Prevention Of Recurrent Preterm Birth Research Articles

348: Utilization of progesterone and cervical length screening for prevention of recurrent preterm birth

348: Utilization of progesterone and cervical length screening for prevention of recurrent preterm birth

A Randomized Controlled Trial of Intramuscular Versus Vaginal Progesterone for the Prevention of Recurrent Preterm Birth

(Abstracted from Int J Gynecol Obstet 2016;134:169–172) Preterm birth (PTB) is responsible for most of the neonatal deaths that occur in the absence of congenital anomalies. It is also a major cause of long-term disabilities, including cerebral palsy, blindness, and deafness in childhood.

17-α Hydroxyprogesterone Caproate for the Prevention of Recurrent Preterm Birth: One Size May Not Fit All.

Spontaneous preterm birth is a syndrome with many causes and thus unresponsive to a single intervention. It logically follows that patients with a prior spontaneous preterm birth are a heterogeneous group unlikely to respond equally to a single preventive intervention such as 17-α hydroxyprogesterone caproate. Further confounding this issue is our fundamental lack of knowledge about the mechanism(s) by which 17-α hydroxyprogesterone caproate reduces preterm birth. Recently, studies demonstrating that responders and nonresponders can be identified based on obstetric history, genotype, physical characteristics, and behavioral factors have begun to provide clues into both 17-α hydroxyprogesterone caproate's mechanism and the pathophysiology of recurrent preterm birth and may allow for more targeted therapy. These studies lend support to speculation that inflammation or nitric oxide metabolism may be common threads between 17-α hydroxyprogesterone caproate's mechanism and preterm birth prevention. It will remain critically important to avoid the temptation to regard prior spontaneous preterm birth as a single disease entity amenable to a single treatment.

Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system

Spontaneous preterm birth remains a leading cause of neonatal morbidity and mortality among nonanomalous neonates in the United States. Spontaneous preterm birth tends to recur at similar gestational ages. Intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent spontaneous preterm birth. Unfortunately, one-third of high-risk women will have a recurrent spontaneous preterm birth despite 17-alpha hydroxyprogesterone caproate therapy; the reasons for this variability in response are unknown. We hypothesized that clinical factors among women treated with 17-alpha hydroxyprogesterone caproate who suffer recurrent spontaneous preterm birth at a similar gestational age differ from women who deliver later, and that these associations could be used to generate a clinical scoring system to predict 17-alpha hydroxyprogesterone caproate response. Secondary analysis of a prospective, multicenter, randomized controlled trial enrolling women with ≥1 previous singleton spontaneous preterm birth <37 weeks' gestation. Participants received daily omega-3 supplementation or placebo for the prevention of recurrent preterm birth; all were provided 17-alpha hydroxyprogesterone caproate. Women were classified as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest previous spontaneous preterm birth. Responders were women with pregnancy extending ≥3 weeks later compared with the delivery gestational age of their earliest previous preterm birth; nonresponders delivered earlier or within 3 weeks of the gestational age of their earliest previous preterm birth. A risk score for nonresponse to 17-alpha hydroxyprogesterone caproate was generated from regression models via the use of clinical predictors and was validated in an independent population. Data were analyzed with multivariable logistic regression. A total of 754 women met inclusion criteria; 159 (21%) were nonresponders. Responders delivered later on average (37.7±2.5 weeks) than nonresponders (31.5±5.3 weeks), P<.001. Among responders, 27% had a recurrent spontaneous preterm birth (vs 100% of nonresponders). Demographic characteristics were similar between responders and nonresponders. In a multivariable logistic regression model, independent risk factors for nonresponse to 17-alpha hydroxyprogesterone caproate were each additional week of gestation of the earliest previous preterm birth (odds ratio, 1.23; 95% confidence interval, 1.17-1.30, P<.001), placental abruption or significant vaginal bleeding (odds ratio, 5.60; 95% confidence interval, 2.46-12.71, P<.001), gonorrhea and/or chlamydia in the current pregnancy (odds ratio, 3.59; 95% confidence interval, 1.36-9.48, P=.010), carriage of a male fetus (odds ratio, 1.51; 95% confidence interval, 1.02-2.24, P=.040), and a penultimate preterm birth (odds ratio, 2.10; 95% confidence interval, 1.03-4.25, P=.041). These clinical factors were used to generate a risk score for nonresponse to 17-alpha hydroxyprogesterone caproate as follows: black+1, male fetus+1, penultimate preterm birth+2, gonorrhea/chlamydia+4, placental abruption+5, earliest previous preterm birth was 32-36 weeks+5. A total risk score >6 was 78% sensitive and 60% specific for predicting nonresponse to 17-alpha hydroxyprogesterone caproate (area under the curve=0.69). This scoring system was validated in an independent population of 287 women; in the validation set, a total risk score >6 performed similarly with a 65% sensitivity, 67% specificity and area under the curve of 0.66. Several clinical characteristics define women at risk for recurrent preterm birth at a similar gestational age despite 17-alpha hydroxyprogesterone caproate therapy and can be used to generate a clinical risk predictor score. These data should be refined and confirmed in other cohorts, and women at high risk for nonresponse should be targets for novel therapeutic intervention studies.

