Overweight or obesity in children born after assisted reproductive technologies in Denmark: A population-based cohort study

Abstract

Background: The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility.

Methods and findings: This Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination [OI/IUI], and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval [CI] 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures.

Conclusions: We found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.

Fig 1. Study cohort.

Notes: Abbreviations: ART, assisted reproductive technologies; cIVF, conventional in vitro fertilization; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; OI, ovulation induction. *Lack of routine anthopometric evaluation did not differ according to exposure or cause of infertility. Lack of anthropometric measurement was consistently 13% among children conceived with ART overall, conventional IVF, ICSI, frozen-thawed embryo transfer, fresh embryo transfer, or OI/IUI, and among children from the general population born after no fertility treatment. Further, children with and without anthropometric measurements had similar parental and birth characteristics (S2 Text).

Fig 2. Overweight and obesity in children born after ARTs compared to OI with or without IUI (OI/IUI), overall and within subgroups defined by underlying causes of infertility.

Notes: We adjusted for parental causes of infertility, maternal and paternal age at conception, maternal and paternal highest educational level at conception, maternal country of origin, maternal BMI, maternal smoking status, maternal and paternal hyperlipidemia/use of lipid-modifying drugs, maternal and paternal hypertension/use of antihypertensive drugs, diabetes (type I or II) diagnosed at any time before conception, parity, and year of conception. P values were calculated by the large-sample Wald (Z) test. Abbreviations: ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; IUI, intrauterine insemination; OI, ovulation induction; POR, prevalence odds ratio.

Fig 3. Overweight and obesity in children born after ICSI compared to cIVF, overall and within subgroups defined by underlying causes of infertility.

Notes: We adjusted for parental causes of infertility, maternal and paternal age at conception, maternal and paternal highest educational level at conception, maternal country of origin, maternal BMI, maternal smoking status, maternal and paternal hyperlipidemia/use of lipid-modifying drugs, maternal and paternal hypertension/use of antihypertensive drugs, diabetes (type I or II) diagnosed at any time before conception, parity, and year of conception. P values were calculated by the large-sample Wald (Z) test. Abbreviations: BMI, body mass index; CI, confidence interval; cIVF, conventional in vitro fertilization; ICSI, intracytoplasmic sperm injection; POR, prevalence odds ratio.

Fig 4. Overweight and obesity in children born after frozen-thawed embryo transfer compared to fresh embryo transfer, overall and within subgroups defined by underlying causes of infertility.

Notes: We adjusted for parental causes of infertility, maternal and paternal age at conception, maternal and paternal highest educational level at conception, maternal country of origin, maternal BMI, maternal smoking status, maternal and paternal hyperlipidemia/use of lipid-modifying drugs, maternal and paternal hypertension/use of antihypertensive drugs, diabetes (type I or II) diagnosed at any time before conception, parity, and year of conception. Distribution of fresh vs. frozen embryo transfer by previous number of ART cycles: 0 cycles: 97.2% vs. 2.75%, 1 cycle: 78.9% vs. 21.1%, 2 cycles: 83.8% vs. 16.2%, ≥3 cycles: 84.5% vs. 15.5%. Distribution of fresh vs. frozen embryo transfer by maternal age (years): <25: 88.6% vs. 11.4%, 25–29: 87.9% vs. 12.1%, 30–34: 87.2% vs. 12.7%, 35–39: 87.1% vs. 12.9%, ≥40: 88.3% vs. 11.7%. P values were calculated by the large-sample Wald (Z) test. Abbreviations: ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; POR, prevalence odds ratio.

Fig 5. Crude and adjusted differences in mean BMI Z-scores, overall and within subgroups defined by underlying causes of infertility.

For children born after: (A) ARTs compared to OI with or without IUI (OI/IUI), (B) ICSI compared to cIVF, and (C) frozen-thawed embryo transfer compared to fresh embryo transfer. Notes: We adjusted for parental causes of infertility, maternal and paternal age at conception, maternal and paternal highest educational level at conception, maternal country of origin, maternal BMI, maternal smoking status, maternal and paternal hyperlipidemia/use of lipid-modifying drugs, maternal and paternal hypertension/use of antihypertensive drugs, diabetes (type I or II) diagnosed at any time before conception, parity, and year of conception. P values were calculated using the large-sample Wald (Z) test. Abbreviation: ART, assisted reproductive technology; BMI, body mass index; CI, confidence interval; cIVF, conventional in vitro fertilization; IUI, intrauterine insemination; OI, ovulation induction.