Infertility and the risk of adverse pregnancy outcomes: a systematic review and meta-analysis.

STUDY QUESTION: Do women who conceive without treatment after a long time to pregnancy (TTP) have an increased risk of preterm birth compared with women in the general obstetric population? SUMMARY ANSWER: Based on this meta-analyses of 14 studies, women with a long TTP are at an increased risk of preterm birth: pooled crude odds ratio (OR): 1.38 (95% CI: 1.25-1.54). WHAT IS KNOWN ALREADY: Several studies have shown that women who conceive without treatment after >12 months of trying have an elevated risk of poor pregnancy outcomes. To date, no systematic review or meta-analysis of this evidence has been published. STUDY DESIGN, SIZE, DURATION: This systematic review identified literature from Embase, Medline and Popline published between January 1974 and October 2011, on the association between infertility in a non-treated population and the risk of preterm birth, low birthweight (LBW), small-for-gestational age and birthweight deficits. PARTICIPANTS/MATERIALS, SETTING,
METHODS: Two authors independently conducted the searches, selected the studies and abstracted the data. A total of 89 full-text articles were assessed for eligibility and 17 met the inclusion criteria. The pooled analysis of the primary outcome led to a total sample size of 1 269 758 births: 19 983 in the exposed/infertile group and 1 249 775 in the unexposed/fertile group. There were a total 68 885 preterm births in the overall sample: 1644 (8.2%) and 67 241 (5.4%) among the infertile and reference groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: A moderate increase in the risk of preterm birth persisted irrespective of the type of pooling. The common OR of the pooled crude preterm birth data compared with the pooled regression-adjusted analysis was modestly attenuated: from 1.38 (95% CI: 1.25, 1.54) to 1.31 (95% CI: 1.21, 1.42), with I² decreasing from 53.2 to 3.9% in the crude to adjusted results, respectively. An association of a similar magnitude was seen between infertility and LBW, due in part to overlapping of outcomes. LIMITATIONS, REASONS FOR CAUTION: Consistency of the estimates across various types of pooling, including the more restricted sensitivity analyses of higher quality studies, is reassuring. While it is possible that systematic error may have been present through misclassification of exposure and confounding, these findings suggest that it would need to be of the same magnitude across diverse studies, which seems unlikely. WIDER IMPLICATIONS OF THE
FINDINGS: A long TTP is only a symptom, research is needed to assess whether specific groups of infertile couples are at increased risk of adverse outcome, or whether the increased risk is due to characteristics common to most infertile couples. As long as the contribution of infertility is not clarified, the risks due to assisted reproductive technologies cannot be properly assessed. STUDY FUNDING/COMPETING INTEREST(S): C.M. was supported by a Canadian Institutes of Health Research doctoral research award at the time of this study. No competing interests are declared.