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Postpartum Hemorrhage and Use of Serotonin Reuptake Inhibitor Antidepressants in Pregnancy

Hanley, Gillian E., PhD; Smolina, Kate, PhD; Mintzes, Barbara, PhD; Oberlander, Tim F., MD, FRCPc; Morgan, Steven G., PhD

doi: 10.1097/AOG.0000000000001200
Contents: Original Research
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OBJECTIVE: To examine whether using selective serotonin reuptake inhibitors and selective serotonin–norepinephrine reuptake inhibitors in pregnancy is associated with an increased risk of postpartum hemorrhage.

METHODS: We conducted a population-based cohort study including 225,973 women with 322,224 pregnancies in British Columbia, Canada, between 2002 and 2011. Women were categorized according to whether they had late-pregnancy exposure (at least 15 of the last 30 days of pregnancy), midpregnancy exposure (in the last 5 months of pregnancy but not the final 30 days), or no exposure. Postpartum hemorrhage was identified using International Classification of Diseases (9th and 10th Revisions) codes in data on all hospitalizations.

RESULTS: We found an increased risk of postpartum hemorrhage associated with exposure to an serotonin–norepinephrine reuptake inhibitor in the final month of pregnancy after adjustment for potential confounders (n=1,390; adjusted odds ratio [OR] 1.76, 95% confidence interval [CI] 1.47–2.11, respectively) corresponding to 4.1 (95% CI 2.4–5.7) additional cases of postpartum hemorrhage per 100 people treated. There was no significant relationship between selective serotonin reuptake inhibitor use in the final month of pregnancy and postpartum hemorrhage (n=6,637; adjusted OR 1.09, 95% CI 0.98–1.21), except when confining the cohort to women with complete body mass index (BMI) information (n=235,031 [73%]) and controlling for BMI (adjusted OR 1.14, 95% CI 1.01–1.28) or when controlling for variables that are possibly on the causal pathway (adjusted OR 1.13, 95% CI 1.02–1.26). Midpregnancy exposure to a serotonin–norepinephrine reuptake inhibitor (n=242) or a selective serotonin reuptake inhibitor (n=1,507) was not associated with an increased postpartum hemorrhage risk.

CONCLUSION: Serotonin–norepinephrine reuptake inhibitor exposure in late pregnancy was associated with a 1.6- to 1.9-fold increased risk of postpartum hemorrhage.

Use of selective serotonin–norepinephrine reuptake inhibitors in the month before delivery is associated with a 1.6- to 1.9-fold increase in risk of postpartum hemorrhage.

Departments of Obstetrics & Gynaecology and Paediatrics, the School of Population and Public Health, and the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; and the Faculty of Pharmacy and Charles Perkins Centre, University of Sydney, Sydney, Australia.

Corresponding author: Gillian E. Hanley, PhD, Diamond Health Care Center, Vancouver General Hospital, 6207A 2775 Laurel Street, Vancouver British Columbia V5Z 1M9, Canada; e-mail: Gillian.hanley@vch.ca.

Supported by two grants from the Canadian Institutes of Health Research (http://www.cihr-irsc.gc.ca/e/193.html) (CIHR DC0190GP and CIHR DC0150GP). Dr. Hanley is supported by the Canadian Cancer Society. Dr. Smolina is funded by the Banting Postdoctoral Fellowship from the Canadian Institutes for Health Research.

Financial Disclosure The authors did not report any potential conflicts of interest.

Postpartum hemorrhage is a leading cause of maternal morbidity and mortality.1,2 Increases in postpartum hemorrhage incidence have been reported in several developed countries in the past decade.3–11 These increases have not been explained by changes in established risk factors, making it important to study other potential risk factors for postpartum hemorrhage.12–14 The use of certain prescription medicines in pregnancy, including antidepressants, may increase the risk of postpartum hemorrhage; however, given the number of women using antidepressants in pregnancy, it appears unlikely that antidepressant use is solely responsible for the temporal increase in postpartum hemorrhage.15

Although research suggests considerable variation both temporally and geographically, two recent Canadian and American studies reported that approximately 5% of women used antidepressants at some point during their pregnancy.16,17 The most commonly used antidepressants are serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors (SSRIs) and selective serotonin–norepinephrine reuptake inhibitors.17,18 The use of serotonin reuptake inhibitors has been associated with an increased risk of bleeding events among nonpregnant participants.19–22 These bleeding risks are thought to result from the inhibition of serotonin's role in platelet aggregation.23 Furthermore, because postpartum hemorrhage is generally prevented through myometrial contractions that are mediated by serotonin, it is hypothesized that serotonin reuptake inhibitors might contribute to atonic postpartum hemorrhage by interfering with this process.24,25

Although some studies have reported an increased risk of postpartum hemorrhage among women using serotonin reuptake inhibitors near the end of pregnancy,15,26–29 other studies have not found such a relationship.30 Among the studies reporting a relationship, numbers of women using serotonin–norepinephrine reuptake inhibitors were small and exposure windows varied considerably, contributing to inadequate power to separately assess serotonin–norepinephrine reuptake inhibitor and SSRI risks. We used large, population-based databases for British Columbia, Canada, to examine the hypotheses that exposure to SSRIs and serotonin–norepinephrine reuptake inhibitors in the month before delivery is associated with increased risk of postpartum hemorrhage and that risk differs between the two classes of medicines, but that exposures ending before the final month of pregnancy are not associated with increased risk of postpartum hemorrhage.

