Pregnancy complications following fertility treatment-disentangling the role of multiple gestation

Abstract

Background: To assess the extent to which multiple gestations mediate risk of pregnancy complications from fertility treatment and to address possible confounding by the underlying infertility.

Methods: From the nearly 1.8 million pregnancies recorded in the Swedish Medical Birth Register between 1996 and 2013, we selected the 9.9% (N = 174 067) that occurred to couples with known trouble conceiving (clinical infertility). Fertility treatment was identified from self-reports, medical records and procedural information from fertility clinics. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (CIs), and decomposed the total effect into direct and mediated effects to estimate the proportion mediated by multiple gestations.

Results: Compared with pregnancies achieved without any assistance, those having received some treatment had higher odds of all studied complications except gestational diabetes. Associations with placenta previa (OR 2.17, 95% CI 1.95-2.40) and placental abruption (OR 1.77, 95% CI 1.54-2.03) were almost entirely independent of multiple gestations. In contrast, the majority of the associations with preterm birth (OR 1.69, 95% CI 1.62-1.77), caesarean delivery (RR 1.15, 95% CI 1.13-1.17) and pre-eclampsia (OR 1.17, 95% CI 1.11-1.22) were mediated by multiple gestations (87%, 62% and 91% of the effect mediated, respectively). Both direct and mediated pathways contributed to the remaining positive associations with chorioamnionitis, labour induction and postpartum haemorrhage. Results were similar when considering primi- and multi-parous women separately, and after restriction to assisted reproductive technologies only.

Conclusion: Multiple gestations are responsible for a large proportion of pregnancy complications associated with fertility treatment, suggesting that interventions to restrict the occurrence of multiples could reduce excess risk of pre-eclampsia, preterm birth and caesarean delivery after fertility treatment. However, the elevated risk of serious placental complications after fertility treatment appears to be largely independent of multiple gestations.

Figure 1.

Directed acyclic graph to illustrate a possible structural relationship between fertility treatment, multiple gestation and pregnancy complications. CC denotes all common causes (confounding factors) of any pair of variables in the graph, measured and unmeasured. Adjusting for infertility (box) blocks the non-causal pathway between fertility treatment and pregnancy complications through potential common causes of infertility and pregnancy complications. The mediated effect is represented by the pathway from fertility treatments to pregnancy complications that goes through multiple gestations and the direct effect is the pathway straight to pregnancy complications.

Figure 2.

Plot of pregnancy complications to couples with known trouble conceiving in the study period 1996–2013.