Prevention Of Recurrent Preterm Birth Research Articles

Society for Maternal-Fetal Medicine Statement: Response to the Food and Drug Administration’s withdrawal of 17-alpha hydroxyprogesterone caproate

On April 5, 2023, the US Food and Drug Administration withdrew the approval of 17-alpha hydroxyprogesterone caproate, effective immediately, because of the lack of evidence that it reduces the risk of recurrent spontaneous preterm birth. This decision withdraws approval for all formulations of 17-alpha hydroxyprogesterone caproate (both intramuscular and subcutaneous) and applies to both brand name (Makena) and generic versions of the medication. We agree with the Food and Drug Administration determination and discourage continued prescribing of 17-alpha hydroxyprogesterone caproate, including through compounding pharmacies. We do not recommend changing indications for cerclage, indications for vaginal progesterone in patients with a short cervix, or recommendations against activity restriction based on the Food and Drug Administration withdrawal of 17-alpha hydroxyprogesterone caproate from the market. We recommend that discussion of the use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length or in those with a cervical length of ≥25 mm includes a shared decision-making process, especially if a progesterone formulation for preterm birth prevention was received in a previous pregnancy. The Food and Drug Administration determined that it would be inappropriate to delay the effective date of the withdrawal to allow patients currently receiving 17-alpha hydroxyprogesterone caproate to finish treatment. We agree with the Food and Drug Administration that there is no evidence of benefit with continued treatment. Patients currently receiving 17-alpha hydroxyprogesterone caproate can be counseled that the Food and Drug Administration's Center for Drug Evaluation and Research has not identified evidence of harm from discontinuation before 37 weeks of gestation.

Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth

Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth

Progesterone therapy for prevention of recurrent preterm birth in a high risk patient population

Progesterone therapy for prevention of recurrent preterm birth in a high risk patient population

Vaginal versus abdominal cerclage for prevention of recurrent preterm birth following prior failed vaginal cerclage

Vaginal versus abdominal cerclage for prevention of recurrent preterm birth following prior failed vaginal cerclage

Index pregnancy placental histology and response to progesterone supplementation for prevention of recurrent preterm birth

Index pregnancy placental histology and response to progesterone supplementation for prevention of recurrent preterm birth

Association of Vaginal Progesterone Treatment With Prevention of Recurrent Preterm Birth

Preterm birth (PTB) is the leading cause of infant morbidity and mortality worldwide. It has been suggested that vaginal progesterone (VP) treatment may reduce the recurrence of PTB. To evaluate the association of VP treatment with prevention of recurrent PTB among patients with a singleton pregnancy. This prospective, observational cohort study, set in a public health care system for inner-city pregnant patients, enrolled patients with prior spontaneous PTB (gestational age, ≤35 weeks) receiving VP from May 15, 2017, to May 7, 2019. Patients who delivered between 1998 and 2011 served as a referent cohort matched 3:1 for obesity, race and ethnicity, and individual specific preterm birth history. Statistical analysis was performed from August 19, 2021, to September 2, 2022. Patients received 90 mg of vaginal progesterone, 8%, nightly, initiated between 16 weeks and 0 days and 20 weeks and 6 days of pregnancy until 36 weeks and 6 days of pregnancy or delivery. The primary outcome was overall rate of recurrent PTB at 35 weeks or less of patients given VP compared with the 3:1 matched untreated historical controls. Secondary outcomes included assessment of PTB according to adherence (≥80% completing scheduled doses), duration of pregnancy relative to index gestational age, progesterone blood levels, and outcomes for those who declined VP. A total of 417 patients (mean [SD] age, 30.4 [5.9] years; 64 Black patients [15.3%]; 272 [65.2%] with a body mass index of ≥30) received VP and were matched with 1251 controls (mean [SD] age, 28.8 [5.7] years; 192 Black patients [15.3%]; 816 [65.2%] with a body mass index of ≥30). The overall rate of recurrent PTB was 24.0% (100 of 417; 95% CI, 20.0%-28.4%) for the VP cohort compared with 16.8% (1394 of 8278) expected in the matched historical controls. Adherence was not associated with lower rates of recurrent PTB compared with nonadherence (odds ratio, 0.87 [95% CI, 0.51-1.41]). The mean difference between historical matched controls and those using VP was 0.2 weeks (95% CI, -1.4 to 1.0 weeks) without improvement in the interval of recurrent PTB after the implementation of VP (P = .73). Progesterone blood levels for patients who were adherent compared with those who were nonadherent were not significantly different at either 24 or 32 weeks (24 weeks: 99 ng/mL [95% CI, 85-121 ng/mL] vs 104 ng/mL [95% CI, 89-125 ng/mL]; P = .16; 32 weeks: 200 ng/mL [95% CI, 171-242 ng/mL] vs 196 ng/mL [95% CI, 155-271 ng/mL]; P = .69). This cohort study of patients with a current singleton pregnancy suggests that VP was not associated with a reduction in recurrent PTB.

