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

The effect of twin-to-twin delivery time intervals on neonatal outcome for second twins

Abstract Background The objective was to examine the effect of twin-to-twin delivery intervals on neonatal outcome for second twins. Methods This was a retrospective, hospital-based study, performed at a university teaching hospital in Western Sweden. Twin deliveries between 2008 and 2014 at ≥32 + 0 weeks of gestation, where the first twin was delivered vaginally, were included. Primary outcome was a composite outcome of metabolic acidosis, Apgar   30 min (p <  0.0001). Conclusions An association, but not necessarily a causality, between twin-to-twin delivery interval and primary outcome was seen. An upper time limit on twin-to-twin delivery time intervals may be justified. However, the optimal time interval needs further studies

Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden

Objective: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. Methods: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely ‘Universal screening’, ‘High-risk-based screening’ (i.e. screening of high-risk women only), ‘Low-risk-based screening’ (i.e. treatment of high-risk population and screening of remaining women) and ‘Nullipara screening’ (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening (‘No screening, treat high-risk group’). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden (‘No screening’). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33–36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with ‘No screening’) and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. Results: All interventions had better health outcomes than did ‘No screening’, with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was ‘Low-risk-based screening’, irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). ‘Low-risk-based screening’ at Cx1 was cost-effective, while ‘Low-risk-based screening’ at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for ‘Low-risk-based screening’ at Cx1 and 36 800 USD for ‘Low-risk-based screening’ at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that ‘Low-risk-based screening’ at Cx1 is cost-effective compared with ‘No screening’ was 71%. Conclusion: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden

Obstetric Outcomes in Women With Turner Karyotype EDITORIAL COMMENT

There is concern over the high risk of cardiovascular complications, hypertensive disorders, and other adverse obstetric outcomes among pregnant women with Turner syndrome (TS). A diagnosis of TS is made in some women late in life or not at all. Spontaneous pregnancies are rare in women with TS and are associated with a high rate of complications, especially miscarriage. The use of assisted reproductive techniques is an option for these women; pregnancy and implantation rates after oocyte donation in women with TS seem to be comparable with those without TS who need this treatment. Few data are available on obstetric outcome in pregnant women with TS. The aim of this retrospective population-based cohort study was to compare maternal and neonatal outcomes among singleton pregnancies of women with and without TS. Data on births occurring between 1973 and 2007 from the Swedish Genetic Turner Register and the Swedish Medical Birth Register were cross-linked. Obstetric outcome in infants born to women with TS was compared with a reference group of 56,000 women from the general population. Mean gestational age and birth weight were adjusted for maternal age. Outcome in TS women with twins was described separately. A total of 115 women with TS gave birth to 208 children (202 singletons and 3 sets of twins) during the study period. The TS diagnosis was unknown in 52% of the women before the first delivery. Women in the TS group were older at the first delivery than women in the reference group; median age was 30 years and 26 years, respectively (P < 0.0001). There was a trend toward more women with TS having preeclampsia during their first pregnancy (6.3 vs. 3.0%; P = 0.07). One woman suffered from an aortic dissection during her second spontaneous pregnancy. Compared with the reference group, the median gestational age was shorter in children in the TS group (-6.4 days, P = 0.0067), and median birth weight was lower (-208 g, P = 0.001); however, no significant difference was found in median standard deviation scores for weight and length at birth. The rate of cesarean delivery was higher in the TS group than in the reference group (35.6% vs. 11.8%, respectively, P < 0.0001). There was no significant difference in birth defects between groups. These findings show that women with a TS karyotype have mostly favorable obstetric outcomes. Singletons of women with TS have a shorter gestational age but a similar size at birth. The data also show no difference in birth defects between women with and without TS