The association between 17-hydroxyprogesterone caproate use and postpartum hemorrhage

Abstract

OBJECTIVE

To evaluate whether receipt of 17α-hydroxyprogesterone caproate within seven days of delivery is associated with increased risk of postpartum hemorrhage.

STUDY DESIGN

This was a retrospective cohort study of women who were receiving 17α-hydroxyprogesterone caproate for preterm birth prevention and delivered between 2010 and 2014. Women were dichotomized by whether a dose of 17α-hydroxyprogesterone caproate was administered within seven days of delivery. Demographic and clinical characteristics were examined, including obstetric history and details of 17α-hydroxyprogesterone caproate receipt. Bivariable analyses were used to compare the frequency of postpartum hemorrhage in women stratified by 17α-hydroxyprogesterone caproate receipt within seven days of delivery. Multivariable analysis was used to adjust for potential confounders.

RESULTS

Of 221 women who met inclusion criteria, 93 (42%) received 17α-hydroxyprogesterone caproate within seven days of delivery and 18 (7.8%) experienced a postpartum hemorrhage. No differences were observed in the frequency of postpartum hemorrhage between women who did and did not deliver within seven days of 17α-hydroxyprogesterone caproate injection (9.7% vs 7.0%, p=0.478). These findings persisted after adjusting for potential confounders (aOR for PPH 2.9, 95% CI, 0.5–15.8).

CONCLUSION

Recent receipt of 17α-hydroxyprogesterone caproate for prevention of recurrent preterm birth is not associated with risk of postpartum hemorrhage.

Introduction

Postpartum hemorrhage (PPH) is a significant source of maternal morbidity and mortality in the United States (U.S.).^1–3 Up to 80% of postpartum hemorrhages occur as a result of uterine atony, with U.S. rates of hemorrhage due to atony increasing from 1.6% of all births in 1994 to 2.4% in 2008.^{2, 4, 5} Early recognition and prompt intervention are crucial to minimizing morbidity and mortality associated with PPH.³ Specifically, it is critical to understand risk factors for PPH, as identification of women at increased risk enables preparation of the delivery team to facilitate earlier initiation of medical interventions.⁶

Receipt of 17α-hydroxyprogesterone caproate (17P) reduces the risk of recurrent preterm birth among women with a history of spontaneous preterm birth.⁷ Accordingly, the American College of Obstetricians and Gynecologists, along with the Society for Maternal-Fetal Medicine, recommends weekly receipt of 17P to women with a history of spontaneous, singleton preterm birth to prevent recurrent preterm birth.⁸ 17P is currently the only agent approved by the Food and Drug Administration for prevention of recurrent preterm birth and its widespread adoption into clinical practice has been hypothesized to contribute to observed decreases in the incidence of preterm birth in the United States.⁹ As early cessation of 17P has been associated with an increased risk of preterm delivery, continuation of 17P until 36 completed weeks of gestation is recommended.¹⁰

The mechanism of action of 17P remains unknown. One suggested theory posits that blocking the action of oxytocin and inhibition of the formation of gap junctions leads to sustained relaxation of myometrial smooth muscle.^{11, 12} This maintained uterine relaxation, in turn, theoretically may also lead to an increased risk of uterine atony and subsequent PPH due to a reduction in effective uterine contraction. To assess whether this association has been previously identified, a literature review for all English language randomized trials of 17P was conducted and the text examined for any report of PPH or estimated blood loss. Of the 68 trials identified, none reported on either of these outcomes. Thus, the objective of this study was to determine whether use of 17P was associated with an increased risk of PPH. We hypothesized women who received 17P injections within seven days of delivery would experience a greater frequency of PPH compared to women who received a 17P injection more than seven days prior to delivery.

Materials and Methods

This was a retrospective cohort study of women who were receiving 17P for recurrent preterm birth prevention at an outpatient practice affiliated with Northwestern Memorial Hospital and delivered between January 2010 and November 2014. Standard of care during the study period at our institution was to recommend administration of 17P to all women with a current singleton pregnancy and a history of a spontaneous preterm birth of a singleton gestation between 20 and 37 weeks of gestation. Women were included if they were 18 years or older, met these criteria for 17P recommendation, and received at least one dose of 17P between 16 0/7 and 36 6/7 weeks. Only women who presented to prenatal care at one of the ambulatory practices of Northwestern University-employed physicians, including both obstetrician specialists and maternal-fetal medicine subspecialists, as well as residents and fellows, were included. Women were excluded if they received 17P via home nursing or another source without available medication administration records; however if records were available these women were included. Women were excluded if prenatal and/or delivery information for the associated pregnancy was not available. Eligible records were identified via query of the electronic medical records.

