Feature
Saturday, February 4th, 2012

Volume 54
February 2009
Number 2
Preterm Birth Prevention by 17 Alpha-Hydroxyprogesterone Caproate vs. Daily Nursing Surveillance
     
Charles Rittenberg, M.D., Roger B. Newman, M.D., Niki B. Istwan, R.N.,  Debbie J. Rhea, M.P.H., and Gary J. Stanziano, M.D.

 

OBJECTIVE: To compare the incidence of spontaneous recurrent preterm delivery (SPTD) between women receiving 17 alpha-hydroxyprogesterone caproate (17P) and women receiving daily perinatal nursing surveillance (dPNS) with home uterine activity monitoring.
STUDY DESIGN: Women enrolled for dPNS or weekly nursing visits with 17P injection were eligible. Included were singletons with previous SPTD, without pre­term labor (PTL), cerclage or vaginal bleeding and <27 weeks at enrollment. 17P and dPNS patients were matched 1:1 by race, marital status, tobacco use and number of SPTDs. Primary study outcome was incidence of spontaneous PTD.
RESULTS: Data from 342 matched pairs were compared. Diagnosis of PTL (39.2% vs. 60.8%) and tocolytic use (12.9% vs. 49.7%) was decreased with 17P vs. dPNS (p<0.001). The incidences of spontaneous PTD at <32, 35 and 37 weeks were similar between the groups.
CONCLUSION: There was no difference in recurrent SPTD between women treated with 17P and those receiving dPNS. (J Reprod Med 2009;54:47–52)

Keywords: home uterine activity monitoring, perinatal nursing surveillance, preterm birth prevention, 17 alpha-hydroxyprogesterone.
     
 Combining 17P with a program for
early detection and treatment of
preterm labor may further enhance
preterm birth prevention efforts for
some patients.


As investigators struggle to understand the complexity of the phenomena behind spontaneous preterm labor and delivery, the rate of preterm birth in the United States continues to rise. Women identifiable as being at high risk are the first challenge in any preventive effort. Women who have already experienced spontaneous preterm delivery are recognized as being at risk for recurrent preterm labor and delivery in subsequent pregnancies.
    Intensive outpatient surveillance of women at risk for preterm delivery with daily perinatal nursing surveillance (dPNS) inclusive of home uterine activity monitoring (HUAM) has been available commercially since the 1980s. A review of the available prospective randomized trials suggests that dPNS can reduce the risk of recurrent preterm birth and improve perinatal outcomes.1 The goal of dPNS is to detect excessive preterm uterine activity, aiding in the early recognition of preterm labor prior to advanced cervical dilatation, when tocolytics can be more effective in prolonging gestation.1,2
    Another promising clinical intervention is 17 alpha-hydroxyprogesterone caproate (17P). Recently, a large, prospective, randomized clinical trial comparing weekly intramuscular injections of 17P to placebo in women with a prior spontaneous preterm birth demonstrated a 33% reduction in the preterm delivery rate.3 The goal of 17P is to prevent preterm labor from occurring, through a mechanism of action that is not yet completely understood. It is not thought that 17P exhibits a direct uterus-relaxant effect,4,5 yet it appears that progestational agents including 17P increase the tocolytic effect of endogenous substances through both genomic and nongenomic mechanisms6 and may attenuate processes related to progressive cervical shortening.7-9
    The purpose of this study was to compare the incidence of recurrent spontaneous preterm delivery between women receiving weekly 17P for preterm birth prevention vs. those receiving dPNS to facilitate the earlier diagnosis and treatment of preterm labor should it occur.
   
