Finally, the sensitivity analysis examining current exposure (women whose supply of medicines overlapped their date of delivery) confirmed a significantly increased risk of postpartum hemorrhage with use of serotonin–norepinephrine reuptake inhibitor monotherapy (adjusted OR 1.76, 95% CI 1.47–2.11) and no significant relationship with SSRI monotherapy at the time of delivery (adjusted OR 1.09, 95% CI 0.98–1.21). Our results changed slightly in models including the covariates that were potential mediators (hypertension, preeclampsia, induction of labor, epidural in labor and delivery, episiotomy, assisted vaginal delivery, cesarean delivery, neonatal birth weight, length of third stage of labor, and perineal tear). Both late pregnancy serotonin–norepinephrine reuptake inhibitor exposure and current serotonin–norepinephrine reuptake inhibitor exposure remained significantly associated with postpartum hemorrhage, and late pregnancy and current SSRI exposure also became significant (adjusted OR 1.13, 95% CI 1.02–1.26 and adjusted OR 1.16, 95% CI 1.04–1.30, respectively) (Table 5). In our analysis on the cohort of women with complete BMI information, after controlling for BMI in the adjusted model, late-pregnancy exposure to SSRIs was associated with significantly increased risk of postpartum hemorrhage (adjusted OR 1.13, 95% CI 1.01–1.28). The effect sizes for late-pregnancy exposure to serotonin–norepinephrine reuptake inhibitors also became slightly larger with adjustment for BMI (adjusted OR 1.88, 95% CI 1.53–2.30).
In this population-based study of pregnant women who delivered in British Columbia, Canada, between 2002 and 2011, late-pregnancy exposure to serotonin–norepinephrine reuptake inhibitors was associated with a 1.6- to 1.9-fold increase in risk of postpartum hemorrhage. Given that serotonin–norepinephrine reuptake inhibitor use in our cohort consisted almost entirely of venlafaxine exposure (98%), with another 1% exposed to desvenlafaxine, an isomer of venlafaxine, we cannot rule out an effect that is specific to venlafaxine. In contrast, neither mid- nor late pregnancy use of SSRIs was significantly associated with an increased risk of postpartum hemorrhage, except when restricting our cohort to women who had complete BMI information and controlling for BMI as a confounder. Risk estimates differed significantly between SSRI and serotonin–norepinephrine reuptake inhibitor users for all exposure windows. Although we cannot rule out the possibility of residual confounding by the underlying mood disorder or anxiety, we think it is unlikely to explain our results because this would require significant differences in the underlying mental health of the women who were prescribed serotonin–norepinephrine reuptake inhibitors compared with those prescribed SSRIs. We found no evidence of such a difference in our data, and we know of no reasons why more seriously ill women would be more likely to receive serotonin–norepinephrine reuptake inhibitors than the SSRIs included in this study. The same can be said of the possibility of unmeasured confounding such as poor nutrition or substance abuse.
Venlafaxine is hypothesized to alleviate depression by inhibiting serotonin and norepinephrine reuptake.40–43 At higher doses and in certain patients, serotonin–norepinephrine reuptake inhibitors have noradrenergic effects, which can lead to tachycardia and hypertension.44–47 Most of the research examining cardiac effects of venlafaxine has been conducted in elderly patients and has suggested that venlafaxine can contribute to acute myocardial infarction, increased heart rate, and heart failure.48–50 Given the demonstrated increased risk of postpartum hemorrhage associated with hypertensive disorders,14,51 and the higher rate of hypertension in the women in our cohort using venlafaxine compared with SSRIs (12.8% compared with 7.0%), it is plausible that venlafaxine may increase the risk of postpartum hemorrhage through similar noradrenergic effects. However, we would expect hypertension to be on the causal pathway between venlafaxine use and postpartum hemorrhage, which was not borne out in our results. This suggests either a more subtle cardiovascular effect, not severe enough to result in a diagnosis of hypertension, or a different biological mechanism.
Our study has a number of limitations. Our findings regarding the near significance of midpregnancy serotonin–norepinephrine reuptake inhibitor exposure may be a result of inaccuracies in the treatment window because dispensation dates rather than dates of use are measured in this data set. It is also possible that women may not be using their medicines immediately after dispensation or exactly as instructed. However, we cannot rule out persistent effects after discontinuation or lack of power as explanations for these findings given that the number of postpartum hemorrhage events among those exposed to serotonin–norepinephrine reuptake inhibitors in midpregnancy was only 25. Thus, these adjusted models need to be interpreted with caution and may be overfitted. Our incomplete BMI data were a limitation because it is clear from our results that there is some degree of confounding by BMI occurring; however, our results suggest the direction of bias from noninclusion was toward the null. We did not have any data on the positive predictive value of our coding algorithm for postpartum hemorrhage; however, our rate was comparable with another study examining atonic postpartum hemorrhage in British Columbia between 2001 and 2009, which reported that atonic postpartum hemorrhage increased from 4.8% in 2001 to 6.3% in 2009.12 We were unable to control for drugs that are available over the counter that might also influence postpartum hemorrhage risk such as aspirin. We risk misclassification of exposure, because our data indicate only that a prescription was filled and not whether the prescription was used. However, more than 90% of women exposed in late pregnancy filled more than one prescription for the medicine during the 5 months before delivery, suggesting that women were likely using these medicines. Finally, we tested multiple hypotheses increasing the likelihood of spurious findings. Although we could have used a stricter P value than .05, we chose to be consistent with previous research.
Our study suggests that exposure to serotonin–norepinephrine reuptake inhibitors in late pregnancy significantly increases the risk of postpartum hemorrhage, whereas similar exposure to SSRIs did not significantly increase the risk. The magnitude of our serotonin–norepinephrine reuptake inhibitor relationship was consistent with effect sizes previously published in a large study of an American Medicaid population, which also reported a larger effect size for risk of postpartum hemorrhage with serotonin–norepinephrine reuptake inhibitor use than SSRI use.26 However, our results suggest a more modest effect of SSRI use on risk of postpartum hemorrhage than has been previously reported,26,28 and all of our reported effect sizes are modest and within the zone of bias (less than 3.0). Further work should investigate the difference in risk of postpartum hemorrhage associated with SSRI compared with serotonin–norepinephrine reuptake inhibitor use in late pregnancy. Women and their physicians should be aware of potential risks associated with serotonin–norepinephrine reuptake inhibitor use near the end of pregnancy. If the differential in risk reported in this study is confirmed in other research, patients and physicians may choose alternative medicines near the end of pregnancy.
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