A randomized controlled trial of intramuscular versus vaginal progesterone for the prevention of recurrent preterm birth

ObjectiveTo compare the efficacy of intramuscular hydroxyprogesterone caproate with that of vaginal progesterone for prevention of recurrent preterm birth. MethodsA prospective randomized controlled trial was conducted at a US tertiary care center between June 1, 2007, and April 30, 2010. Women with singleton pregnancies (16–20 weeks) and a history of spontaneous preterm birth were randomly allocated using a computer-generated randomization sequence to receive either a weekly intramuscular injection of hydroxyprogesterone caproate (250 mg) or a daily vaginal progesterone suppository (100 mg). Participants, investigators, and assessors were not masked to group assignment. The primary outcome was birth before 37 weeks of pregnancy. Per-protocol analyses were performed: participants who completed follow-up were included. ResultsAnalyses included 66 women given intramuscular progesterone and 79 given vaginal progesterone. Delivery before 37 weeks was recorded among 29 (43.9%) women in the intramuscular progesterone group and 30 (37.9%) in the vaginal progesterone group (P=0.50). ConclusionWeekly intramuscular administration of hydroxyprogesterone caproate and daily vaginal administration of a progesterone suppository exhibited similar efficacy in reducing the rate of recurrent preterm birth.ClinicalTrials.gov: NCT00579553.

533: The effect of partial compliance on the prevention of recurrent preterm birth in women receiving weekly 17 alpha-hydroxyprogesterone caproate injections

To analyze the effect of partial compliance on the prevention of preterm birth (PTB; defined as less than 37 weeks of gestation) among women with previous preterm births and receiving 17 alpha-hydroxyprogesterone caproate (17-P). This is a secondary analysis of a multicenter trial for the prevention of recurrent PTB. Women with a history of PTB were enrolled between 16 and 20 weeks and randomly assigned to weekly injections of either 17-P or placebo. Noncompliance was defined by a gap of at least 10 days between any two injections. Women with 100% compliance rate were compared to those with a compliance rate between 40-80%. Cases with missing data were excluded. The rate of recurrent PTB was the primary outcome. Relative risks were calculated and adjusted to race and the number of previous PTBs. Student's t, Chi-square and mantel-haenszel tests were used as appropriate. A total of 409 women were studied: 370 were 100% compliant, whereas 35 had a compliance rate of 40-80%. The average compliance rate (%) in the group with partial compliance was 62 ± 13. The average gestational age at delivery in the full compliance group was 36w0d ± 4.7 weeks; whereas women with partial compliance delivered in average at 34w1d ± 5.7 weeks. In each group, the PTB rate was significantly reduced in pregnancies receiving 17-P compared to placebo [table]. Women on 17-P whether they were 100% or partially (40-80%) compliant had statistically similar PTB rates [table]. Comparing the homogeneity of both relative risks, the rate of recurrent PTB prevention in both groups was not statistically different (p= 0.1). A 17-P injection compliance rate of 40-80% did not reduce the efficacy of 17-P for the prevention of recurrent preterm birth. This may be explained by the recently reported long half-life of 17-P of 16 days. A randomized trial might help in determining the frequency of injections and the interval between injections of 17-P to prevent recurrent preterm birth. If confirmed, our findings could lead to a dramatic decrease in costs related to prevention of recurrent preterm.