Materials and Methods
We performed a retrospective, matched cohort analysis of prospectively collected clinical information on women enrolled in outpatient perinatal management and surveillance programs provided by Matria Healthcare (now Alere). Data maintained in the relational database are collected from patients and their health care providers during the course of care and includes medical and pregnancy history, current pregnancy risk factors and diagnoses, biometric clinical data relative to services provided, and maternal and neonatal outcome data. All information is collected using standard operating procedures, forms and computer systems. All outpatient services are prescribed by the patients’ obstetric providers. Women must have a suitable home environment and consent to participate in outpatient services. Written authorization is received from patients at enrollment allowing the use of their deidentified data for research and reporting purposes.
    The study groups were identified from data collected between 1995 and 2005. Patients eligible for study inclusion were singleton pregnancies having a history of prior spontaneous preterm delivery, referred for weekly 17P administration services or dPNS, and enrolled at less than 27 weeks of gestation. Women enrolled simultaneously for 17P and dPNS services or having a diagnosis of preterm labor, cerclage or vaginal bleeding at enrollment were excluded.
    For those patients prescribed 17P, intramuscular injections of 250 mg were administered every 7–10 days in the patient’s home by a perinatal nurse until the patient reached 36 weeks’ gestation. During this weekly visit, patients were questioned regarding signs and symptoms of preterm labor, and a nursing assessment was performed. Nurses and pharmacists were available to the patient by telephone at any time for questions or concerns regarding her treatment. Reports regarding patient compliance with treatment and a summary of nursing assessments were provided to the patient’s obstetric provider on a weekly and as-needed basis. Unit dose preservative-free vials of 17P were delivered to the patient’s home for nurse administration. The pharmacy compounding the 17P utilized an International Organization for Standardization (ISO) class 5 clean room and matched the exact specifications and formulation of the 17P used in the Meis/National Institutes of Health trial,3 including the vehicle (castor oil).
    Patients enrolled for dPNS received education regarding signs and symptoms of preterm labor from a qualified perinatal nurse. Nursing assessment of patient-reported signs and symptoms of preterm labor was performed daily, and ongoing patient education occurred on a scheduled and as-needed basis. HUAM was performed twice daily and as needed if symptoms of preterm labor occurred. Uterine data were transmitted daily and as needed via the telephone line to a call center, where nurses reviewed the tracings and discussed the results with the patient. Nursing and physician intervention occurred as necessary based on collected data. Assessment and management of tocolytic medications were performed as prescribed by the patient’s physician.
    Data were stratified into 2 groups: women receiving weekly 17P (n=385) and women receiving dPNS without 17P (n=546). To control for maternal factors known to influence preterm delivery, patients receiving 17P were matched 1:1 to patients receiving dPNS prior to analysis of pregnancy outcome. Matching was performed on 4 characteristics: maternal race (African American or other), marital status (married, yes or no), tobacco use (during pregnancy, yes or no) and number of preterm deliveries. Gestational age of the prior preterm delivery was not available for comparison. A match-merge process was used to combine the data for the two cohorts. Both data sets were sorted and matched on the 4 variables listed above. Whenever a woman from the 17P group was matched with >1 woman from the dPNS group, we randomly selected 1 case using a random number table from the multiple matches to create the comparison group. This procedure generated a data set with 342 women in each cohort.
    Pregnancy outcomes for patients receiving weekly 17P were compared with those receiving dPNS using McNemar’s 2 and Wilcoxon Signed Rank test statistics, with significant results defined as those with 2-sided values of p<0.05. The primary study outcome examined was the incidence of spontaneous preterm delivery. Secondary study outcomes included the incidence of hospitalization for suspected preterm labor (>24 hour length of stay), the diagnosis of preterm labor (hospitalization with uterine contractions and cervical change resulting in either preterm delivery or acute tocolysis) and the use of tocolysis for preterm labor.
    
Results
Maternal characteristics of the study groups are presented in Table I. As expected, women receiving weekly 17P initiated treatment at an earlier gestational age than those enrolled for dPNS. The majority of 17P patients (80.4%) began receiving 17P injections at <21 weeks’ gestation. Overall in the matched study design, 74.3% were married, 10.8% were smokers, 22.8% were African American, and 34.8% had had >1 prior preterm delivery (65.2% had had 1 prior preterm delivery, 27.8% had had 2 prior preterm deliveries, 6.4% had had 3, and 0.6% had had 4). Women in the 17P group received a mean of 15.5 injections of 250 mg of 17P at a mean interval of 7.1 days between injections. Compliance with treatment was similar between the groups, with 32 (9.4%) of women receiving 17P and 25 (7.3%) of women receiving dPNS discontinuing treatment at <34 weeks for reasons other than delivery (p=0.333).
   

   

    Women receiving 17P had lower rates of hospitalization for suspected preterm labor (with >24 hours, length of hospital stay), diagnosis of preterm labor and tocolytic use compared to those women receiving dPNS (Table II). However, despite these differences, the lengths of gestation and rates of recurrent preterm delivery were similar for patients receiving weekly 17P and patients receiving dPNS (Table III). These similarities in the rates of recurrent preterm delivery remained true whether overall rates were considered or rates specifically associated with spontaneous preterm labor. Rates of medically indicated preterm delivery were also similar between the groups. Forty women in the 17P group (11.7%) and 44 women in the dPNS group (12.9%) experienced medically indicated preterm delivery. The incidences of preterm premature rupture of membranes were similar in the 2 groups.
   
