Successful implantation and continuation of a pregnancy to term requires adjustments in the maternal immune system to prevent rejection of fetal tissue and to avoid the inflammatory cascade, which can lead to preterm labor.1–7 Numerous studies support the theory that progesterone plays a role in many of these immune modifications. With receptors on various immune cells, progesterone promotes a decrease in the Th1-to-Th2 cytokine ratio.8,9 In animal studies, progesterone supplementation delayed rejection of allografts placed in the uterus.10
17α-hydroxyprogesterone caproate administration during pregnancy has been shown to decrease the risk of preterm delivery in women with a prior preterm birth.11 The mechanism by which progesterone prevents preterm labor is currently unknown. Some theorize that it functions as a uterine relaxant by inhibiting the formation of myometrial gap junctions and the expression of oxytocin receptors. Others point to its inhibition of prostaglandin synthesis and its immunosuppressive properties.12
Given the known immunomodulatory effects of progesterone, there is reasonable concern that women (and their neonates) treated with 17α-hydroxyprogesterone caproate could be at increased risk for infection during and immediately after pregnancy. In one study, there was an increased rate of human immunodeficiency virus transmission among users of injectable progesterone contraceptives13; however, it is unknown whether 17α-hydroxyprogesterone caproate may show a similar association with infection.
The aim of this study was to evaluate whether 17α -hydroxyprogesterone caproate has an effect on the rate of infection in women or neonates delivering preterm.
MATERIALS AND METHODS
This is a retrospective cohort study of preterm deliveries at a single academic tertiary care institution. After approval was obtained from the Women & Infants Hospital of Rhode Island institutional review board (#12-0079), the medical records of women who delivered at Women & Infants Hospital in Providence, Rhode Island, between January 1, 2005, and December 31, 2012, were reviewed. Pharmacy records were used to identify those women exposed to 17α-hydroxyprogesterone caproate. At this institution, for all patients in either inpatient or outpatient settings, 17α-hydroxyprogesterone caproate was dispensed only through the main hospital pharmacy, which compounded 17α-hydroxyprogesterone caproate and provided it at a low cost during the study period. Criteria for inclusion in the study were delivery at a gestational age between 24 0/7 weeks and 36 6/7 weeks. A preterm cohort was selected as a result of the higher incidence of infectious complications and the likelihood of significant morbidity in this population. Exclusion criteria were primiparity and multiple gestation, human immunodeficiency virus, or other immunosuppressed status because of the risk of infection unrelated to 17α-hydroxyprogesterone caproate. Women exposed to 17α-hydroxyprogesterone caproate were then matched to unexposed women by gestational age (±4 days) and date of delivery (±1 year). Absence of exposure to 17α-hydroxyprogesterone caproate in women in the control group was confirmed through review of each medical record.
Medical records were hand-abstracted by a single investigator (A.D.M.) and data collected on the following variables: demographic characteristics, history of prior preterm birth, antenatal steroid administration, mode of delivery, duration of labor, and membrane rupture. To determine infection outcomes, data were collected on vital signs intra- and postpartum, documentation of fundal tenderness, placental pathology, and administration of antibiotics. Data on neonatal outcomes were collected as well, specifically birth weight, admission to the neonatal intensive care unit, culture results, antibiotic administration, and specific neonatal morbidities or mortality.
The primary study outcome was a composite of infection diagnoses, comprised of clinical or histologic chorioamnionitis, endometritis, and early-onset neonatal sepsis. Clinical chorioamnionitis was defined using Gibbs' criteria: maternal oral temperature greater than or equal to 37.8°C and two of the following: maternal tachycardia, fetal tachycardia, maternal leukocytosis, uterine tenderness, or foul-smelling amniotic fluid.14 Histologic chorioamnionitis was defined as the diagnosis stated in the placental pathology report. Endometritis was defined as a postpartum maternal oral temperature of greater than or equal to 37.8°C and either documented uterine tenderness or administration of therapeutic antibiotics. Early-onset neonatal sepsis was defined as a positive blood culture within 72 hours after delivery.
To detect a 15% difference in the anticipated rate of this primary outcome between women exposed to 17α-hydroxyprogesterone caproate and those unexposed (two-tailed α=0.05 and power=80%), 183 patients per group were required. A 15% difference was chosen because in the authors' opinion, this is a clinically meaningful difference that may affect health care provider willingness to expose patients to the medication. Data analysis was performed with SAS 9.2. Categorical variables were compared by χ2 or Fisher's exact test, and continuous variables were compared using a two-sided t test or nonparametric Wilcoxon rank-sum test with P <.05 considered statistically significant. Logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs) with CIs excluding 1.0 considered statistically significant.
We identified 185 women who were exposed to 17α-hydroxyprogesterone caproate and met inclusion criteria and matched them to 185 unexposed women by gestational age and date of delivery (Table 1). Exposed women and their matched women in a control group differed in gestational age by less than 1 day in 89% of patients (overall range 0–4 days), and dates of birth were within 3 months in 76% of matched pairs (overall range 0–11 months).
Women exposed to 17α-hydroxyprogesterone caproate had a higher median gravidity, lower median term deliveries, and higher median preterm deliveries. As anticipated, women on 17α-hydroxyprogesterone caproate were also more likely to have a history of a prior preterm birth. No significant differences were found between the groups in terms of tobacco or drug use, group B streptococcal colonization, mode of delivery, duration of labor, or duration of ruptured membranes. Women exposed to 17α-hydroxyprogesterone caproate were more likely to have experienced spontaneous labor and to have received betamethasone during the pregnancy.