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MATERIALS AND METHODS

We conducted a retrospective cohort study of all women who delivered a live neonate in the Canadian province of British Columbia (population of 4.3 million) between 2002 and 2011. With approval of all data stewards, we used Population Data BC to access all medical services records, all hospital discharge records, and all BC PharmaNet (a prescription dispensation database into which all prescriptions dispensed must be entered by law) records for these women.31–34 The completeness, accuracy, and validity of the databases are high.35–37 All inferences, opinions, and conclusions drawn in this manuscript are those of the authors and do not reflect the opinions or policies of the Data Stewards. The Behavioural Research Ethics Board at the University of British Columbia approved this study. To ensure complete data capture, we restricted our analysis to women who resided in the province for at least 275 days per year in the year they gave birth and in the year prior.

Hospital records over the period of study included diagnostic codes based on the International Classification of Diseases, 9th and 10th Revisions (ICD-9 and ICD-10). Women with diagnostic codes for postpartum hemorrhage (ICD-9 666.x and ICD-10 O72.x) during the admission to the hospital for delivery or who were hospitalized with a relevant postpartum hemorrhage diagnostic code within 7 days after the delivery date were classified as having postpartum hemorrhage.

We classified serotonin reuptake inhibitor antidepressants into two groups: SSRIs and serotonin–norepinephrine reuptake inhibitors. We excluded all women using “other antidepressants” (such as amitriptyline, bupropion, and trazodone) from our final analyses. Women using combination SSRI and serotonin–norepinephrine reuptake inhibitor therapy were also excluded. Because the length of the potential carryover effect of serotonin reuptake inhibitors on the risk of postpartum hemorrhage after discontinuation of use is unclear,38 we examined several different exposure windows. Using the date of dispensation, the numbers of days of medicine dispensed, and the neonate's birth date, we created the following exposure groups for SSRIs and serotonin–norepinephrine reuptake inhibitors:

  1. Late-pregnancy exposure: a supply of medicines indicating use for more than 15 days of the 30 days before delivery. These women could also have been exposed in midpregnancy and early pregnancy.
  2. Midpregnancy exposure: a supply of medicines ending between 5 months and 30 days before delivery.
  3. Current exposure: a supply of medicines that overlapped the date of delivery.
  4. Unexposed (in mid- to late pregnancy): no supply of any antidepressants in the 5 months before delivery.

We included known risk factors for postpartum hemorrhage as potential confounders. We controlled for maternal age at delivery, parity, multifetal pregnancy, gestational and pre-existing diabetes, and coagulopathy in the 5 months before delivery (identified by ICD codes); smoking during pregnancy; blood thinner, anxiolytic, and antipsychotic use in the month before delivery; and preterm birth. Given that postpartum hemorrhage rates increased over the study period in British Columbia, we also controlled for year of delivery in all analyses. Body mass index (BMI, calculated as weight [kg]/[height (m)]2) data based on prepregnancy weight were available for 73% of the women in our cohort. We also had data on several covariates that were considered potential mediators or were hypothesized to be on the causal pathway. These variables included hypertension and preeclampsia (because previous research has suggested an increased risk of these maternal conditions after serotonin reuptake inhibitor use in pregnancy39), induction of labor, epidural in labor and delivery, episiotomy, mode of delivery (assisted vaginal delivery and cesarean delivery in particular), length of third-stage labor, neonatal birth weight, and perineal tear.

Because confounding by indication is an important consideration, we examined the administrative data sets that included all physician and hospital visits in the 5 months before delivery for diagnosis codes indicating a mood or anxiety disorder (diagnostic codes in online Appendices 1 and 2, available online at http://links.lww.com/AOG/A750). In our adjusted model we controlled for the presence of a mood disorder (defined as any of the following disorders: bipolar disorder, depression, or adjustment reaction) as well as for anxiety disorders, any visits to a psychiatrist, and any inpatient hospitalizations with a psychiatric diagnostic code in the 5 months before delivery.

We compared risks for postpartum hemorrhage between women who were unexposed to antidepressants during mid- to late pregnancy and women with midpregnancy or late-pregnancy exposure to SSRI monotherapy or serotonin–norepinephrine reuptake inhibitor monotherapy. We used logistic regression models and all models accounted for correlations among women who gave birth more than once during our study period. We ran unadjusted models (adjusted only for the year of delivery) and models adjusted for covariates described previously. We considered anything with a P<.05 to be statistically significant.

