Preterm birth before 37 weeks of gestation is the leading cause of neonatal death and long-term neurologic disabilities in children1,2 and creates a huge burden for families, society, and the health care system. The annual cost of caring for the more than 500,000 neonates born prematurely in the United States each year exceeds $26 billion.1,2
Approximately 75% of all preterm births are categorized as spontaneous, occurring after preterm labor or preterm ruptured membranes.1,2 Major research efforts have been devoted to prevention of preterm birth. In a randomized placebo-controlled trial, prophylactic 17α-hydroxyprogesterone caproate given weekly reduced the risk of recurrent preterm birth before 37 weeks of gestation in women with one or more previous spontaneous preterm births (relative risk 0.66, 95% confidence interval [CI] 0.54–0.81).3 Progesterone administered vaginally has been shown to reduce spontaneous preterm birth in women with a short cervix.4−8 It has been estimated that nearly 10,000 spontaneous preterm births before 37 weeks of gestation could be prevented annually if all pregnant women with a prior preterm birth were treated with prophylactic progestins.9 This estimate does not include the potential decrease in neonatal morbidity and mortality that might accrue for neonates born preterm but at a later gestational age than might have occurred without progestin therapy. However, there are few studies of the effect of progestin prophylaxis in clinical practice.10,11 We sought to identify a treatment effect of prophylactic progestins for women with a prior preterm birth who were cared for in a prematurity clinic between 1998 and 2012.
MATERIALS AND METHODS
We performed a retrospective cohort study of women cared for in the Prematurity Clinic at The Ohio State University Wexner Medical Center, a large urban academic medical center, between January 1, 1998, and June 30, 2012. Data collected during the course of clinical care in the prematurity clinic have been abstracted and entered into an electronic database by a single prematurity nurse in an institutional review board-approved deidentified database since 1998. Demographic data, health and reproductive histories, care plans, and pregnancy outcomes are documented in this database.
The Prematurity Clinic provides comprehensive prenatal care for women with a history of preterm birth. Treatment protocols are revised periodically to reflect published literature.12 Eligible women meet with specialty-trained registered nurses, nutritionists, social workers, smoking cessation counselors, residents, fellows, and faculty physicians. Visit intervals are scheduled every 2 weeks with more frequent visits as needed and an “open door” policy for unscheduled visits. Women are counseled about signs and symptoms of preterm parturition and are encouraged to contact prematurity nurses with symptoms or questions between visits. At each visit, symptoms including pelvic pressure, cramps, contractions, back pain, change in vaginal discharge, leaking of fluid, vaginal bleeding, or “feeling like it did last time” are recorded. Digital cervical examinations, transvaginal ultrasonography, or both cervical examinations and ultrasonography for cervical length measurements are performed at each visit with recommendations for cerclage placement, antenatal corticosteroid administration, physical activity, admission to the hospital, or a combination of these based on these objective findings.
Progestin prophylaxis for women with a history of spontaneous preterm birth was adopted by our clinic in 2004. Weekly injections of 250 mg 17α-hydroxyprogesterone caproate3 were prescribed almost exclusively until 2011, when women who declined injections were offered daily 200-mg vaginal suppositories.4 Both medications were supplied by a local compounding pharmacy.
In 2008, community health leaders asked the clinic to expand access to progestin prophylaxis for women with a prior preterm birth. A review of potential barriers identified multiple obstacles to timely initiation of 17α-hydroxyprogesterone caproate, including late entry to prenatal care, delayed recognition of women eligible for progestins, slow registration and approval processes for private and public insurance, and delays related to the preparation, delivery, and safe administration of prescribed injections.
Each obstacle was addressed. Women requesting a new prenatal appointment were screened for a history of birth between 16 and 36 weeks of gestation. Women who answered affirmatively were given an accelerated first appointment in the prematurity clinic rather than the previous practice of scheduling all new prenatal visits in a low-risk clinic with subsequent referral to specialty clinics. Attempts to “select out” women who were unlikely to be eligible for progestin prophylaxis (ie, those with a prior indicated preterm birth) were abandoned such that all women with a prior preterm delivery, regardless of the etiology, were seen in our clinic in a timely fashion for an in-depth review of their history. Initial prematurity clinic appointments were scheduled at 10–14 weeks of gestation instead of 14–16 weeks of gestation to accelerate the process of obtaining insurance coverage and approval for progestin therapy. This was a major obstacle because Ohio does not yet have presumptive eligibility for Medicaid coverage of prenatal care. Prematurity clinic staff worked with the medical and women's health directors of managed care and fee-for-service Medicaid services to accelerate approvals and initiation of progestin prophylaxis. A standard protocol for preparation of compounded 17α-hydroxyprogesterone caproate, developed in concert with a local compounding pharmacy, was promoted widely and integrated with public and private managed care providers so that delays related to drug preparation were reduced for all patients. These changes were intended to allow progestin prophylaxis to begin before 17 0/7 weeks of gestation.