The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study

ObjectivesTo evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. Study designAn explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. ResultsWe included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. ConclusionAspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.

Vaginal progesterone vs intramuscular 17-hydroxyprogesterone caproate for prevention of recurrent preterm birth: a randomized controlled trial

Preterm birth is the leading cause of neonatal morbidity and mortality, and previous preterm birth is one of the strongest risk factors for preterm birth. National and international obstetrical societies have different recommendations regarding progesterone formulation for the prevention of recurrent preterm birth. This study aimed to determine whether vaginal progesterone is superior to 17-hydroxyprogesterone caproate in the prevention of recurrent preterm birth in patients with singleton pregnancies who had a previous spontaneous preterm birth. This was an open-label multicenter pragmatic randomized controlled trial at 5 US centers of patients with singleton pregnancies at <24 weeks of gestation who had a previous spontaneous preterm birth randomized 1:1 to either 200 mg vaginal progesterone suppository nightly or 250 mg intramuscular 17-hydroxyprogesterone caproate weekly from 16 to 36 weeks of gestation. Based on the estimated recurrent preterm birth rate of 36% with 17-hydroxyprogesterone caproate, 95 participants were needed in each arm to detect a 50% reduction in preterm birth rate with vaginal progesterone, with 80% power and 2-sided alpha of 0.05. The primary outcome was preterm birth at <37 weeks of gestation. Prespecified secondary outcomes included preterm birth at <34 and <28 weeks of gestation, mean gestational age at delivery, neonatal morbidity and mortality, and measures of adherence. Analysis was by intention to treat. The chi-square test and Student t test were used as appropriate. P<.05 was considered significant. Overall, 205 participants were randomized; 94 participants in the vaginal progesterone group and 94 participants in 17-hydroxyprogesterone caproate group were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9±1.4 vs 17.8±2.5 weeks; P=.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%; P=.61). There was no significant difference in preterm birth at <37 (31% vs 38%; P=.28; relative risk, 0.81 [95% confidence interval, 0.54-1.20]), <34 (9.6% vs 14.9%; P=.26; relative risk, 0.64 [95% confidence interval, 0.29-1.41]), or <28 (1.1% vs 4.3%; P=.37; relative risk, 0.25 [95% confidence interval, 0.03-2.20]) weeks of gestation. Participants in the vaginal progesterone group had a later mean gestational age at delivery than participants in the 17-hydroxyprogesterone caproate group (37.36±2.72 vs 36.34±4.10 weeks; mean difference, 1.02 [95% confidence interval, 0.01-2.01]; P=.047). Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared with 17-OHPC; however, vaginal progesterone may lead to increased latency to delivery. This trial was underpowered to detect a smaller, but still clinically significant, difference in the efficacy of preterm birth prevention. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Effectiveness of 17-OHP for Prevention of Recurrent Preterm Birth: A Retrospective Cohort Study.

17-α-hydroxyprogesterone caproate (17-OHP) has been recommended by professional societies for the prevention of recurrent preterm birth, but subsequent clinical studies have reported conflicting efficacy results. This study aimed to contribute to the evidence base regarding the effectiveness of 17-OHP in clinical practice using real-world data. A total of 4,422 individuals meeting inclusion criteria representing recurrent spontaneous preterm birth (sPTB) were identified in a database of insurance claims, and 568 (12.8%) received 17-OHP. Crude and propensity score-matched recurrence rates and risk ratios (RRs) for the association of receiving 17-OHP on recurrent sPTB were calculated. Raw sPTB recurrence rates were higher among those treated versus not treated; after propensity score matching, no association was detected (26.3 vs. 23.8%, RR = 1.1, 95% CI: 0.9-1.4). We failed to identify a beneficial effect of 17-OHP for the prevention of spontaneous recurrent preterm birth in our observational, U.S. based cohort. · We observed higher risk for sPTB in the group receiving 17-OHP in the unmatched analysis. · After propensity-score matching, we still failed to identify a beneficial effect of 17-OHP on sPTB. · Sensitivity analyses demonstrated robustness to the inclusion criteria and modeling assumptions..