We conducted the following sensitivity analyses:

  1. The current exposure group was examined as a sensitivity analysis to examine whether increased risk of postpartum hemorrhage is associated with concurrent exposure to serotonin reuptake inhibitor on the date of delivery.
  2. Because obesity is a known risk factor for postpartum hemorrhage but was incompletely measured in our data, we originally excluded BMI; however, to determine whether this could be confounding our results, we ran the models on the subset of pregnancies with complete BMI information (n=235,031 [73%]).
  3. We ran a model including the variables that were considered to be potentially on the causal pathway or to mediate the relationship between serotonin reuptake inhibitor use and postpartum hemorrhage.
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RESULTS

Our cohort included 322,224 pregnancies among 225,973 women who delivered in British Columbia, Canada, between 2002 and 2011. We excluded 1,800 pregnancies (0.5% of all pregnancies) because the expectant mothers were using combination serotonin–norepinephrine reuptake inhibitor and SSRI therapy (n=131) or one of the other antidepressants excluded from the study (n=1,669). In 8,027 (2.5%) of the remaining 320,424 pregnancies, the mothers were exposed to serotonin–norepinephrine reuptake inhibitor or SSRI monotherapy in late pregnancy (15 or more of the last 30 days of pregnancy), and 2,148 (0.7%) had midpregnancy prescriptions that began at least 5 months before delivery and ended at least 1 month before delivery (Table 1). Most late-pregnancy exposure involved SSRIs (n=6,637 [83%]), most commonly citalopram (n=2,033 [31%]); 1,390 (17%) involved serotonin–norepinephrine reuptake inhibitors (almost entirely venlafaxine, n=1,368 [98%]). Similar patterns were observed for midpregnancy serotonin reuptake inhibitor use.

Table 1

Table 1

Tables 2 and 3 indicate that compared with unexposed women, women exposed to SSRIs or serotonin–norepinephrine reuptake inhibitors in late or midpregnancy were more likely to have a diagnosis of a mood or an anxiety disorder and to exhibit behaviors that are commonly associated with a mood or an anxiety disorder (eg, women with mood or anxiety disorders are more likely to smoke). Health status was similar between the groups with the exception of a higher rate of diabetes, hypertension, and preeclampsia among women with late pregnancy serotonin–norepinephrine reuptake inhibitor exposure. With respect to labor and delivery characteristics, serotonin reuptake inhibitor users appeared to have similar or slightly lower risks of labor interventions than unexposed women with the exception of epidural analgesia (Table 3).

Table 2

Table 2

Table 3

Table 3

Table 4 shows the rate of postpartum hemorrhage in each of the exposure groups as well as the unadjusted and adjusted associations between serotonin reuptake inhibitor use and postpartum hemorrhage for the various exposure and exposure periods. We have combined all forms of postpartum hemorrhage with atonic postpartum hemorrhage representing 77% of all postpartum hemorrhage cases, a share that was stable across all exposure groups. The rate of postpartum hemorrhage in the unexposed study population was 7.0% (95% confidence interval [CI] 6.9–7.1) and was similar to that in the SSRI exposure groups at 7.3% (95% CI 6.7–7.9) for late pregnancy exposure, 6.6% (95% CI 5.3–7.8) for midpregnancy, and 7.4% (95% CI 6.9–8.1) for current exposure (P=.477). Among the serotonin–norepinephrine reuptake inhibitor exposure groups, the rate was considerably higher at 11.1% (95% CI 9.4–12.7) for late pregnancy exposure, 10.3% (95% CI 6.5–14.2) for midpregnancy exposure, and 11.8% (95% CI 10.0–13.6) for current exposure (P<.001). The unadjusted models (adjusted only for year of delivery) revealed significantly increased risk of postpartum hemorrhage with late pregnancy serotonin–norepinephrine reuptake inhibitor monotherapy (odds ratio [OR] 1.61, 95% CI 1.36–1.92), whereas the relationship between SSRI monotherapy and postpartum hemorrhage was nonsignificant (OR 1.05, 95% CI 0.95–1.15). The adjusted models also found no significantly increased risk of postpartum hemorrhage with late pregnancy exposure to an SSRI (adjusted OR any postpartum hemorrhage 1.07, 95% CI 0.97–1.18); the effect size for serotonin–norepinephrine reuptake inhibitor monotherapy changed very little after adjustment (OR 1.64, 95% CI 1.38–1.96). Serotonin–norepinephrine reuptake inhibitor exposure in midpregnancy was not statistically significantly associated with an increased risk of postpartum hemorrhage (adjusted 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 postpartum hemorrhage per 100 people treated with serotonin–norepinephrine reuptake inhibitors in late pregnancy compared with those unexposed to serotonin–norepinephrine reuptake inhibitors in late pregnancy. The risk difference between serotonin–norepinephrine reuptake inhibitor and SSRI users indicates that there is an additional 3.7 (95% CI 2.0–5.5) cases per 100 people treated with serotonin–norepinephrine reuptake inhibitors in late pregnancy compared with those treated with SSRIs in late pregnancy.

Table 4

Table 4

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).

Table 5

Table 5

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DISCUSSION

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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