699: Transgenerational alteration of estrus cycle proportion in F1 female mice obtained from F0 males neonatally exposed to 17α-hydroxyprogesterone caproate

The FDA has approved 17α-hydroxyprogesterone caproate (17OHPC), for the prevention of recurrent preterm birth. Altering the steroid hormone milieu during fetal development has potential long-term adverse consequences as observed with in utero diethylstilbestrol exposure. Recently, we reported that neonatal 17OHPC-exposure altered the periodicity of the estrus cycles with suppressed estrogen-responsiveness in uterine and vaginal transcriptome of adult mice. Our current objective was to evaluate the potential developmental and transgenerational effects of 17OHPC-exposure on female reproductive tract function. Neonatal mice (C57BL/6J) were given 5 daily SC injections (day 0-4) of 5 μg/pup or 50 μg/pup 17OHPC or 20 μL of vehicle (sesame oil) control (F0-mice). At 3 months of age, both male and female F0-mice (control, 5 μg or 50 μg 17OHPC-exposed) were mated with control mice to evaluate the reproductive abilities of F0-mice and to obtain F1-mice. At 3 months of age, the periodicity of the estrus cycle and reproductive organs were analyzed in both male and female F0 and F1-mice. Both male and female F0-mice were fertile. Neonatal exposure to 17OHPC altered the periodicity of the estrus cycle at 3 months of age in F1-female mice; however, tissue mass of the reproductive organs were not significant affected by neonatal exposure to 17OHPC in either male or female sex of F1-mice. Intriguingly, F1- mice showed effects of F0 paternal 17OHPC-exposure on the periodicity of the estrus cycle, which had a longer diestrus compared to control females. Paternal contribution to the transgenerational effects of 17OHPC-exposure on the function of the female reproductive in the next generation was elucidated. Developmental alteration of the progestogen milieu in male F0-mice can be transferred to the next generation female F1-mice. Further investigations are required in mice as well as in human to understand the potential multi-generational effects of 17OHPC-exposure.

Use and attitudes of obstetricians toward 3 high-risk interventions in MFMU Network hospitals

We sought to evaluate the frequency of, and factors associated with, the use of 3 evidence-based interventions: antenatal corticosteroids for fetal lung maturity, progesterone for prevention of recurrent preterm birth, and magnesium sulfate for fetal neuroprotection. A self-administered survey was conducted from January through May 2011 among obstetricians from 21 hospitals that included 30 questions regarding their knowledge, attitudes, and practice of the 3 evidence-based interventions and the 14-item short version of the Team Climate for Innovation survey. Frequency of use of each intervention was ascertained from an obstetrical cohort of women between January 2010 and February 2011. A total of 329 obstetricians (74% response rate) who managed 16,946 deliveries within the obstetrical cohort participated in the survey. More than 90% of obstetricians reported that they incorporated each intervention into routine practice. Actual frequency of administration in women eligible for the treatments was 93% for corticosteroids, 39% for progesterone, and 71% for magnesium sulfate. Provider satisfaction with quality of treatment evidence was 97% for corticosteroids, 82% for progesterone, and 57% for magnesium sulfate. Obstetricians perceived that barriers to treatment were most frequent for progesterone (76%), 30% for magnesium sulfate, and 17% for corticosteroids. Progesterone use was more frequent among patients whose provider reported the quality of the evidence was above average to excellent compared with poor to average (42% vs 25%, respectively; P < .001), and they were satisfied with their knowledge of the intervention (41% vs 28%; P = .02), and was less common among patients whose provider reported barriers to hospital or pharmacy drug delivery (31% vs 42%; P = .01). Corticosteroid administration was more common among patients who delivered at hospitals with 24 hours a day-7 days a week maternal-fetal medicine specialist coverage (93% vs 84%; P = .046), CONCLUSION: Obstetricians in Maternal-Fetal Medicine Units Network hospitals frequently use these evidence-based interventions; however, progesterone use was found to be related to their assessment of evidence quality. Neither progesterone nor the other interventions were associated with overall climate of innovation within a hospital as measured by the Team Climate for Innovation. National Institutes of Health Consensus Conference Statements may also have an impact on use; there is such a statement for antenatal corticosteroids but not for progesterone for preterm prevention or magnesium sulfate for fetal neuroprotection.

17-hydroxyprogesterone caproate significantly improves clinical characteristics of preeclampsia in the reduced uterine perfusion pressure rat model.

