Within-Family Analysis of Interpregnancy Interval and Adverse Birth Outcomes

Abstract

Objective To examine associations between interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors. Methods In this prospective cohort study we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months), and adverse birth outcomes [i.e., preterm birth (PTB, < 37 weeks), low birth weight (LBW, <2,500 g), small for gestational age (SGA, > 2 standard deviations below average weight for gestational age)]. Analyses included cousin- and sibling-comparisons, and postbirth intervals (ie, the interval between second- and third-born offspring predicting second-born outcomes), to address unmeasured familial confounding. Results Traditional cohort-wide analyses showed higher odds of PTB [adjusted odds ratio (aOR)=1.51, 99% CI=1.39-1.63, 5.99% PTBs)] and LBW (aOR=1.25, 99% CI=1.13-1.39, 3.32% LBW) after short interpregnancy interval (0-5 months) compared to offspring born after an interpregnancy interval of 18-23 months (3.21% PTBs, 1.92% LBW). For pregnancy intervals of 60 months or more, odds of PTB (aOR=1.51, 99% CI=1.43-1.60, 5.07% PTBs), LBW (a OR=1.61, 99% CI=1.50-1.73, 3.43% LBW births), and SGA (aOR=1.54, 99% CI=1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Except for PTB (aOR=1.72, 99% CI=1.26-2.35), associations were attenuated in cousin-comparisons. A small association between short interpregnancy interval and PTB remained in sibling-comparisons (aOR=1.22, 99% CI=1.11-1.35), but associations with LBW (aOR=0.83, 99% CI=0.74-0.94) and SGA (aOR=0.74, 99% CI=0.64-0.85) reversed direction. Associations between long interpregnancy interval and adverse birth outcomes remained through cousin- and sibling-comparisons. Post birth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals. Conclusion Familial confounding explains most of the association between short interpregnancy interval and adverse birth outcomes while associations with long interpregnancy intervals were independent of measured and unmeasured factors.

Short interpregnancy interval and poor fetal growth: Evaluating the role of pregnancy intention

“…30 Within-woman or within-family analyses may have limited generalisability as they are restricted to women who have had discrepant birth outcomes among their second and third livebirth. 21,26 Our findings, which are estimated from a cohort derived through population-based recruitment in three Scandinavian counties, lend support to these previous studies which challenge the causal link between short interpregnancy interval and adverse perinatal outcomes. 21,26,29…”

“…25 These variations may due to the inherent complexity of pregnancy intention which make it difficult to measure. 22,25 However, our results are consistent with the recent study by Class et al, 26 which performed a sensitivity analysis that did not find significant cohort effects in a Scandinavian study population ranging from 1973 to 2009. In addition, previous studies have proposed possible causal mechanisms between short interpregnancy interval and adverse pregnancy outcomes, for example that maternal nutrition remains depleted from a prior pregnancy after a short interval, 27 which would not be expected to exert differential effects at the time of the original study period compared to the time of our analyses.…”

“…found that long interpregnancy intervals remained associated with small for gestational age birth while short interpregnancy intervals did not, suggesting that the impact of long interpregnancy intervals may not be fully explained by confounders that remain constant within the same woman across pregnancies. These findings were supported by Class et al, who found that despite within‐woman analysis, within‐family analysis, and controlling for post‐birth intervals, the associations between long interpregnancy intervals and small for gestational age birth remained significant while those between short interpregnancy intervals and small for gestational age birth were fully attenuated or showed reversed associations. Similarly, Hanley et al found that although short interpregnancy intervals were associated with small for gestational age birth in traditional between‐woman analyses, this association reversed direction without statistical significance in the within‐woman analyses.…”

“…These studies found significantly attenuated or no associations between short interpregnancy interval and small for gestational age birth, suggesting that unmeasured confounding may account for the associations seen in previous studies. 21,26,29 Comparing a traditional between-woman analysis with a within-woman analysis, Ball et al 21 found that long interpregnancy intervals remained associated with small for gestational age birth while short interpregnancy intervals did not, suggesting that the impact of long interpregnancy intervals may not be fully explained by confounders that remain constant within the same woman across pregnancies. These findings were supported by Class et al, 26 who found that despite within-woman analysis, within-family analysis, and controlling for post-birth intervals, the associations between long interpregnancy intervals and small for gestational age birth remained significant while those between short interpregnancy intervals and small for gestational age birth were fully attenuated or showed reversed associations.…”

“…This approach aims to reduce confounding by factors that tend to remain consistent within one woman or family (eg socio‐economic status). These studies found significantly attenuated or no associations between short interpregnancy interval and small for gestational age birth, suggesting that unmeasured confounding may account for the associations seen in previous studies . Comparing a traditional between‐woman analysis with a within‐woman analysis, Ball et al .…”