Vaginal versus Intramuscular Progesterone for Prevention of Recurrent Preterm Birth (VIP): a randomized controlled trial

To determine whether vaginal progesterone is superior to intramuscular 17-hydroxyprogesterone caproate (17OHPC) in prevention of recurrent preterm birth (PTB) in singletons with prior spontaneous preterm birth (sPTB).

A Comparison of Vaginal and Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth.

This study aimed to examine whether vaginal progesterone is noninferior to 17-α hydroxyprogesterone caproate (17OHP-C) in the prevention of recurrent preterm birth (PTB). This retrospective cohort study included singleton pregnancies among women with a history of spontaneous PTB who received prenatal care at a single tertiary center from 2011 to 2016. Pregnancies were excluded if progesterone was not initiated prior to 24 weeks or the fetus had a major congenital anomaly. The primary outcome was PTB <37 weeks. A priori, noninferiority was to be established if the upper bound of the adjusted two-sided 90% confidence interval (CI) for the difference in PTB fell below 9%. Inverse probability of treatment weighting (IPTW) was used to carefully control for confounding associated with choice of treatment and PTB. Adjusted differences in PTB proportions were estimated via IPTW regression, with standard errors adjustment for multiple pregnancies per woman. Secondary outcomes included PTB <34 and <28 weeks, spontaneous PTB, neonatal intensive care unit admission, and gestational age at delivery. Among 858 pregnancies, 41% (n = 353) received vaginal progesterone and 59% (n = 505) were given 17OHP-C. Vaginal progesterone use was more common later in the study period, and among women who established prenatal care later, had prior PTBs at later gestational ages, and whose race/ethnicity was neither non-Hispanic white nor non-Hispanic Black. Vaginal progesterone did not meet noninferiority criteria compared with 17-OHPC in examining PTB <37 weeks, with an IPTW adjusted difference of 3.4% (90% CI: -3.5, 10.3). For secondary outcomes, IPTW adjusted differences between treatment groups were generally small and CIs were wide. We could not conclude noninferiority of vaginal progesterone to 17OHP-C; however, women and providers may be willing to accept a larger difference (>9%) when considering the cost and availability of vaginal progesterone versus 17OHP-C. A well-designed randomized trial is needed. · Vaginal progesterone is not noninferior to 17OHP-C.. · PTB risk may be 10% higher with vaginal progesterone.. · Associations did not differ based on obesity status..

A Possible Mechanism of Action of 17α-Hydroxyprogesterone Caproate: Enhanced IL-10 Production.

The rate of recurrent spontaneous preterm birth (PTB) was reduced by 33% in the Maternal-Fetal Medicine Unit (MFMU) Network trial of 17α-hydroxyprogesterone caproate (17-OHPC), but the mechanism of action, 17 years later, remains elusive. The robustness of the interleukin-10 (IL-10) response to lipopolysaccharide (LPS) stimulation of leukocytes in pregnant women with a prior PTB correlates with gestational age at delivery. This study sought to determine if there is a relationship between the concentration of 17-OHPC and response to LPS stimulation. We performed a secondary analysis of data from the Omega-3 MFMU trial which evaluated the effectiveness of omega-3 fatty acid supplementation in reducing recurrent PTB. We utilized previously characterized data from a subanalyses of the Omega-3 trial of IL-10 and tumor necrosis factor alpha (TNF-α) levels from peripheral blood mononuclear cells stimulated with LPS. Blood was obtained from enrolled women at 16 to 22 weeks' gestation (baseline) and 25 to 28 weeks' gestation (posttreatment). All women received 17-OHPC and plasma 17-OHPC concentrations were measured at 25 to 28 weeks' gestation. We analyzed these data to determine if there was a relationship between 17-OHPC concentration and cytokine production. We then performed an in vitro study to determine if 17-OHPC could directly alter cytokine production by THP-1-derived macrophages. In the clinical samples, we found that 17-OHPC plasma concentrations were correlated with the quantity of the LPS-stimulated production of IL-10. TNF-α production after LPS stimulation was unrelated to 17-OHPC concentration. In the in vitro study, we demonstrate a 17-OHPC concentration dependent increase in IL-10 production. In women receiving 17-OHPC for PTB prevention, we demonstrate a relationship between plasma 17-OHPC and LPS-stimulated IL-10 production by circulating leukocytes. We also demonstrate that, in vitro, 17-OHPC treatment affects IL-10 production by LPS-stimulated macrophages. Collectively, these findings support an immunomodulatory mechanism of action of 17-OHPC in the prevention of recurrent PTB. · 17-OHPC plasma concentrations and LPS-stimulated IL-10 levels correlate in clinical samples in women at risk for recurrent preterm birth.. · 17-OHPC can modulate the response of LPS-stimulated macrophages to increase IL-10 production.. · There was no relationship between TNF-α and plasma concentration of 17-OHPC in clinical samples or in vitro..

