Venlafaxine Tied to Increased Postpartum Hemorrhage Risk

Tara Haelle

February 15, 2016

Use of serotonin–norepinephrine reuptake inhibitors (SNRIs) in the last month of pregnancy increases the risk for postpartum hemorrhage, according to a retrospective cohort study published online February 4 in Obstetrics & Gynecology.

"Women and their physicians should be aware of potential risks associated with [SNRI] use near the end of pregnancy," write Gillian E. Hanley, PhD, from the University of British Columbia in Vancouver, Canada, and colleagues. "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."

The researchers investigated selective serotonin reuptake inhibitor (SSRI) and SNRI exposure among 320,424 pregnancies in 225,973 women in British Columbia between 2002 and 2011. They compared rates of postpartum hemorrhage among those patients with no SSRI/SNRI exposure, those with late-pregnancy exposure (defined as at least 15 of the last 30 days of pregnancy), and those with midpregnancy exposure only.

Late-pregnancy exposure was seen in 2.5% of the pregnancies (n = 8027). SSRIs, especially citalopram, made up 83% of these (n = 6637), and of the 1390 SNRI exposures, nearly all (1368; 98%) were venlafaxine.

The odds of postpartum hemorrhage were 1.61 times before adjustment (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.36 - 1.92) among the 1390 individuals with SNRI exposure in late pregnancy compared with those with no exposure. After adjustment for potential confounders, the risk was 1.64 (95% CI, 1.38 - 1.96).

Those with current exposure (overlapping delivery) had the highest risk (adjusted OR, 1.76; 95% CI, 1.47 - 2.11).

Midpregnancy exposure, defined as SSRIs/SNRIs in the last 5 months, but not the last 30 days, occurred in less than 1% of the pregnancies, with similar proportions of specific medications as seen in the late-exposure group.

No increased risk for postpartum hemorrhage was detected among the 242 women with midpregnancy SNRI exposure or the 1507 women with mid-pregnancy SSRI exposure. The adjusted risk associated with SNRI midpregnancy exposure did not reach significance (OR, 1.52; 95% CI, 1.00 - 2.31).

"Our results suggest that there is an additional 4.1 (95% CI 2.4–5.7) cases of post-partum hemorrhage per 100 people treated with [SNRIs] in late pregnancy compared with those unexposed to [SNRIs] in late pregnancy," the study authors state.

Similarly, they suggest there are an additional 3.7 (95% CI, 2.0 - 5.5) cases per 100 people treated with SNRIs compared with those treated with SSRIs.

Unadjusted absolute risks for postpartum hemorrhage were similar between unexposed and SSRI-exposed people but were higher in SNRI-exposed individuals:

  • 7.0% of unexposed,

  • 7.3% of late-pregnancy SSRI-exposed,

  • 6.6% of midpregnancy SSRI-exposed,

  • 7.4% for current SSRI exposure,

  • 11.1% of late-pregnancy SNRI-exposed,

  • 10.3% of midpregnancy SNRI-exposed, and

  • 11.8% for current SNRI exposure.

Potential mediators for postpartum hemorrhage risk include 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.

Including these in the analysis shifted the odds of hemorrhage to 1.13 (95% CI, 1.02 - 1.26) for SSRI exposure in late pregnancy, to 1.16 (95% CI, 1.04 - 1.30) for current SSRI exposure, to 1.80 (95% CI, 1.50 - 2.17) for SNRI exposure in late pregnancy, and to 1.93 (95% CI, 1.60 - 2.33) for current SNRI exposure.

Further, when including only women with complete body mass index information, and controlling for body mass index, risk shifted again to 1.14 greater odds for late-pregnancy SSRI exposure (95% CI, 1.01 - 1.28) and 1.88 greater odds for late-pregnancy SNRI exposure (95% CI, 1.53 - 2.30).

"At higher doses and in certain patients, serotonin–norepinephrine reuptake inhibitors have noradrenergic effects, which can lead to tachycardia and hypertension," the authors write. They add that venlafaxine is thought to contribute to myocardial infarction, increased heart rate, and heart failure in elderly patients.

"Given the demonstrated increased risk of postpartum hemorrhage associated with hypertensive disorders, 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," they write.

However, they note, their results did not bear out the expectation that hypertension would be part of the causal mechanism between venlafaxine and postpartum hemorrhage.

"This suggests either a more subtle cardiovascular effect, not severe enough to result in a diagnosis of hypertension, or a different biological mechanism," they conclude.

The research was funded by the Canadian Institutes of Health Research with additional researcher funding from the Canadian Cancer Society. The authors have disclosed no relevant financial relationships.

Obstet Gynecol. 2016;127:553-561. Abstract

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