The Risk of Birth Defects With Conception by ART

Barbara Luke; Morton B. Brown; Ethan Wantman; Nina E. Forestieri; Marilyn L. Browne; Sarah C. Fisher; Mahsa M. Yazdy; Mary K. Ethen; Mark A. Canfield; Stephanie Watkins; Hazel B. Nichols; Leslie V. Farland; Sergio Oehninger; Kevin J. Doody; Michael L. Eisenberg; Valerie L. Baker

Disclosures

Hum Reprod. 2021;36(1):116-129. 

In This Article

Results

Characteristics of the Study Population

The final study population included 1 236 016 children (135 051 ART, 23 647 ART siblings, 9396 OI/IUI-conceived and 1 067 922 naturally conceived); 25 035 children (2.0%) had a major birth defect. There were 1 145 017 singleton children (78 362 ART, 22 301 ART siblings, 6597 OI/IUI-conceived and 1 037 757 naturally conceived), and 90 999 twin children (56 689 ART, 1346 ART siblings, 2799 OI/IUI-conceived and 30 165 naturally conceived); 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. The characteristics of the study population are shown in Table I for singletons and Supplementary Table SII for twins. The majority of women in the fertile group were between the ages of 18–29 years, compared to 30–37 years for the OI/IUI group and ART-treated women using autologous oocytes, and 41 years and older for ART-treated women using donor oocytes. Women with naturally conceived children were more likely to be Hispanic, and less likely to be white, to have completed college, be of lower parity, or have diabetes or hypertension compared to the other groups; the results were similar for twins. The prevalence of major birth defects (both chromosomal and nonchromosomal) among singletons was 1.9% among the naturally conceived group, 2.1% among the OI/IUI group, 2.0% among ART siblings, and within the ART group, 2.3–2.7% by oocyte source-embryo state category. Among twins, the prevalence of major birth defects was 3.2% among the naturally conceived group, 3.1% among the OI/IUI group, 3.9% among ART siblings and within the ART group, 3.0–3.8% by oocyte source-embryo state category. Within the ART group, women using autologous oocytes were more likely to have the diagnoses of male factor, endometriosis, ovulation disorders, other tubal factors or unexplained, whereas women using donor oocytes were more likely to have the diagnosis of diminished ovarian reserve or other reason for ART (includes immunologic, chromosomal or other serious disease), as shown in Table II. Sperm source and the use of ICSI was only reported for cycles using fresh embryos; in both autologous and donor oocyte cycles partner sperm were used in about 90% of cycles, and ICSI was used in more than 60% of cycles, higher in the presence of male factor infertility than without this diagnosis; the results were similar for twins (Table I and Table II and Supplementary Table SII and Supplementary Table SIII).

Risk of Birth Defects in ART and non-ART Groups

The results of the logistic regression models for singleton children are presented in Table III for singletons and Supplementary Table SIV for twins. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (adjusted odds ratio (AOR) 1.18, 95% CI 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40) and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos with the use of ICSI) the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16,1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). Assisted hatching was not associated with birth defects in singletons or twins (data not shown). This analysis also confirmed known associations between risks for birth defects and older maternal age, higher BMI, diabetes, hypertension, and male sex of the infant, independent of subfertility and ART conception.

Risk of Birth Defects by ART Treatment Parameters

Table IV shows the rates per 10 000 singleton children and risks for each birth defect category for ART births by oocyte source-embryo state combinations, and the use of ICSI in fresh embryos. Among children conceived with fresh embryos, compared to children conceived from autologous oocytes without ICSI, the risks were increased for a major nonchromosomal defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defect (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defect (AOR 2.21, 95% CI 1.28, 3.82), and any defect (AOR 1.11, 95% CI 1.01, 1.22) with autologous oocytes and ICSI, and the risk of chromosomal defects was decreased (AOR 0.18, 95% CI 0.05, 0.67) with donor oocytes and ICSI. In models including children conceived with fresh and thawed embryos, compared to children conceived with autologous oocytes and fresh embryos, the use of donor oocytes was associated with decreased risks of chromosomal defects (donor, fresh, AOR 0.12, 95% CI 0.04, 0.43; donor, thawed, AOR 0.09, 95% CI 0.01, 0.67).

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