Women and neonates exposed to 17α-hydroxyprogesterone caproate had a very similar composite infection rate compared with those unexposed (Table 2). No significant differences were found between the two groups in occurrence of clinical or histologic chorioamnionitis or early-onset neonatal sepsis. Slightly more women who were exposed to 17α-hydroxyprogesterone caproate developed endometritis than those unexposed.
Neonates born to mothers taking 17α-hydroxyprogesterone caproate did not differ significantly compared with those born to unexposed mothers in any of the outcomes identified (Table 3). Median birth weights were similar. Most neonates were admitted to the neonatal intensive care unit, and no significant difference was seen between those born to mothers exposed to 17α-hydroxyprogesterone caproate compared with those unexposed. Likewise, no significant differences were seen in rates of respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy, or neonatal death.
Logistic regression was performed to adjust for the following possible confounding variables: history of prior spontaneous preterm birth, because these women may be more susceptible to peripartum infection, and exposure to betamethasone given the immunosuppressive effect of glucocorticoids. Adjusted odds ratios show no significant difference in odds of composite infection or clinical or histologic chorioamnionitis, endometritis, or early-onset neonatal sepsis in women exposed to 17α-hydroxyprogesterone caproate compared with those unexposed (Table 4).
This study found no difference in rates of peripartum infection between women and neonates delivering preterm who were exposed to 17α-hydroxyprogesterone caproate during pregnancy and those who were not. Similar rates of clinical and histologic chorioamnionitis as well as early-onset neonatal sepsis were observed in both groups. Although slightly more women exposed to 17α-hydroxyprogesterone caproate developed postpartum endometritis compared with those unexposed, once the confounders of a history of prior spontaneous preterm birth and exposure to betamethasone were controlled for, no significant difference persisted between the two groups. Strengths of this study include its large sample size and that the estimated rate of infection used in determining power was accurate. Therefore, if a true difference exists in rate of infection of women exposed to 17α-hydroxyprogesterone caproate compared with those unexposed, this study likely would have detected it.
Some inherent differences existed between the two groups of patients at baseline. Women on 17α-hydroxyprogesterone caproate were more likely to have had a prior spontaneous preterm birth as well as a higher rate of spontaneous labor during the current pregnancy. It is less clear why women on 17α-hydroxyprogesterone caproate would have had higher rates of exposure to betamethasone before delivery compared with women not on 17α-hydroxyprogesterone caproate. It is possible that women on 17α-hydroxyprogesterone caproate were followed more closely by their health care providers or that their higher rate of spontaneous labor allowed presentation to a health care setting early enough to administer steroids before delivery. History of prior preterm birth and exposure to betamethasone could potentially influence rates of infection; however, after adjusting for these potential confounding variables, there remained no difference in rates of infection between the two groups.
Our findings add to the evolving body of research on the relationship between 17α-hydroxyprogesterone caproate and infection. Progesterone's effect on the immune system is well described,1,2,8–10; however, much is still unknown about the clinical significance of administration of 17α-hydroxyprogesterone caproate specifically and its relationship with infection in pregnant women and neonates. A case report of an idiopathic vertebral abscess during pregnancy in a woman on 17α-hydroxyprogesterone caproate raised the question of increased risk for this rare infection as a result of progesterone-driven immunomodulation.15 A recent in vitro study compared immune cells from women on 17α-hydroxyprogesterone caproate and gestational age-matched women in a control group, finding attenuated immunoreactivity in the cells from women exposed to the drug.16 A more clinically significant outcome was noted in the Short Cervix and Nulliparous (SCAN) trial, a randomized controlled trial of 17α-hydroxyprogesterone caproate in nulliparous women with a short cervix. The trial was designed to evaluate whether 17α-hydroxyprogesterone caproate reduced the rate of preterm birth in this population and found no improvement in preterm birth rates but did detect a lower rate of neonatal sepsis in neonates born to women given the drug, a difference that was statistically significant.17
The main limitation of this study is its retrospective design, which limited our ability to find the outcome of interest by quality of documentation in the medical record. It is possible that incidences of infection were missed if symptoms or diagnoses were not recorded adequately. In addition, not all placentas were sent to pathology, so it is possible that the true incidence of histologic chorioamnionitis does differ between the two groups. It should also be noted that cases of histologic chorioamnionitis did not necessarily have clinical manifestations of infection; therefore, this study was underpowered to detect a difference in rates of clinical infection. Likewise, given the low rates endometritis and early-onset neonatal sepsis, the study is underpowered to detect differences in these individual infection rates. The scope of this study is limited to those outcomes of peripartum infection, so our results cannot be generalized to other infections throughout pregnancy. In addition, the study population was restricted to women who delivered preterm in an effort to select a higher risk population; therefore, results cannot be generalized to patients who deliver at term.
Given these limitations, future research should expand on these data using a prospective study design. It would be especially interesting to assess for a dose–response effect of 17α-hydroxyprogesterone caproate on infection. Additional infectious outcomes should be included as well such as pyelonephritis and common viral infections that can cause morbidity throughout the pregnancy and postpartum period. Finally, expanding the study population to include women who deliver at term would improve generalizability.
There has been significant concern that injectable progesterone contraceptives may cause immunosuppression given data showing higher rates of human immunodeficiency virus transmission in women using this medication.13 This raises the concern that 17α-hydroxyprogesterone caproate could also lead to higher rates of infection but was not confirmed in this study.
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