Eligibility, Utilization, and Effectiveness of 17-Alpha Hydroxyprogesterone Caproate in a Statewide Population-Based Cohort of Medicaid Enrollees.

The primary objective was to estimate the initiation and adherence rates of 17 α-hydroxyprogesterone caproate (17OHPC) among eligible mothers in a statewide population-based cohort of Medicaid enrollees. The secondary objectives were to (1) determine the association of maternal sociodemographic and clinical characteristics with 17OHPC utilization and (2) assess the real-world effectiveness of 17OHPC on recurrent preterm birth prevention and admission to neonatal intensive care unit (NICU). This is a retrospective cohort study using a linked, longitudinal administrative dataset of birth certificates and medical assistance claims. Medicaid-enrolled mothers in Pennsylvania were included in this study if they had at least one singleton live birth from 2014 to 2016 following at least one spontaneous preterm birth. Maternal Medicaid claims were used to ascertain the use of 17OHPC from various manufacturers, including compounded formulations. Propensity score matching was used to create a covariate balance between 17OHPC treatment and comparison groups. We identified 4,781 Medicaid-covered 17OHPC-eligible pregnancies from 2014 to 2016 in Pennsylvania, 3.4% of all Medicaid-covered singleton live births. The population-based initiation rate was 28.5% among eligible pregnancies. Among initiators, 50% received ≥16 doses as recommended, while 10% received a single dose only. The severity of previous spontaneous preterm birth was the strongest predictor for the initiation and adherence of 17OHPC. In the matched treatment (n = 1,210) and comparison groups (n = 1,210), we found no evidence of 17OHPC effectiveness. The risks of recurrent preterm birth (relative risk [RR] 1.10, 95% confidence interval [CI] 0.97-1.24) and births admitted to NICU (RR 1.00, 95% CI 0.84-1.18) were similar in treated and comparison mothers. The 17OHPC-eligible population represented 3.4% of singleton live births. Less than one-third of eligible mothers initiated treatment. Among initiators, 50% were treatment adherent. We found no difference in the risk of recurrent preterm birth or admission to NICU between treatment and comparison groups. · About 3.4% of singleton live births were eligible for 17OHPC.. · About 30% of eligible mothers initiated treatment.. · We found no association of 17OHPC with recurrent preterm birth..

17-alpha hydroxyprogesterone caproate for the prevention of recurrent preterm birth among singleton pregnant women with a prior history of preterm birth: a systematic review and meta-analysis of six randomized controlled trials.

To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that investigated the clinical benefits of 17-alpha hydroxyprogesterone caproate (17OHPC) in the prevention of recurrent preterm birth (PTB) among singleton pregnant women with a previous history of PTB. We searched four major databases up till April 2021 and assessed the risk of bias in the included studies. We meta-analyzed various maternal-neonatal endpoints (n=18) and pooled them as mean difference or risk ratio (RR) with 95% confidence interval (CI) using the random-effects model. Six RCTs met the inclusion criteria, comprising 2,573 patients (17OHPC=1,617, control=956). RCTs revealed an overall low risk of bias. The rates of PTB <35 weeks (n=5 RCTs; RR, 0.77; 95% CI, 0.63–0.93; P=0.008), PTB <32 weeks (n=3 RCTs; RR, 0.68; 95% CI, 0.51–0.91; P=0.009), neonates with low birth weight (<2.5 kg) at delivery (n=3 RCTs; RR, 0.63; 95% CI, 0.5–0.79; P<0.001), and neonatal death (n=4 RCTs; RR, 0.41; 95% CI, 0.20–0.84; P=0.02) were significantly reduced in the 17OHPC group compared with the control group. Moreover, 17OHPC treatment correlated with a significantly decreased rate of retinopathy (n=2 RCTs; RR, 0.42; 95% CI, 0.18–0.97; P=0.004). However, there were no significant differences in the rates of neonatal intensive care unit admission, cesarean delivery, and other preterm-related complications between both the groups. Among singleton pregnant women with a prior history of PTB, 17OHPC may favorably decrease the risks of recurrent PTB and reduce the rate of neonatal death.