Preeclampsia is characterized by increased uterine artery resistance index, chronic immune activation, and decreased circulating nitric oxide levels. 17-α-Hydroxyprogesterone caproate (17-OHPC) is a synthetic metabolite of progesterone used for the prevention of recurrent preterm birth. We hypothesized that 17-OHPC could reduce mean arterial pressure by decreasing inflammation, whereas improving vasodilation by increasing nitric oxide bioavailability and uterine artery resistance index during late gestation in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. 17-OHPC (3.32 mg/kg) was intraperitoneally administered on gestation day 18 into RUPP rats, carotid catheters inserted, and mean arterial pressure, blood, and tissues were collected on day 19. Mean arterial pressure in normal pregnant (NP; n=13) was 92±2.0 and increased to123±2.0 in RUPP (n=18; P<0.0001), which was improved to 116±1.5 mm Hg in RUPP+17-OHPC (n=10; P<0.05). Circulating CD4+ T cells were 1.19%±1.0% of gated cells in NP (n=7), which increased to 8.52%±2.4% in RUPP rats (n=10; P<0.05) but was reduced to 2.72%±0.87% (n=14; P<0.05) in RUPP+17-OHPC. Circulating nitrate/nitrite was 26.34±3.5 µmol/L in NP (n=12) but was reduced to14.58±3.1 in RUPP rats (n=8; P=0.03) and increased to 22.69±1.62 in RUPP+17-OHPC (n=7; P=0.05). Endothelial nitric oxide synthase expression was 0.65±0.11 AU in NP (n=4), which decreased to 0.33±0.01 in RUPP rats (n=4; P=0.05) but increased to 0.57±0.01 in RUPP+17-OHPC (n=5; P=0.03). Uterine artery resistance index was 0.54±0.02 in NP (n=3), 0.78±0.03 in RUPP (n=4), and 0.63±0.038 in RUPP+17-OHPC (n=8; both P<0.05). Our findings demonstrate that even though modest, lowering blood pressure with 17-OHPC could be a viable treatment option for suppressing inflammation, uterine artery vasoconstriction while improving litter size.

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Objectives Preeclampsia (PE), new onset hypertension at 20 weeks of gestation, is characterized by increased uterine artery resistance index (UARI), chronic immune activation and decreased of vasodilators such as nitric oxide (NO). 17-alpha-hydroxyprogesterone caproate (17-OHPC) is a synthetic metabolite of progesterone used for the prevention of recurrent preterm birth. The objective of this study was to determine whether 17-OHPC could reduce blood pressure (MAP), inflammation, UARI, as well as increase NO bioavailability in a hypertensive rat model of PE. Methods 17-OHPC (3.32 mg/kg) was intraperitoneally administered on day 18 of gestation into Reduced Uterine Perfusion Pressure (RUPP) rats and carotid catheters were inserted. MAP, blood and tissues were collected on day 19. Results MAP in NP rats ( n = 13) was 92 ± 2; 123 ± 2 in RUPP ( n = 18), and 116 ± 1 mmHg in RUPP + 17-OHPC ( n = 10). UARI was 0.78 ± 0.03 in RUPP ( n = 4) and 0.63 ± 0.038 in RUPP + 17-OHPC ( n = 8). Circulating CD4+ T cells were 1.19 ± 1.0% of gated cells in NP ( n = 7), which increased to 8.52 ± 2.4% in RUPP rats ( n = 10) but was significantly reduced to 2.72 ± 0.87% ( n = 14) in RUPP + 17-OHPC. Circulating nitrate/nitrite was 26.34 ± 3.5 μM in NP ( n = 12); 14.58 ± 3.1 in RUPP rats ( n = 8) and increased to 26.69 ± 1.62 in RUPP + 17-OHPC ( n = 7. eNOS expression was 0.65 ± 0.11 A.U in NP ( n = 4), which decreased to 0.33 ± 0.01 in RUPP rats ( n = 4) but increased to 0.57 ± 0.01 in RUPP+17-OHPC ( n = 5). Levels of TNF-alpha were 65.84 ± 17.7 pg/ml in RUPP rats ( n = 5) but were blunted to 17.24 ± 3.9 in RUPP + 17-OHPC ( n = 8). Conclusions In conclusion, 17-OHPC improves inflammation, UARI, hypertension, and NO bioavailability in response to placental ischemia during pregnancy. Disclosures L.M. Amaral: None. D.C. Cornelius: None. J. Moseley: None. J.N. Martin: None. B. LaMarca: None.

