 weeks to less than 24 weeks should be stabilised so that all stillbirths from 22 completed weeks of gestation onwards can be reliably compared

Time trends in placenta-mediated pregnancy complications after assisted reproductive technology in the Nordic countries

Background The use of assisted reproductive technology (ART) is increasing worldwide and conception after assisted reproduction currently comprises 3-6% of birth cohorts in the Nordic countries. The risk of placenta-mediated pregnancy complications is higher after ART compared to spontaneously conceived pregnancies. Whether the excess risk of placenta-mediated pregnancy complications in pregnancies following assisted reproduction has changed over time, is unknown. Objectives To investigate whether time trends in risk of pregnancy complications (hypertensive disorders in pregnancy, placental abruption and placenta previa) differ for pregnancies after ART compared to spontaneously conceived pregnancies during three decades of assisted reproduction treatment in the Nordic countries. Study Design In a population-based cohort study, with data from national health registries in Denmark (1994-2014), Finland (1990-2014), Norway (1988-2015) and Sweden (1988-2015), we included 6,830,578 pregnancies resulting in delivery. Among these, 146,998 (2.2%) were pregnancies after assisted reproduction (125,708 singleton pregnancies, 20,668 twin pregnancies and 622 of higher order plurality) and 6,683,132 (97.8%) pregnancies were conceived spontaneously (6,595,185 singleton pregnancies, 87,106 twin pregnancies and 1,289 of higher order plurality). We used logistic regression with post-estimation to estimate absolute risks and risk differences for each complication. We repeated analyses for singleton and twin pregnancies, separately. In sub-samples with available information, we also adjusted for maternal body mass index, smoking during pregnancy, previous cesarean section, culture duration and cryopreservation. Results The risk of each placental complication was consistently higher in pregnancies following ART compared to spontaneously conceived pregnancies across the study period, except for hypertensive disorders in twin pregnancies, where risks were similar. Risk of hypertensive disorders increased over time in twin pregnancies for both conception methods, but more strongly for pregnancies following ART (risk difference 1.73 percentage points per 5 years, 95% confidence interval 1.35 to 2.11) than for spontaneously conceived twins (risk difference 0.75 percentage points, 95% confidence interval 0.61 to 0.89). No clear time trends were found for hypertensive disorders in singleton pregnancies. Risk of placental abruption decreased over time in all groups (risk difference -0.16 percentage points, 95% confidence interval -0.19 to -0.12 and -0.06 percentage points, 95% confidence interval -0.06 to -0.05 for pregnancies after assisted reproduction and spontaneously conceived pregnancies, respectively, for singletons and multiple pregnancies combined). Over time, the risk of placenta previa increased in pregnancies after assisted reproduction among both singletons (risk difference 0.21 percentage points, 95% confidence interval 0.14 to 0.27) and twins (risk difference 0.30 percentage points, 95% confidence interval 0.16 to 0.43), but remained stable in spontaneously conceived pregnancies. When adjusting for culture duration, the temporal increase in placenta previa became weaker in all groups of ART pregnancies, whereas adjustment for cryopreservation moderately attenuated trends in ART twin pregnancies. Conclusions The risk of placenta-mediated pregnancy complications following ART remains higher compared to spontaneously conceived pregnancies, despite declining rates of multiple pregnancies. For hypertensive disorders in pregnancy and placental abruption, pregnancies after assisted reproduction follow the same time trends as the background population, whereas for placenta previa, risk has increased over time in pregnancies after ART.Peer reviewe

Trends over time in congenital malformations in live-born children conceived after assisted reproductive technology