Understanding barriers to utilization of 17-hydroxyprogesterone caproate and other interventions to prevent preterm birth in Fresno County, California

Objective Preterm birth is one of the leading causes of neonatal morbidity and mortality. A history of prior spontaneous preterm birth is a known risk factor for recurrent preterm birth. While 17-alpha-hydroxyprogesterone caproate (17P) has been found in some studies to reduce recurrent preterm birth by 34%, many women who could have benefited from its use did not receive this intervention. We sought to investigate the rate of and reasons for underutilization of 17P in Fresno County, California, where the preterm birth rate trend from 2017 and recent 2020 data showed a significantly higher rate at 10.1% and 9.8% respectively, when compared to the state average of 8.6% and 8.8% respectively. Methods We conducted a retrospective chart review of patients who delivered at Community Regional Medical Center in Fresno from January to December 2016, and surveys of providers and patients, to help identify barriers to 17P utilization. Results After controlling for age, body mass index, interpregnancy interval, and race/ethnicity, we determined that women who had private insurance were 3 times more likely to have received 17P compared to women with public insurance (adjusted odds ratio 2.97, 95% CI: 1.6–6.51, p&lt;.001). We also found that only 23.3% of patients eligible for 17P actually received this intervention. The surveys identified difficulty with completing the insurance approval process and receiving the treatment within the clinically recommended timeline as primary barriers to 17P utilization. Conclusion This study confirmed that 17P intervention for prevention of recurrent preterm birth was underutilized and disproportionately affected patients with inadequate prenatal care and those who had public insurance.

Patient and Provider Perspectives on Acceptability, Access, and Adherence to 17-Alpha-Hydroxyprogesterone Caproate for Preterm Birth Prevention.

Background: Preterm birth (PTB) is a pressing maternal and child health issue with long-standing racial inequities in outcomes and care provision. 17-Alpha-hydroxyprogesterone caproate (17OHPC) has been one of few clinical interventions for recurrent PTB prevention. Little is known about the factors influencing successful administration and receipt of 17OHPC among mothers in the Medicaid program.Materials and Methods: We conducted individual semistructured interviews with 17OHPC-eligible pregnant women and obstetric providers from two academic medical centers in Philadelphia, PA. Patient participants were publicly insured, eligible for 17OHPC treatment, and purposively sampled as either (1) actively receiving treatment or (2) declining/discontinuing treatment. Providers had experience providing care to Medicaid-enrolled patients. Interview transcripts were coded and analyzed to identify themes related to treatment acceptability, access, and adherence.Results: Of the 17 patient participants, the mean age was 30 years. Ten providers (MDs, nurse practitioners, and registered nurses) were also interviewed. Factors facilitating 17OHPC uptake and adherence among patients included severity of prior PTB, provider counseling, and coordination among the clinic, pharmacy, and insurance. Pain was cited as the most significant barrier to 17OHPC for patients, while providers perceived social adversity and beliefs about patients' commitment to treatment to be primary patient barriers. For providers, clinical experience and practice guidelines contributed to their use of 17OHPC. Administrative complexity and coordination of services were the primary provider barrier to 17OHPC administration.Conclusions: Patient–provider communication is a primary driver of 17OHPC acceptability and adherence. Comprehensive patient-centered consultation may improve uptake of clinical therapies among pregnant women at high risk for PTB.

Withdrawing Approval of Makena—A Proposal From the FDA Center for Drug Evaluation and Research

(Abstracted from N Engl J Med 2020;383:e131(1)–e131(4)) Makena (hydroxyprogesterone caproate injection) is currently the only drug on the market for the prevention of recurrent preterm birth (PTB). The Food and Drug Administration (FDA) granted accelerated approval for this drug in 2011.

17-Hydroxyprogesterone Caproate for the Prevention of Recurrent Preterm Birth - A Systematic Review and Meta-analysis Taking into Account the PROLONG Trial.