Most women choose the intramuscular 17α-hydroxyprogesterone caproate given by home health care nurses who are specifically trained to identify signs and symptoms of preterm parturition and the side effects of progestins. Others receive injections at community clinics or at their prematurity clinic visits. Because the injections were given either in a clinic environment or by home health nursing services, compliance with therapy was determined easily with this preparation. In the 42 women who chose vaginal suppositories, though, compliance was documented based only on patient report. Women are encouraged to speak frequently by telephone to the prematurity nurses who emphasize the importance of reporting signs of parturition and medication side effects and who monitor compliance with therapy. The ultimate goal is to streamline the process to make progestin prophylaxis as easy and as cost-effective as possible for patients, caregivers, pharmacies, and payers.
For the purpose of this study, we reviewed rates of recurrent spontaneous preterm birth in women with one or more prior early delivery between 1998 and 2012 comparing preterm delivery rates before routine progestin prophylaxis (January 1, 1998, to December 31, 2003) with progestin prophylaxis only (January 1, 2004, to December 31, 2007) and after adoption of a program to promote prompt access to care and initiation of progestin treatment (January 1, 2008, to June 30, 2012). The rates of spontaneous preterm birth before 37, 35, and 32 weeks of gestation over time were selected a priori as the primary outcomes of interest. We limited our analysis to women with a history of at least one prior preterm birth who were seen in the clinic and delivered between January 1, 1998, and June 30, 2012. To avoid concerns regarding the correlated nature of pregnancy outcomes, we also limited the analysis to the first pregnancy of a given woman who was seen during this time. Furthermore, we excluded patients with multiple gestations, known uterine anomalies, and late prenatal care. Data were examined for missing and outlying values.
Statistically, we first examined the characteristics of participants by preterm birth at less than 37 weeks of gestation. χ2 tests were used for categorical variables, whereas Kruskal-Wallis tests were used for continuous variables. We then looked at the crude (unadjusted) trends in preterm delivery rates at less than 37, less than 35, and less than 32 weeks of gestation by progestin prophylaxis status. Statistical significance of trends was assessed using a nonparametric test for trend. To examine cohort effects on rates of preterm birth after adjustment for relevant covariates, we used unconditional logistic regression with an indicator for time (1998–2007 compared with 1998–2012) forced into the model. All analyses were conducted using Stata 11.0.
Among the 1,414 women seen in the clinic from January 1, 1998, to June 30, 2012, 1,066 (75.4%) met the inclusion criteria for analysis with each observation representing a single pregnancy to a unique woman. The 24.6% of patients excluded from analysis were those with multiple gestations, known uterine anomalies, late prenatal care, and prior indicated preterm births. Of the included patients, the majority received 17α-hydroxyprogesterone caproate prophylaxis with only 42 patients (3%) opting for vaginal suppositories during this time period. The demographic characteristics of the study population are shown in Table 1.
Rates of birth before 37, 35, and 32 weeks of gestation declined after 2008 in comparison to 2007 and earlier (Fig. 1). Before 2004, preterm births were as follows: 144 (42.6%) less than 37 weeks, 85 (25.2%) less than 35 weeks, and 33 (9.8%) less than 32 weeks of gestation. From 2004 to 2007, preterm deliveries were as follows: 156 (49.8%) less than 37 weeks, 97 (31%), less than 35 weeks, and 48 (15.3%) less than 32 weeks of gestation. Finally, between 2008 and mid-2012, preterm births were as follows: 159 (39.6%) less than 37 weeks, 87 (21.6%) less than 35 weeks, and 58 (14.4%) less than 32 weeks of gestation. In comparing the odds of preterm birth before and after 2008, we observed significant reductions in odds of birth before 37 (adjusted odds ratio [OR] 0.75, 95% CI 0.58–0.97) and 35 weeks (adjusted OR 0.70, 95% CI 0.52–0.94) of gestation after 2008 (Table 2). We did not see an association with birth at less than 32 weeks of gestation. However, our statistical power to detect a difference in the occurrence of this outcome was low. To identify reasons for the decline in preterm birth rates after 2008, we first looked at the demography and risk profile of women seen in the clinic. In general, as depicted in Table 1, there were significant differences in several demographic categories including race and body mass index, but the trend was toward a higher risk population in later years, including a higher percentage of black patients, who are known to be at an increased risk for spontaneous preterm birth compared with white women. There was also a significant change in the mean gestational age at the first visit to the clinic over time, from 19.6 weeks of gestation in 1998–2003 to 17.4 weeks in 2004–2008 to 15.5 weeks of gestation after 2008 (P<.01). Furthermore, prophylactic progestin use increased from 0.6% in 1998–2003 to 50.8% in 2004–2007 to 80.3% after 2008 (P<.05).