Demographic and clinical data collected included maternal age, self-reported race/ethnicity and insurance status. Obstetric data abstracted included parity, number of prior spontaneous preterm births, gestational age at delivery, mode of delivery and total estimated blood loss. Details of 17P receipt were also abstracted, including the number of days from cessation of 17P until delivery.

During the study period, the electronic medical record delivery form allowed for either numeric entry of EBL or selection of several ranges (e.g. <500 mL or 500mL – 1000mL). For women whose EBL was recorded as a range, the mean of that range was used for analyses. For the purposes of analysis, PPH was classified as estimated blood loss (EBL) of at least 500cc for a vaginal delivery and at least 1000cc for a cesarean delivery. At this institution, the volume of blood loss is routinely estimated by the delivering provider or obstetric anesthesiologist. EBL may be determined either by clinical or volumetric assessment based on the clinical scenario. All providers underwent training in the assessment and management of postpartum hemorrhage as has been previously described.¹³

Women were dichotomized by whether 17P was given within seven days of delivery given that administration of 17P is recommended every seven days for eligible patients.⁷ Bivariable analyses were used to compare the incidence of PPH between women who did and did not receive 17P within seven days of delivery. Student’s t-test and Mann Whitney U tests were used for continuous variables, as statistically appropriate. Chi squared tests were used for categorical variables. Multivariable analysis including linear and logistic regression was used to adjust for potential confounders (p<0.05 on bivariable analyses). Data were analyzed with Stata Version 14 (College Station, TX). This study was approved by the Northwestern University Institutional Review Board with a waiver of consent prior to its initiation.

Results

Of the 221 women who met inclusion criteria during the study period, 42% (N=93) received 17P within seven days of delivery and 8% (N=18) experienced PPH. Of the 128 of women who did not receive 17P within seven days of delivery, 95 (74.2%) delivered after 38 weeks (i.e. at least 7 days after 17P receipt would have been recommended). Demographic and clinical characteristics of these women are depicted in Table 1. Women who received 17P within seven days of delivery more often had multiple prior preterm births, delivered at earlier gestational ages, and, correspondingly, had neonates with lower birth weights. These variables were considered potential confounders for entry into the logistic regression. There were no differences in maternal age, race/ethnicity, or incidence of cesarean between the cohorts.

Table 1:

Patient characteristics stratified by timing of last 17P injection

	Within seven days prior to delivery n=93	More than seven days prior to delivery n=128	p value
Age (y)	32.1 ± 5.3	32.3 ± 5.1	0.784
Race/ethnicity			0.285
Non-Hispanic white	37 (39.8%)	44 (34.4%)
Non-Hispanic black	39 (42.0%)	46 (35.9%)
Hispanic	8 (8.6%)	19 (14.8%)
Other/Unknown	9 (9.7%)	19 (14.8%)
Parity	1 (1–2)	1 (1–2)	0.291
More than one PTB	27 (29.0%)	19 (14.8%)	0.010
GA at delivery (weeks)	34.1 (29.5–36.0)	38.6 (37.6–39.2)	<0.001
Birthweight (g)	2275 (1698–2740)	3260 (2965–3568)	<0.001
Cesarean delivery	22 (23.7%)	25 (19.5%)	0.459
Total number of 17P doses given	16.5 (11–19)	20 (18–21)	<0.001

17P = 17-alpha-hydroxyprogesterone caproate; PTB = preterm birth; GA = gestational age

Data presented as mean ± standard deviation, n (%), or median (interquartile range)

No differences were observed in the frequency of PPH or median EBL between women who did and did not deliver within seven days of 17P injection (Table 2). These findings persisted after adjusting for potential confounders (aOR for PPH 2.9, 95% CI, 0.5–15.8; β for EBL 107, 95% CI, 72 – 287) suggesting that receipt of 17P was not associated with a statistically significant increase in either PPH or EBL at the time of delivery.

