Twenty-five observational studies were included in the analysis. A total of 28,638 ART infants were included.
The majority of the 7 studies deemed to be of good quality had large sample sizes, and outcomes were ascertained without knowledge of conception status. All 7 studies included adjusted data or data matched for maternal age or parity. Methodological limitations were present in the remaining 18 studies, details of which were tabulated. Inter-reviewer agreement on the classification of validity of the 11 selected papers was 73%.
The results of the meta-analysis of the 7 good-quality studies showed a pooled OR of 1.40 (95% CI: 1.28, 1.53), representing a significantly increased risk of birth defects in infants exposed to ART. There was no significant heterogeneity amongst these studies (P=0.12). The pooled OR for all studies combined (n=25) showed a similar trend (OR 1.29, 95% CI: 1.21, 1.37). Statistically significant heterogeneity was observed amongst these studies (P<0.10).
In the subgroup analysis, the trend towards a higher risk of birth defect in ART infants was similar, regardless of how the data were grouped. Pooled OR estimates were high and statistically significant when the analysis was restricted to studies that provided separate data on major birth defects; the OR based on 3 good-quality studies was 2.01 (95% CI: 1.49, 2.69), while the OR based on all 15 studies was 1.32 (95% CI: 1.20, 1.45). No statistically significant heterogeneity was observed. For defects in singleton births, the OR was 1.35 (95% CI: 1.20, 1.51) when based on 6 good-quality studies and 1.31 (95% CI: 1.17, 1.46) when based on all 15 studies. Again, no statistically significant heterogeneity was observed. Similar inferences were evident from the random-effects analysis.
Publication bias was detected and attributed to 3 specific outlying studies. Further analysis that excluded these studies (and those with higher weight) did not substantially alter the pooled estimates.
The pooled ORs from the 7 studies selected for meta-analysis showed a NNTH of between 250 and 62, given a baseline population prevalence of between 1 and 4%.