Background Prior spontaneous preterm birth is a strong risk factor for the recurrence of spontaneous preterm birth in a subsequent pregnancy and has been evaluated in prevention studies using progesterone (natural progesterone administered orally or vaginally, and 17-hydroxyprogesterone caproate [17-OHPC]) as a selection criterion. Based on the findings of a randomized, placebo-controlled study, 17-OHPC was approved for use in 2011 by the Food and Drug Administration in the USA for the prevention of recurrent preterm birth. The approval was granted with qualification that a subsequent confirmatory study would need to be carried out, the results of which have just been published (PROLONG trial). Method A systematic literature search for the period from 1970 to April 2020 using the search terms “preterm birth” and “17-OHPC” or “progesterone” was carried out. Only randomized, placebo-controlled studies of women with singleton pregnancies who received 17-OHPC to prevent recurrent preterm birth were included in the subsequent meta-analysis. The relative risk and associated 95% confidence intervals were calculated. The heterogeneity between studies was evaluated with I 2 statistics. Results In addition to the original study used for the approval and the PROLONG trial, only one other study was found which met the inclusion criteria (total number of patients: 2221). With considerable heterogeneity between the studies, particularly with respect to the risk factors for preterm birth, the comparison between 17-OHPC and placebo showed no significant reduction in preterm birth rates before 37, 35 and 32 weeks of gestation and no significant differences with regard to the prevalence of miscarriage before 20 weeks of gestation or fetal deaths (antepartum or intrapartum) after 20 weeks of gestation and neonatal morbidity. Conclusion Based on the currently available data, 17-OHPC cannot be recommended for the prevention of recurrent preterm birth. Further randomized, placebo-controlled studies with clearly defined, comparable risk factors are required to identify the group of pregnant women which could benefit from the use of 17-OHPC to prevent preterm birth.

17-Hydroxyprogesterone caproate improves hypertension and renal endothelin-1 in response to sFlt-1 induced hypertension in pregnant rats.

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7μg·kg-1·day-1 for 6days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), pup and placenta weights, renal cortex PPET-1 mRNA levels and nitrate-nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 115±1 (n=13) vs. 99±2mmHg (n=12, p<0.05). 17-OHPC attenuated this hypertension reducing MAP to 102±3mmHg in sFlt-1 treated pregnant rats (n=8). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Importantly, renal cortex PPET-1 mRNA levels were elevated 3 fold in NP+sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 44±9µM in NP rats (n=9), 20±3µM in NP+sFlt-1 (n=7), which increased to 42±11µM NP+sFlt-1+17OHPC (n=6). Administration of 17-OHPC improves clinical characteristics of preeclampsia in response to elevated sFlt-1 during pregnancy.

SUN-255 The Synthetic Progestin, 17-alpha-hydroxyprogesterone Caproate, Used in Human Pregnancy Alters Prefrontal Cortical Development in Rats

17-alpha-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestin commonly prescribed for the prevention of recurrent preterm birth. Treatment with 17-OHPC in high-risk pregnant women begins between gestational weeks 16-20, and continues through week 36 1. Recent studies suggest that 17-OHPC is not an effective treatment for reducing rates of preterm delivery 2,3. Most concerning is the timing of 17-OHPC administration, which coincides with critical periods of mesocortical dopamine pathway development in the fetus 4. Regulating behaviors of executive function, the mesocortical pathway originates in dopaminergic neurons of the ventral tegmental area (VTA) that innervate the medial prefrontal cortex (mPFC). Disruptions in mesocortical dopamine pathway development are believed to underlie deficits in cognitive functioning 5,6.In rodent models of cortical development, the developing mesocortical dopamine pathway is sensitive to progestins. There is transient expression of nuclear progesterone receptors (PR) in both the VTA and mPFC 7. PR are powerful transcription factors that can alter gene expression and fundamentally alter neural development 8,9. When rodents are treated with 17-OHPC during mesocortical dopamine pathway development, there are significant sex-specific alterations in dopaminergic innervation of the mPFC and deficits in cognitive behaviors in adulthood 10. Microglia, the resident immune cells of the central nervous system, play a critical role in establishing dopaminergic circuitry of the forebrain 11. The following experiment tested the hypothesis that 17-OHPC alters microglia activity in a sex-specific manner. Our results reveal that there is an innate sex difference in the number of reactive microglia, where control group females had significantly more than males. Treatment with 17-OHPC abolishes this sex difference by reducing the number of reactive microglia in 17-OHPC treated females to male-like levels in both the prelimbic (PL) and infralimbic (IL) mPFC. There is also a significant reduction in the percentage of reactive microglia in 17-OHPC treated animals compared to controls. These results suggest that early 17-OHPC exposure may decrease functional microglial activity during critical periods of cortical development, and that females are more vulnerable than males. Consideration should be given to the potential effects of 17-OHPC on neural and cognitive development in children.