IntroductionChildren born after assisted reproductive technology, particularly singletons, have been shown to have an increased risk of congenital malformations compared with children born after spontaneous conception. We wished to study whether there has been a change in the past 20 years in the risk of major congenital malformations in children conceived after assisted reproductive technology compared with children spontaneously conceived. Material and methodsPopulation-based cohort study including 90 201 assisted reproductive technology children and 482 552 children spontaneously conceived, born in Denmark, Finland, Norway and Sweden. Both singletons and twins born after in vitro fertilization, intracytoplasmatic sperm injection and frozen embryo transfer were included. Data on children were taken from when the national Nordic assisted reproductive technology registries were established until 2007. Multiple logistic regression analyses were used to estimate the risks and adjusted odds ratios for congenital malformations in four time periods: 1988-1992, 1993-1997, 1998-2002 and 2003-2007. Only major malformations were included. ResultsThe absolute risk for singletons of being born with a major malformation was 3.4% among assisted reproductive technology children vs. 2.9% among children spontaneously conceived during the study period. The relative risk of being born with a major congenital malformation between all assisted reproductive technology children and children spontaneously conceived remained similar through all four time periods (p = 0.39). However, we found that over time the number of children diagnosed with a major malformation increased in both groups across all four time periods. ConclusionWhen comparing children conceived after assisted reproductive technology and spontaneously conceived, the relative risk of being born with a major congenital malformation did not change during the study period.Peer reviewe

Epidemiological analysis of peripartum hysterectomy across nine European countries

Introduction Peripartum hysterectomy is a surgical procedure performed for severe obstetric complications such as major obstetric hemorrhage. The prevalence of peripartum hysterectomy in high-resource settings is relatively low. Hence, international comparisons and studying indications and associations with mode of birth rely on the use of national obstetric survey data. Objectives were to calculate the prevalence and indications of peripartum hysterectomy and its association with national cesarean section rates and mode of birth in nine European countries. Material and methods We performed a descriptive, multinational, population-based study among women who underwent peripartum hysterectomy. Data were collected from national or multiregional databases from nine countries participating in the International Network of Obstetric Survey Systems. We included hysterectomies performed from 22 gestational weeks up to 48 hours postpartum for obstetric hemorrhage, as this was the most restrictive, overlapping case definition between all countries. Main outcomes were prevalence and indications of peripartum hysterectomy. Additionally, we compared prevalence of peripartum hysterectomy between women giving birth vaginally and by cesarean section, and between women giving birth with and without previous cesarean section. Finally, we calculated correlation between prevalence of peripartum hysterectomy and national cesarean section rates, as well as national rates of women giving birth after a previous cesarean section. Results A total of 1302 peripartum hysterectomies were performed in 2 498 013 births, leading to a prevalence of 5.2 per 10 000 births ranging from 2.6 in Denmark to 10.7 in Italy. Main indications were uterine atony (35.3%) and abnormally invasive placenta (34.8%). Relative risk of hysterectomy after cesarean section compared with vaginal birth was 9.1 (95% CI 8.0-10.4). Relative risk for hysterectomy for birth after previous cesarean section compared with birth without previous cesarean section was 10.6 (95% CI 9.4-12.1). A strong correlation was observed between national cesarean section rate and prevalence of peripartum hysterectomy (rho = 0.67, P < .05). Conclusions Prevalence of peripartum hysterectomy may vary considerably between high-income countries. Uterine atony and abnormally invasive placenta are the commonest indications for hysterectomy. Birth by cesarean section and birth after previous cesarean section are associated with nine-fold increased risk of peripartum hysterectomy

Perinatal health monitoring in Europe: results from the EURO-PERISTAT project

Data about deliveries, births, mothers and newborn babies are collected extensively to monitor the health and care of mothers and babies during pregnancy, delivery and the post-partum period, but there is no common approach in Europe. We analysed the problems related to using the European data for international comparisons of perinatal health. We made an inventory of relevant data sources in 25 European Union (EU) member states and Norway, and collected perinatal data using a previously defined indicator list. The main sources were civil registration based on birth and death certificates, medical birth registers, hospital discharge systems, congenital anomaly registers, confidential enquiries and audits. A few countries provided data from routine perinatal surveys or from aggregated data collection systems. The main methodological problems were related to differences in registration criteria and definitions, coverage of data collection, problems in combining information from different sources, missing data and random variation for rare events. Collection of European perinatal health information is feasible, but the national health information systems need improvements to fill gaps. To improve international comparisons, stillbirth definitions should be standardised and a short list of causes of fetal and infant deaths should be developed