Cardiovascular disease, obesity, and type 2 diabetes in children born after assisted reproductive technology: A population-based cohort study.

BACKGROUND: Some earlier studies have found indications of significant changes in cardiometabolic risk factors in children born after assisted reproductive technology (ART). Most of these studies are based on small cohorts with high risk of selection bias. In this study, we compared the risk of cardiovascular disease, obesity, and type 2 diabetes between singleton children born after ART and singleton children born after spontaneous conception (SC). METHODS AND FINDINGS: This was a large population-based cohort study of individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015. Data were obtained from national ART and medical birth registers and cross-linked with data from national patient registers and other population-based registers in the respective countries. In total, 122,429 children born after ART and 7,574,685 children born after SC were included. Mean (SD) maternal age was 33.9 (4.3) years for ART and 29.7 (5.2) for SC, 67.7% versus 41.8% were primiparous, and 45.2% versus 32.1% had more than 12 years of education. Preterm birth (<37 weeks 0 days) occurred in 7.9% of children born after ART and 4.8% in children born after SC, and 5.7% versus 3.3% had a low birth weight (<2,500 g). Mean (SD) follow-up time was 8.6 (6.2) years for children born after ART and 14.0 (8.6) years for children born after SC. In total, 135 (0.11%), 645 (0.65%), and 18 (0.01%) children born after ART were diagnosed with cardiovascular disease (ischemic heart disease, cardiomyopathy, heart failure, or cerebrovascular disease), obesity or type 2 diabetes, respectively. The corresponding values were 10,702 (0.14%), 30,308 (0.74%), and 2,919 (0.04%) for children born after SC. In the unadjusted analysis, children born after ART had a significantly higher risk of any cardiovascular disease (hazard ratio [HR] 1.24; 95% CI 1.04-1.48; p = 0.02), obesity (HR 1.13; 95% CI 1.05-1.23; p = 0.002), and type 2 diabetes (HR 1.71; 95% CI 1.08-2.73; p = 0.02). After adjustment, there was no significant difference between children born after ART and children born after SC for any cardiovascular disease (adjusted HR [aHR]1.02; 95% CI 0.86-1.22; p = 0.80) or type 2 diabetes (aHR 1.31; 95% CI 0.82-2.09; p = 0.25). For any cardiovascular disease, the 95% CI was reasonably narrow, excluding effects of a substantial magnitude, while the 95% CI for type 2 diabetes was wide, not excluding clinically meaningful effects. For obesity, there was a small but significant increased risk among children born after ART (aHR 1.14; 95% CI 1.06-1.23; p = 0.001). Important limitations of the study were the relatively short follow-up time, the limited number of events for some outcomes, and that the outcome obesity is often not considered as a disease and therefore not caught by registers, likely leading to an underestimation of obesity in both children born after ART and children born after SC. CONCLUSIONS: In this study, we observed no difference in the risk of cardiovascular disease or type 2 diabetes between children born after ART and children born after SC. For obesity, there was a small but significant increased risk for children born after ART. TRIAL REGISTRATION NUMBER: ISRCTN11780826.

School performance in children born after ICSI.

