Interpretation
GWG has been associated with subsequent risks of adverse pregnancy outcomes, such as preterm birth, pre-eclampsia and caesarean section, has been suggested[18,19], but evidence to clarify the relationship between gestational weight gain and maternal VTE have been sporadic[13,20]. A Norwegian hospital-case control study reported that large weight gains (>p90 or >21.0kg) were associated with 60% increased odds of postpartum VTE, while small maternal weight gain is an independent antenatal risk factor for VTE[13]. In a Washington State, USA population-based, case-control study, women with large weight gains during pregnancy (>22kg), independently of BMI, were more likely to have VTE (1.5, 95%CI 1.2-2.1)[20]. In line with these studies, we observed that higher GWG in whole pregnancy was associated with higher risk of PE. Over weight gain during pregnancy accompanied with increased intraabdominal pressure can encourage blood stasis through iliac vessels compression. Furthermore, elevated inflammatory cytokines and adipokines with increased fat deposition promote endothelial dysfunction and platelet hyperreactivity. Fat deposition also skews the hemostatic-fibrinolytic balance through elevation of procoagulant factors including von Willebrand factor, fibrinogen, factor VII, factor VIII, issue factor, and impairment of fibrinolysis by elevation of plasminogen activator inhibitor[21]. On top of differential inflammatory responses, women with high weight have longer durations of labor, greater rates of chorioamnionitis, postpartum hemorrhage and surgical complications, which may all lead to the observed greater risk of VTE after delivery[22].
There is growing recognition that the impacts of gestational stage-specific weight gain on pregnancy outcomes may vary[23-27]. GWG in early pregnancy largely reflects maternal fat deposition, whereas GWG in mid and late pregnancy is also attributed to maternal and amniotic fluid expansion, and growth of the fetus, placenta and uterus[28]. In this study, we found that higher GWG in early pregnancy was associated with higher risks of PE in normal-weight women. As for underweight and overweight women, results from the categorical model for early pregnancy weight gain indicated an increased risk at both low and high weight gain for PE. Studies have found that mothers with increased fat deposition during early pregnancy may involve the multifactorial engagement of alterations to blood flow, hypercoagulability, chronic low-grade inflammation and endothelial dysfunction, which may lead to PE[21,29]. Therefore, GWG in early pregnancy, prior to the development of pregnancy outcomes, might be as or more important than GWG in late pregnancy with respect to pregnancy outcomes.
GWG below average in overweight and obese mothers were also at an increased risk of PE in our analysis. This finding, if true, could result from low amniotic fluid volume and fetal weight by ischemic placental disease (including preeclampsia, intrauterine growth retardation, stillbirth, and placental abruption), perhaps a potential for embolism, leading to PE[1]. Blondon et al found that the delivery of a newborn with low birth weight is associated with a 3-fold increased risk of maternal postpartum VTE[1]. In another Norwegian hospital-based, case–control study, mothers of newborns with IUGR were at 3.8-fold risk of postpartum VTE[13]. Moreover, hypertension during pregnancy and preeclampsia are also associated with an increased VTE risk during pregnancy and postpartum period[9,30]. However, a randomized clinical trial indicated that pre-pregnancy weight loss intervention has favorable effects on the early intrauterine environment[31]. Lifestyle intervention during pregnancy could to some extent limit GWG and improve maternal and infant health[32]. Therefore, pre-pregnancy weight interventions integrated into intensive weight management that continues through pregnancy may be indispensable to decrease the risks of PE.
There was no statistical association between maternal weight gain and DVT or all VTE across all BMI categories. Similarly, Matthew et al retrospectively analyzed a large database from American found that only the risk of PE is elevated in patient classification as heavier categories after surgery, whereas there was no positive association between DVT and BMI[33,34]. Explanations for this observed association exist, of which anticoagulation used for VTE prophylaxis during pregnancy is most plausible. All pregnant women in Shanghai are managed based on RCOG Green-top Guidelines[35] and Quensland Clinical Guidelines[36,37]. Briefly, they will undergo a documented assessment of risk factors for VTE throughout pregnancy, intrapartum and the puerperium. Any woman with risk factors shown in Table S2 should be considered for prophylactic low-molecular-weight heparin (LMWH). Previous studies have evaluated the efficacy of LMWH for thromboprophylaxis, revealed that LMWH probably results in little to no difference in the incidence of PE in patients undergoing knee arthroscopy, but reduce the risk of asymptomatic DVT[38]. Similarly, eight RCTs showed no clear differences between the LMWH and no prophylaxis or placebo groups in patients with lower-limb immobilization for PE, but less DVT in the LMWH groups[39]. Therefore, aggressive pharmacologic anticoagulation regimens during pregnancy can decrease the DVT rate but have not been shown to affect the rate of PE. Meanwhile, common risk factors for DVT, like history of multiple deliveries, smoking, and obesity are less frequently observed in China[15,40]. These may be the reasons for the higher incidence of PE in this study. However, the evidence is very uncertain, and further high-quality very large-scale randomized trials are needed to determine effects of currently used treatments in women with different VTE risk factors.