770: Pharmacokinetics and tolerability of oral 17-hydroxyprogesterone caproate (HPC) relative to intramuscular (IM) HPC

To determine the pharmacokinetic profile and assess tolerability of an oral HPC capsule (LPCN 1107) relative to an IM control in healthy non-pregnant women. This was an open-label, 3-period, active controlled study in ten healthy non-pregnant women 18-30 years of age. In Periods 1 and 2 volunteers were administered in a randomized, cross-over fashion, either one dose of LPCN 1107 400 mg (QD) or two doses of LPCN 1107 400 mg given 12 hours apart (Q12) with a standard meal. In Period 3 all subjects received a single dose of HPC 250 mg IM. There was a washout of one week between treatment Periods. Blood samples were collected over 24 hours following QD dosing, 36 hours following Q12 hour dosing and over 30 days following the IM dosing. HPC concentrations in plasma were analyzed using a validated LC-MS/MS method. Steady state simulations (SS) were modeled from single dose pharmacokinetic parameters using WinNonlin. Following administration of HPC the maximum concentration (Cmax, ng/mL) of HPC was 13.5, 23.1, 7.3 and area under the curve (AUC0-t, ng*h/mL) was 69, 173, 2101 for the QD, Q12 and IM treatments respectively. Given the intrinsic difference in dosing regimen between the oral and IM forms, SS was simulated based on single dose pharmacokinetic parameters for the 400 mg Q12 and 250 mg weekly IM doses. The simulated steady state pharmacokinetic parameters showed that 400 mg Q12 exposure was about 55% of weekly 250 mg IM product. LPCN 1107 was well tolerated with no SAEs. This study is the first to report significant oral absorption of HPC. Based on the steady state simulation, LPCN 1107 could provide serum exposures comparable to weekly IM injection at an appropriate dose and the oral treatments demonstrate good dose response. LPCN 1107 is currently in clinical development and if approved, has the potential to become the first oral HPC therapy for the prevention of recurrent preterm birth.

Abstract 093: Progesterone Supplementation Improves Blood Pressure And Uterine Artery Resistance In Response To Placental Ischemia During Pregnancy

Preeclampsia (PE), new onset hypertension at 20 weeks of gestation, is characterized by increased uterine artery resistance index (UARI), chronic immune activation and decreased of vasodilators such as nitric oxide (NO). Despite being one of the leading causes of death in pregnant women, currently there is no effective treatment for PE except for early delivery of the fetus. We have demonstrated that PE women have significantly lower circulating progesterone than normal pregnant (NP). 17-alpha-hydroxyprogesterone caproate (17-OHPC) is a synthetic metabolite of progesterone used for the prevention of recurrent preterm birth and although the mechanism is not understood, is suspected to have vasodilatory and anti-inflammatory effects. Therefore, we hypothesized that progesterone (17-OHPC) supplementation could reduce blood pressure (MAP), pro-inflammatory cytokines, CD4+ T cells, UARI, as well as increase NO bioavailability in a hypertensive rat model of PE. To address this question 17-OHPC (3.32mg/kg) was intraperitoneally administered on day 18 of gestation into Reduced Uterine Perfusion Pressure (RUPP) rats and carotid catheters were inserted. MAP, blood and tissues were collected on day 19. MAP in NP rats (n=13) was 92±2; 123±2 in RUPP (n=18), and 116 ±1 mmHg in RUPP+17-OHPC (n=10), p &lt;0.05. UARI was 0.78±0.03 in RUPP (n=4) and 0.63±0.038 in RUPP+17-OHPC (n=8), p&lt;0.05. Circulating CD4+ T cells were 1.19±1.0% of gated cells in NP (n=7), which increased to 8.52±2.4% in RUPP rats (n=10) but was significantly reduced to 2.72±0.87% (n=14) in RUPP + 17 O-HPC, p &lt;0.05. Total circulating nitrate/nitrite was 26.34 ±3.5 μM in NP (n=12); 14.58±3.1 in RUPP rats (n=8) and increased to 26.69±1.62 in RUPP+17-OHPC (n=7), p &lt;0.05. Aortic eNOS expression was 0.65±0.11 A.U in NP (n=4), which decreased to 0.33±0.01 in RUPP rats (n=4) but increased to 0.57±0.01 in RUPP+17-OHPC (n=5), p &lt;0.05. Levels of TNF-alpha were 65.84±17.7 pg/ml in RUPP rats (n=5) but were blunted to 17.24±3.9 in RUPP+17-OHPC (n=8), p &lt;0.05. In conclusion, 17-OHPC supplementation improves inflammation, UARI, hypertension, and nitric oxide bioavailability in response to placental ischemia during pregnancy and should therefore be considered further for addition to the clinical management of PE