STUDY QUESTION: Do children conceived after ICSI have similar school performance as children born after IVF? SUMMARY ANSWER: Children born after ICSI have similar school performance compared to children born after IVF. WHAT IS KNOWN ALREADY: Studies concerning the cognitive skills of children born after ICSI have shown diverging results. STUDY DESIGN, SIZE, DURATION: This nationwide, register-based cohort study included all singleton children born after ICSI (n = 6953), IVF (n = 11 713) or spontaneous conception (SC) (n = 2 022 995), in Sweden between 1985 and 2006. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singleton children born after ICSI were identified in national IVF registers, cross-linked with the Medical Birth Register (MBR), the National Patient Register (NPR) and the Swedish Cause of Death Register (CDR) for characteristics and medical outcomes. Data on school performance, parental education and other parental characteristics were obtained through cross-linking to the National School Registry and to Statistics Sweden. The main control group, which consisted of children born after IVF, was identified in the national IVF registries while the second control group, consisting of children born after SC, was identified from the MBR. Simple and multivariable linear regression was used for analysis of continuous variables, and logistic regression was used for the analysis of binary outcomes. Adjustments were made for sex, year of birth, maternal smoking during pregnancy, parental age, parity, parental region of birth, parental level of education and frozen embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: In the adjusted analyses, there was no significant difference between ICSI and IVF children for total score (adjusted odds ratios (AORs) 1.03; 95% CI -0.22 to 2.28; P = 0.11), specific subjects, qualifying for secondary school (AOR 1.02; 95% CI 0.82-1.26; P = 0.87) or poor school performance (AOR 0.92; 95% CI 0.75-1.14; P = 0.47). In the third grade, children born after ICSI had a significantly lower chance of passing all of the subtests in Mathematics (AOR 0.89; 0.83-0.96; P = 0.002) and Swedish (AOR 0.92; 0.85-0.99; P = 0.02) compared to children born after SC. When cross-linking children with missing data on school performances (2.1% for ICSI, 2.0% for IVF and 2.3% for SC) with the Cerebral Palsy Follow-up Register (CPUP) for cerebral palsy, 2.7% of ICSI children, 5.7% of IVF children and 1.7% of SC children without registered education were found. When cross-linking children with missing data on school performances with the NPR for mental retardation, 29.9% of ICSI children, 32.6% of IVF children and 35.0% of SC children with missing data were registered under such a diagnosis. LIMITATIONS, REASONS FOR CAUTION: The main limitation was that test scores were missing in a small percentage in both ICSI and IVF children. Although we were able to cross-link this subpopulation with the CPUP and the NPR, these diagnoses only partly explained the missing scores. Other limitations were unmeasured and unknown possible confounders, such as information about infertility diagnoses and indication for ICSI, were not available. WIDER IMPLICATIONS OF THE FINDINGS: These findings are important to most countries where IVF and ICSI are used since there may be differences in choice of procedure. In recent years, there has been an increasing trend towards using ICSI not only for treatment of male infertility but also when the sperm quality is normal. Our results indicate that the school performance of children born after ICSI is reassuring. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received through Sahlgrenska University Hospital (ALFGBG - 70 940), Hjalmar Svensson Research Foundation and Nordforsk, project number 71 450. None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

School performance in singletons born after assisted reproductive technology.