We observed a cohort effect after 2008 in decreasing rates of spontaneous preterm birth before 37, 35, and 32 weeks of gestation in women who received prenatal care in our Prematurity Clinic. The decline was significant for births before 37 and 35 weeks of gestation, but not for births before 32 weeks of gestation. The cause of the decrease is uncertain, but the decline in preterm birth rates occurred concurrently with adoption of a program that facilitated earlier initiation of progestin prophylaxis, whereas the population enrolled did not change.
Preterm birth rates reported from clinical trials of prematurity prevention clinics have been mixed but are mostly disappointing.13−16 The March of Dimes Prematurity Project, a multicenter randomized trial that compared intensive patient education and frequent visits to routine care in more than 3,000 high-risk women, reported no significant differences in rates of preterm birth.13 In contrast, the West Los Angeles Preterm Birth Prevention Project showed a 19% reduction in preterm birth rates in high-risk patients exposed to increased education and more frequent obstetric visits.16 This project enrolled women with variable criteria for preterm birth risk and did not limit the outcome to spontaneous early delivery.
Results from studies evaluating the effect of progestin prophylaxis in clinical practice have also been inconsistent. Manuck et al10 reported a recurrent spontaneous preterm birth rate of 48.6% before 37 weeks of gestation in 70 women seen in a preterm birth prevention program compared with 63.4% in 153 women who received routine prenatal care. Progestin prophylaxis was initiated in 68.6% of women in the prematurity program compared with 39.1% in the routine clinic.10 The mean gestational age at birth (36.1 week compared with 34.9 weeks) and the rate of composite neonatal morbidity were significantly better in women cared for in the prematurity program.11 In a study similar to ours that compared spontaneous preterm birth rates before and after progestin prophylaxis was offered to eligible patients, Bastek et al11 found no difference in the rates of delivery before 37 weeks of gestation (16.7% compared with 16.9%). However, women who received progestin prophylaxis were delivered at a mean gestational age of 33.1 weeks of gestation compared with 31.6 weeks of gestation in those cared for before progestin use.11 Rates of progestin use were not reported in this study.11
The strengths of our study include a large number of women who were cared for at a single institution over 15 years using protocols designed and supervised by one attending physician and implemented by two prematurity clinic nurses. Compliance with receipt of progestin prophylaxis was high because 17α-hydroxyprogesterone caproate was prescribed and monitored for the large majority of women. The study is limited by its observational design. One or more unmeasured confounders might have contributed to the decline in prematurity rates after 2008; however, we were able to control for key measured confounders using logistic regression. The demographic characteristics our clinic population and the acuity of their obstetric histories did not change between 1998 and 2012. Rates of preterm birth in our region (specifically in Franklin County where Columbus, Ohio, is located) did not improve between 1998 and 2008 or between 2008 and 2012. Furthermore, there were no significant additional changes in obstetric care during the time period that would be expected to confound these results. It should be noted that our institution implemented an initiative to prevent nonmedically indicated scheduled births before 39 weeks of gestation in late 2008, but this mainly influences delivery rates at 37–38 weeks of gestation, not those before 37 weeks of gestation. Finally, the clinic structure did not significantly change during the time period either. An additional nurse and extra support staff (dieticians and social workers) were added, a factor that allowed us to increase the volume of patients seen but did not alter the care that individual patients received. Thus, we are left with the introduction of a more aggressive appointment process that facilitated elimination of barriers to early initiation of progestin as the likely explanation for our findings.
Timely initiation of progestin prophylaxis for women with a prior spontaneous preterm birth or short cervix is uniquely affected by administrative barriers. Our report suggests that progestin prophylaxis can reduce the rate of recurrent spontaneous preterm birth when barriers to care and treatment are aggressively removed and that the gestational age at initiation may affect the success of progestin prophylaxis. It should be noted, however, that our clinic is unique in that it is managed by maternal-fetal medicine specialists and focuses solely on women who are at the highest risk for preterm birth, factors that may limit the generalizability of our findings. Our results, however, suggest that such a specialized approach may be indicated in these women. Regardless, dissemination of this approach to a larger population is necessary to demonstrate external validity of our findings.
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© 2014 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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