473: Cost-effectiveness of compounded versus commercially manufactured 17-alpha hydroxyprogesterone caproate (17P) for the prevention of recurrent preterm birth

To estimate the costs and outcomes of commercially manufactured 17P compared to compounded 17P or no treatment in women with a history of prior preterm birth (PTB). Using a Markov model, we estimated the costs and outcomes of weekly treatment with 17P to prevent recurrent PTB (HR for delivery 0.7, 95% CI 0.56, 0.84) in two populations. The National Center for Health Statistics (NCHS) was used to obtain data on racial distribution and gestational age at first prenatal visit and delivery among women with a history of prior PTB. Racial distribution and risk of PTB was then modified to approximate the placebo arm of the MFMU trial. Compounded 17P differed from commercial 17P in cost ($30 vs. $695/dose), likelihood of receiving an ineffective dose, and risk of sepsis from contaminated drug. All outcomes, including long-term disabilities, and first-year costs were based on gestational age at delivery, and derived from NCHS data and/or the literature. Costs were in 2012 US dollars, and future costs and quality-adjusted life years (QALYs) were discounted at 3% annually. The model was run as a microsimulation (500,000 iterations), with the values for each parameter drawn from probability distributions. Compounded 17P was cost-saving (lower costs and better outcomes) compared to no treatment in the majority of simulations in both populations (Table). Commercial 17P was cost-effective compared to no treatment, but expensive relative to compounded 17P, with considerable uncertainty around estimates, primarily driven by variability in the baseline risk of PTB and the risk of ineffective dosing with compounded 17P. At current prices, commercial 17P is cost-effective compared to no treatment. Cost-effectiveness of compounded 17P relative to commercial 17P is dependent on the effect of variability in drug potency on overall efficacy of prevention of PTB.Tabled 1*Negative numbers indicate cost-savings. Open table in a new tab

Abstract 542: Progesterone Supplementation Attenuates Hypertension And AT1-AA in Response Tt Elevated IL-6 During Pregnancy

Preeclampsia is a multi-system disorder defined as new-onset hypertension with proteinuria developing after 20 weeks gestation. Preeclampsia remains a significant contributor to maternal morbidity and mortality, with great impact in perinatal morbidity. Research efforts throughout the world have focused on alternative therapies for the treatment of preeclampsia to the mainstay treatment of delivery of the fetus and placenta. 17-alpha-hydroxyprogesterone caproate (17-OHP) is a synthetic metabolite of progesterone used effectively for the prevention of recurrent preterm birth in singleton pregnancies. Previously we identified potential role for 17-OHP as an anti-inflammatory that suppressed inflammatory cytokines, hypertension and endothelin-1 in response to placental ischemia in the RUPP rat model of preeclampsia. In the current study we examined a role 17-OHP to blunt the pathophysiological effects to elevated IL-6 during pregnancy. IL-6 induced hypertension during pregnancy occurs with increased renin activity, autoantibodies to the angiotensin II type I receptor (AT1-AA) and reduced kidney function. This experiment was performed in the following groups of normal pregnant rats: NP (n=5); NP+17-OHP (n=6); NP+IL-6 (n=10); NP+IL-6+17-OHP (n=10). To test our hypothesis IL-6 (5ng/day) was infused via miniosmotic pump into normal pregnant rats beginning on day 14 of gestation and 17-OHP (3.32mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (MAP) determination and serum collection was performed on day 19 of gestation. MAP in NP was 100+3mmHg which increased with IL-6 to 112+4mmHg, p &lt;0.05. Pregnant rats given 17-OHP alone had a MAP of 99+3mmHg and MAP only increased to 103+2mmHg in IL-6+17-OHP. AT1-AA was 1.2+0.5 bpm in NP rats and increased to 17+9 bpm with IL-6 infusion. Administration of 17-OHP significantly blunted AT1-AA to 4+0.8bpm in NP+IL-6+17-OHP. Importantly, this study illustrates that 17-OHP attenuates hypertension and AT1-AA in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia.