STUDY QUESTION: Is school performance in children conceived after assisted reproductive technology (ART) comparable to those conceived after spontaneous conception (SC)? SUMMARY ANSWER: Singleton children born after ART performed better in the crude analysis than singleton children born after SC although after adjustment, small differences were observed in total scores in favour of SC children. WHAT IS KNOWN ALREADY: While it is well known that ART children, also singletons, have an adverse perinatal outcome, studies on cognitive skills in ART children are inconsistent and only few studies have been published on school performances. Although these studies indicate good school performances in ART children many studies suffer from low participation rate and few participants. STUDY DESIGN, SIZE, DURATION: This retrospective population-based cohort study included all singleton children in Sweden, born after ART (n = 8323) or SC (n = 1 499 667), between 1985 and 2001. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singleton children born after ART, identified in national IVF registries, were cross-linked with the Medical Birth Registry (MBR), the National Patient Registry (NPR) and the Swedish Cause of Death Registry (CDR) for characteristics and medical outcomes. Data on school performances, parental education and other parental characteristics was obtained through cross-linking to the National School Register and to Statistics Sweden. The control group was identified from the MBR and consisted of all singletons born after SC during the same time period. The primary outcome was school performance after 9 years at primary school and based on a mean total score of 16 subjects (0-320). The secondary outcomes were the mean school grade in specific subjects (mathematics, Swedish, English, physical education), 'qualified to enter secondary school' (i.e. approved in mathematics, Swedish and English) and 'poor school performance' (total score <160). Since the distribution of school grades was skewed, percentiles were used. Simple and multivariable linear regression was used for analysis of percentiles and logistic regression was used for the corresponding analysis of binary outcomes. Adjustments were made for child gender and year of birth, maternal age, parity, maternal smoking, paternal age, parental region of birth, parental education and socioeconomic class. MAIN RESULTS AND THE ROLE OF CHANCE: Data on 1 507 990 singletons in the ninth grade and registered by the Swedish School Authority were included. In the crude analysis, mean total scores were significantly higher for ART children (mean total score 230.2 (SD 57.2), corresponding to mean percentiles 60.2 (SD 27.7)), than for their SC counterparts (mean total score of 209.7 (SD 63.9), corresponding to mean percentiles 50.2 (SD 29.0)). However, after adjustments for several confounders, SC children had a significant advantage (adjusted mean difference [percentiles] -0.72, 95% confidence interval [CI] -1.31 to -0.12; P = 0.018). When analysing boys and girls together, no significant difference between children born after ART and children born after SC was found in mathematics, Swedish, English or physical education. Neither was there any significant difference between ART children and SC children in qualifying for secondary school (adjusted odds ratio [AOR] 1.05; 95% CI 0.95-1.17, P = 0.35) or in poor school performance (AOR 0.98; 95% CI, 0.89-1.09, P = 0.73). When cross-linking children with missing data on school performances (2.7% for ART and 2.8% for SC) with the NPR for mental disability, 35% of ART and 34% of SC children with missing data, were registered under such a diagnosis. LIMITATIONS, REASONS FOR CAUTION: The main limitation was that test scores were missing in a small percentage in both ART and SC children. Although we were able to crosslink this subpopulation with the NPR using codes for mental disability, such diagnosis only partly explained the missing scores. Other limitations are residual confounding caused by unknown confounders. WIDER IMPLICATIONS OF THE FINDINGS: The findings are generally reassuring and indicate, in the crude analysis, that school performances of ART children compared to children born after SC are better. After adjustment small differences were observed in total scores in favour of SC children. There were no significant differences, when analysing boys and girls together in specific subjects, in secondary school qualification or poor school performance. STUDY FUNDING/COMPETING INTEREST(S): Financial support was received through Sahlgrenska University Hospital (ALFGBG-70 940), Hjalmar Svensson Research Foundation and Nordforsk, project number 71450. None the authors declare any conflict of interest.

Pregnancy outcome and long-term follow-up after in vitro fertilization in women with renal transplantation.

STUDY QUESTION: What is the child morbidity after IVF in women who have received a kidney transplant? SUMMARY ANSWER: Overall, obstetric outcome and morbidity in children of women who had undergone renal transplantation and IVF treatment were favourable. WHAT IS KNOWN ALREADY: There are several studies of the obstetric outcome in women with spontaneous conception after solid organ transplantation as well as studies of obstetric outcome after IVF in general. There are only a few case reports of women with kidney or pancreas-kidney transplantation and deliveries after IVF treatment. STUDY DESIGN, SIZE, DURATION: A population-based retrospective register study was carried out in Sweden including all women with solid organ transplantation and deliveries after IVF; however, only women with kidney transplants were recruited. It also included information on all singleton deliveries after kidney transplantation and spontaneous conception between 1973 and 2012. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We cross-linked the IVF registers with the Medical Birth Register, the Patient Register and the Cause of Death Register. Study group 1 consisted of women with kidney transplantation and deliveries after IVF treatment. Study group 2 consisted of women with kidney transplantation and singleton deliveries after spontaneous conception. Group 3 (control group to singletons in study group 1) consisted of women without organ transplantation and with singleton deliveries after IVF, matched for maternal age, parity and date of birth. Group 4 (control group to study group 2) consisted of women without organ transplantation and with singleton deliveries after spontaneous conception, matched for maternal age, parity and year of birth. MAIN RESULTS AND THE ROLE OF CHANCE: Seven singletons and one set of twins were born after organ transplantation and IVF. All women in this group had renal transplants. Among singletons, two (28.6%) were preterm births (PTB), one (14.3%) had very low birthweight (VLBW) (672 g) and one (14.3%) was small for gestational age (SGA). Two infants had minor birth defects. One woman developed pre-eclampsia (14.3%). Mean age at follow-up of the children was 9.7 years (SD 4.2). Two children were diagnosed with hyperactivity disorders. There were 199 singletons born after renal transplantation and spontaneous conception. The rates of pre-eclampsia (23.6%), PTB (48.5%), LBW (43.7%) and SGA (21.2%) were significantly higher in pregnancies of women with renal transplants who had conceived spontaneously than in pregnancies where there was no transplantation and conception was spontaneous. Neonatal morbidity, early neonatal and infant mortality were all significantly higher. No increase in birth defects was seen. Mean age at follow-up of the children was 14.7 years (SD 9.4). Acute bronchitis, systemic lupus erythematosus and hyperactivity disorders were more common in children delivered to women with renal transplantation than in children delivered to women with no transplanted organs. Otherwise, long-term child morbidity was comparable. LIMITATIONS, REASONS FOR CAUTION: The women who had received renal transplants and who had given birth after IVF were a small group and may represent a selected group of comparatively healthy women. WIDER IMPLICATIONS OF THE FINDINGS: The results are important to transplant recipients with infertility problems. Neonatal outcomes after maternal renal transplantation and spontaneous conception were in agreement with the literature. Long-term follow-up of this group of children has long been asked for and findings are included in this report. STUDY FUNDING/COMPETING INTERESTS: No conflict of interest was reported. The study was supported by grants from Swedish Association of Local Authorities and Regions and by grants from the University of Gothenburg/Sahlgrenska University hospital (LUA/ALF 70940).