Table 2:

Risk of postpartum hemorrhage by proximity of 17P injection to delivery

	Within seven days prior to delivery n=93	More than seven days prior to delivery n=128	p value
Postpartum hemorrhage	9 (9.7%)	9 (7.0%)	0.478
Estimated blood loss (mL)
Vaginal delivery	250 (200–300)	250 (200–250)	0.444
Cesarean	700 (600–950)	800 (650–950)	0.502

17P = 17-alpha-hydroxyprogesterone caproate

Data presented as N (%) or median (interquartile range).

A post-hoc power calculation with an alpha of 5% demonstrated that this study had 80% power to detect a three-fold increased risk of PPH associated with 17P injection within seven days of delivery.

Conclusion

Identifying risk factors for PPH is an important step towards reducing maternal morbidity and mortality from hemorrhage. Although we hypothesized that 17P receipt may be associated with PPH due to potential uterine relaxation, these data demonstrate receipt of 17P proximate to delivery is not associated with an increased frequency of PPH or a higher EBL at delivery. These findings persisted after controlling for confounding factors.

The mechanism of 17P for preterm birth prevention remains unclear. Thus, one potential explanation for why 17P is not associated with PPH may be the existence of an alternate mechanism by which 17P acts to prevent preterm birth. Progesterone and 17P are inherently similar, and though their names are often used interchangeably by clinicians and professional organizations, 17P is a synthetic progestogen with different physiologic and pharmacologic properties than the steroid hormone progesterone.¹⁴ As such, it is possible that the differences in chemical properties between progesterone and synthetic 17P may be responsible for their potential different mechanisms of action, although further research is necessary into the extent of these differences.

For example, it has been theorized that 17P may act through alternative mechanisms of action independent of the signal transduction pathways associated with contractions or the progesterone-mediated regulators of uterine quiescence.^{14, 15} Progestogens may act as anti-inflammatory agents¹⁶, which may result in inhibition of chemokines that increase in maternal serum during preterm and term labor.¹⁷ Labor is a state of inflammation^{18, 19}, and untimely activation of inflammatory pathways can result in preterm labor.²⁰ Existing data suggest that labor-associated inflammatory changes are higher in preterm labor than term labor.²¹ Progestational agents such as 17P can potentially inhibit inflammation-induced preterm parturition, which would not be expected to affect uterine atony.¹⁶

Current guidelines continue to recommend the weekly administration of 17P for women with a history of a spontaneous preterm birth.⁸ Given its increasing use, examining the link between 17P receipt and morbidities such as PPH is an important step towards more fully understanding its potential risks. To the best of our knowledge, there are no prior publications that address the association between 17P and PPH. This study offers further reassurance about the safety of 17P when used to prevent recurrent preterm birth.

There are several limitations to this study. First, the relatively small sample size precludes identification of potentially clinically significant smaller effect sizes. Indeed, point estimates from our research demonstrate a near 40% increase in the incidence of PPH associated with receipt of 17P within seven days of delivery. Additional research with larger sample sizes is required to reach definitive conclusions. Second, this study was conducted at a single tertiary care institution with a robust PPH prevention and treatment protocol and thus we cannot assume the results of this study are generalizable to the sites without the same preparedness protocols. Additionally, this study was limited to women recommended to use 17P, and thus cannot make inferences about differences in risk of PPH between women on 17P (of any proximity to delivery) compared to those who never had 17P exposure during pregnancy. Finally, these data are subject to the limitations of the electronic medical record, including potential misclassification or acquisition biases. Nevertheless, these findings offer reassurance to providers that recent 17P use among women with a prior preterm birth is not significantly associated with PPH.

AJOG at a Glance.

1. The purpose of this study was to investigate the association between receipt of 17α-hydroxyprogesterone caproate within seven days of delivery and postpartum hemorrhage.

2. Recent receipt of 17α-hydroxyprogesterone caproate for prevention of recurrent preterm birth is not associated with risk of postpartum hemorrhage.

3. These findings offer reassurance to providers that recent 17α-hydroxyprogesterone caproate use among women with a prior preterm birth is not significantly associated with postpartum hemorrhage.