Prevention of Recurrent Preterm Birth: Role of the Neonatal Follow-up Program

Preterm birth (PTB) is a public health crisis in need of effective preventative strategies. Multi-disciplinary Neonatal Follow-up Programs (NFPs) provide health services to preterm infants at high risk for developmental problems after discharge from US newborn intensive care units. We aimed to determine whether NFPs are a potentially effective venue for specialized maternal counseling and intervention aimed at reducing the high rate of recurrent PTB in this population. This prospective case series enrolled women with preterm children evaluated in the Utah Department of Health NFP, 2010-2012. Women were interviewed, received Maternal Fetal Medicine (MFM) counseling services, and maternal and neonatal records were abstracted. We assessed maternal demographics, medical history, and characteristics of the index pregnancy. We calculated the proportion of women with knowledge of PTB recurrence risk and available prevention strategies, and assessed current contraceptive use and reproductive plans. Ninety-six women with a history of early PTB (≤26 weeks and/or birth weight < 1,250 g) were evaluated. Nearly 1 in 5 women (19.8 %) evaluated reported sexual activity, desire to avoid pregnancy, and no current contraceptive use, and were therefore at imminent risk of unintended pregnancy. Of women without permanent contraception, only 24.3 % were aware of their individual PTB recurrence risk. Of women with a history of spontaneous PTB, only 4 % were aware of effective pharmacologic preventative strategies. Introduction of MFM consultation as part NFP multi-disciplinary services is a novel approach with the potential to reduce recurrent PTB in an exceptionally high-risk population.

Change in Mononuclear Leukocyte Responsiveness in Midpregnancy and Subsequent Preterm Birth

To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-α, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. Interleukin-10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-α Δ also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-α at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Δ and tumor necrosis factor-α Δ were unaffected by either omega-3 supplementation or fish diet. Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. II.

829: Utility of qualitative research for assessment of attitudes and knowledge on preterm birth in a low resource setting

attitudes and knowledge on preterm birth in a low resource setting Judy Levison, Debora Nanthuru, Grace Chiudzu, Peter Kazembe, Henri Phiri, Kjersti Aagaard Baylor College of Medicine, Obstetrics&Gynecology, Houston, TX, Kamuzu Central Hospital, Obstetrics&Gynecology, Lilongwe, Malawi, Kamuzu Central Hospital, Children’s Clinical Center of Excellence, Lilongwe, Malawi OBJECTIVE: Malawi has one of the highest preterm birth (PTB) rates in the world at 20.3%. At the start of a funded initiative in the largest populated district (Lilongwe), we sought to complete a needs assessment and gap analyses employing validated qualtitative field research methodologies in order to focus potential high-impact interventions. STUDY DESIGN: In mentored partnership with regional providers 14 and 50 km from the central referral hospital, investigative teams comprised of clinician investigators, data recorder, and interpreters held focus groups for voluntary participants (n 28) of community health workers (CHWs), patient couples, midwives and clinical officers. Directed, non-directed, structured and unstructured questions facilitated PTB discussion, including definitions, perception, causation, management, and accepted interventions. RESULTS: Robust discussion occurred in all groups. Among patient couples, a total of 162 questions were asked with 298 answers given (1:1.84), the majority answered by women (55.6%-87.6%). No knowledge gap was observed for accepted dating and length of gestation, biologic causation of PTB, and presumptive benefit of antenatal care, nutrition, and optimized maternal health. Generalized concensus among all groups defined the threshold of viability by gestational age at 26-28 weeks, which was discordant with similarly defined birthweight threshold at 1.4-1.9 kg. Knowledge and prevention-intervention gaps were uniformly observed among all participants regarding any prevention or intervention strategies, including antenatal corticosteroids, prevention of recurrent PTB, PTB risk-managment and interventions, and referral service-line utilization. CONCLUSION: Qualitative research into community baseline gaps and needs is essential. Applied and informed dynamic education and knowledge dissemination, accepted prevention-intervention strategies, and inpatient and outpatient referral networks are under development as a result of this study.

530: Next generation sequencing identifies the IL-12 receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity

receptor beta gene as a potential mediator in the response to 17-alpha-hydroxyprogesterone caproate for the prevention of recurrent prematurity Tracy Manuck, Scott Watkins, Sean Esplin, Marc Jackson, Lynn Jorde, Michael Varner University of Utah, Obstetrics and Gynecology, Salt Lake City, UT, University of Utah, Human Genetics, Salt Lake City, UT, Intermountain Healthcare, Maternal Fetal Medicine, Salt Lake City, UT OBJECTIVE: 17-alpha-hydroxyprogesterone caproate (17P) reduces recurrent preterm birth (PTB) in some, but not all, women. We hypothesized that genetic polymorphisms affect variable response to 17P. STUDY DESIGN: Women with a history of 1 spontaneous singleton PTB 34 wks who received weekly 17P were recruited prospectively from a prematurity prevention clinic from 2008-2010. Women were classified as a 17P responder or non-responder based on the difference in delivery gestational age (GA) between their 17P treated and untreated pregnancy/pregnancies. Whole exome sequencing was performed using Illumina® HiSeq2000 next generation technology. Each individual was sequenced for 180,000 protein-coding exons. Genomes were compared between responders and non-responders using the Variant Annotation, Analysis & Search Tool (VAAST), a probabilistic search tool for identifying disease causing variants in personal genome sequences. Genome-wide significance was set at p 2.4x10. RESULTS: 24 women (19 responders, 5 non-responders), all Caucasian, were included. Responder and non-responder groups did not differ with regards to median number of pregnancies (3 vs. 4, p 0.67), history of cervical insufficiency (26% vs. 20%, p 0.77), or history of PPROM (32% vs. 40%, p 0.72). The GA of each woman’s earliest PTB also did not differ (27.9 vs. 29.7 wks, p 0.35), but responders achieved 9.1 wks longer with 17P, vs. 1.5 wks for nonresponders (p 0.001). All samples met genotype quality filters. The average genome-wide coverage depth was 47.3 (range 20.1-64.6). We assumed recessive inheritance and locus heterogeneity. VAAST identified IL12RB1 (Interleukin-12 receptor beta) as associated with nonresponse to 17P (p 3.03 10 ). CONCLUSION: Response to 17P for the prevention of recurrent PTB may be genetically mediated. These results should be confirmed in a larger cohort and may lead to the development of a ‘17P response panel.’

Cerclage for the prevention of preterm birth in high risk women receiving intramuscular 17-α-hydroxyprogesterone caproate

Objective: To assess cerclage benefit in women with short cervix also receiving 17-α-hydroxyprogesterone caproate (17P) to prevent recurrent preterm birth (PTB). Methods: Secondary analysis of a multicenter trial of ultrasound-indicated cerclage for shortened cervical length (CL). Women with prior spontaneous PTB at 16–33 6/7 weeks, singleton gestation and CL < 25 mm between 16 and 22 6/7 weeks were counseled on use of 17P and randomized to cerclage or no cerclage. Outcomes of women who received 17P were analyzed by randomization group. Primary outcome was PTB < 35 weeks. Results: 99 women received 17P: 47 cerclage; 52 no cerclage. Rates of PTB < 35 weeks were similar, 30% for cerclage and 38% for no cerclage (aOR 0.64 (0.27–1.52)). In women with CL < 15 mm, PTB < 35 weeks was reduced for the cerclage group (17% vs. 75%, p = 0.02). However, this difference was nullified after controlling for total progesterone doses received (p = 0.40). Conclusions: Cerclage was shown not to offer additional benefit for the prevention of recurrent PTB in women with short CL < 25 mm receiving 17P, but the sample size is insufficient for a definite conclusion given the 36% nonsignificant decrease in the odds of PTB < 35 weeks. Cerclage may further offer substantial benefit to women with very short CL < 15 mm and further study is needed.

Preconceptional laparoscopic abdominal cerclage: a multicenter cohort study

The purpose of this study was to evaluate the effectiveness of laparoscopic abdominal cerclage placement in the prevention of recurrent preterm birth. We conducted a multicenter cohort study with retrospective Dutch (32 patients) and Boston (34 patients) cohorts who had undergone preconceptional laparoscopic abdominal cerclage placement. Eligible patients had at least 1 second/third trimester fetal loss or delivered at <34 weeks of gestation because of cervical insufficiency and/or a short or absent cervix. Primary outcome was delivery of an infant at ≥ 34 weeks of gestation with neonatal survival. Secondary outcome measures included surgical and pregnancy outcomes and patients' satisfaction (Dutch cohort). Surgical outcomes of 66 patients were excellent, with 3 minor complications. After preconceptional laparoscopic abdominal cerclage, 35 pregnancies were evaluated. Twenty-five patients (71.4%) delivered at ≥ 34 weeks of gestation; 3 patients (8.6%) experienced a second-trimester fetal loss. The total fetal survival rate was 90.0%. Preconceptional laparoscopic abdominal cerclage shows encouraging and favorable perinatal outcomes in patients with a poor obstetric history.