Comparison of the performances of survival analysis regression models for analysis of conception modes and risk of type-1 diabetes among 1985-2015 Swedish birth cohort.

The goal is to examine the risk of conception mode-type-1 diabetes using different survival analysis modelling approaches and examine if there are differentials in the risk of type-1 diabetes between children from fresh and frozen-thawed embryo transfers. We aimed to compare the performances and fitness of different survival analysis regression models with the Cox proportional hazard (CPH) model used in an earlier study. The effect of conception modes and other prognostic factors on type-1 diabetes among children conceived either spontaneously or by assisted reproductive technology (ART) and its sub-groups was modelled in the earlier study. We used the information on all singleton children from the Swedish Medical Birth Register hosted by the Swedish National Board of Health and Welfare, 1985 to 2015. The main explanatory variable was the mode of conception. We applied the CPH, parametric and flexible parametric survival regression (FPSR) models to the data at 5% significance level. Loglikelihood, Akaike and Bayesian information criteria were used to assess model fit. Among the 3,138,540 singletons, 47,938 (1.5%) were conceived through ART (11,211 frozen-thawed transfer and 36,727 fresh embryo transfer). In total, 18,118 (0.58%) of the children had type-1 diabetes, higher among (0.58%) those conceived spontaneously than the ART-conceived (0.42%). The median (Interquartile range (IQR)) age at onset of type-1 diabetes among spontaneously conceived children was 10 (14-6) years, 8(5-12) for ART, 6 (4-10) years for frozen-thawed embryo transfer and 9 (5-12) years for fresh embryo transfer. The estimates from the CPH, FPSR and parametric PH models are similar. There was no significant difference in the risk of type-1 diabetes among ART- and spontaneously conceived children; FPSR: (adjusted Hazard Ratio (aHR) = 1.070; 95% Confidence Interval (CI):0.929-1.232, p = 0.346) vs CPH: (aHR = 1.068; 95%CI: 0.927-1.230, p = 0.361). A sub-analysis showed that the adjusted hazard of type-1 diabetes was 37% (aHR = 1.368; 95%CI: 1.013-1.847, p = 0.041) higher among children from frozen-thawed embryo transfer than among children from spontaneous conception. The hazard of type-1 diabetes was higher among children whose mothers do not smoke (aHR = 1.296; 95%CI:1.240-1.354, p<0.001) and of diabetic mothers (aHR = 6.419; 95%CI:5.852-7.041, p<0.001) and fathers (aHR = 8.808; 95%CI:8.221-9.437, p<0.001). The estimates from the CPH, parametric models and the FPSR model were close. This is an indication that the models performed similarly and any of them can be used to model the data. We couldn't establish that ART increases the risk of type-1 diabetes except when it is subdivided into its two subtypes. There is evidence of a greater risk of type-1 diabetes when conception is through frozen-thawed transfer.