     

   
Discussion
Among women with a history of prior spontaneous preterm birth there was no difference in the rate of recurrent preterm delivery between those receiving 17P and those receiving dPNS. The incidences of spontaneous preterm delivery were almost identical at <37, <35 and <32 weeks’ gestation for these well-matched cohorts of women treated with 17P and dPNS. Given the 15.7% magnitude of difference in rates of spontaneous recurrent preterm delivery in the National Institute of Child Health and Development–Maternal-Fetal Medicine Units (NICHD-MFMU) study,3 the authors believed that at least a 10% magnitude difference in the rate of spontaneous preterm delivery in the observed population would be clinically relevant. The present study had 76% power to detect such a difference; 33 additional matched pairs would have yielded the conventional 80% power. While the gestational age at the prior preterm delivery is an important missing element, an effort was made to carefully match 17P and dPNS patients on other clinical factors known to influence recurrent preterm delivery. Without a standard care control group, it is impossible to prove whether both interventions were effective or both interventions were ineffective, which is obviously a major limitation of this investigation. That acknowledged, the currently available literature supports the effectiveness of both of these interventions for the indication of previous spontaneous preterm delivery.
    Two recent prospective, randomized, controlled trials3,7 evaluated the use of progesterone supplementation as a preventive therapy for women with singleton pregnancies with a prior preterm birth. Both studies found that supplemental progesterone reduced the rate of recurrent preterm delivery. In the study conducted by the NICHD-MFMU network, 17P was administered via weekly intramuscular injection. 17P was shown to reduce the incidence of recurrent preterm birth by 33% as compared to placebo.3 Meta-analysis including both older and current studies has provided further support for the use of 17P for preterm birth prevention,10 although the mechanism of action by which 17P prevents preterm birth remains poorly understood. The American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice, in a committee opinion, recommends that progesterone supplementation be considered only for women with a history of a prior spontaneous preterm delivery at <37 weeks’ gestation.11 A recent survey examining the attitudes of board-certified maternal-fetal medicine specialists regarding the use of progesterone for preterm birth prevention noted that 67% of responders used progesterone therapy; nonuse of 17P was due to physician concern regarding efficacy, safety, long-term neonatal effects and need for more data.12 In the present study, rates of recurrent spontaneous preterm birth at <37, <35 and <32 weeks for both patients receiving 17P and those receiving dPNS were almost exactly the same as those observed in the progesterone treatment group in the NIH-MFMU trial.
    A potential limitation of the study is that the inclusion criteria allowed initiation of the 17P to occur later than in the Meis trial. Recent publications have suggested that later initiation of 17P (up to 27 weeks) may still impart benefit for women with prior preterm delivery and a current singleton gestation.13,14 In addition, the mean gestational age at initiation of 17P in the current cohort was 19.3 ± 2.9 weeks’, with a median of 18.7 weeks’ gestation, and 80.4% of women initiated 17P treatment at <21 weeks’ gestation.
    With dPNS, patients are assessed via telephone by skilled perinatal nurses on a daily and as-needed basis regarding the signs and symptoms of preterm labor. The biometric data obtained by HUAM are collected at least twice daily, trended over time and placed into context by the perinatal nurse performing subjective patient assessment. In addition to providing social support and positive reinforcement, patient-centered support provided by the perinatal nurse may help the patient learn to distinguish uterine contractions from fetal movement.15 When subtle changes in the patient’s condition are recognized, there is the opportunity for additional assessment and possible intervention. The consistent benefit of dPNS in reducing the risk of preterm birth and adverse neonatal outcomes has been lost in the controversy regarding HUAM and the difficulty in differentiating the benefits of uterine contraction monitoring from that of daily perinatal nursing contact.16,17 When compared to standard care-control groups, dPNS with or without HUAM has consistently proven effective in making an earlier diagnosis of preterm labor and reducing the incidence of preterm birth.18,19 Based on these studies, both the American College of Obstetricians and Gynecologists in 1992 and the U.S Preventive Services Task Force in 1993 endorsed daily provider-initiated contact as an effective intervention to reduce the risk of preterm birth.20,21
    Beyond the benefit of daily provider-initiated contact, HUAM alone has proven capable of identifying the crescendo of subclinical uterine activity that precedes the clinical diagnosis of preterm labor by 24–48 hours.22,23 In a prospective, randomized, blinded, multicenter study, Mou et al24 evaluated the effect of HUAM alone (without nursing contact) on the diagnosis of preterm labor. Detection of preterm labor before 2-cm cervical dilatation was accomplished in 73.1% of monitored subjects vs. only 27.8% of unmonitored subjects (p<0.001). In that trial, the earlier diagnosis of preterm labor allowed more-effective tocolysis, resulting in a significantly greater prolongation of pregnancy, greater gestational age at delivery and birth weight, and significantly fewer low-birth-weight deliveries, very-low-birth-weight deliveries and neonatal intensive care unit (NICU) admissions.24,25 Using a similar prospective, randomized design, Wapner et al26 found that cervical dilatation was significantly less at diagnosis of preterm labor in women using HUAM alone as compared to those not monitored (1.7 vs. 2.8 cm, respectively). Again, the earlier diagnosis of preterm labor was associated with a significantly longer prolongation of pregnancy (21 vs. 3 days), a greater gestational age at delivery, heavier birth weights, fewer NICU admissions and fewer NICU days.26 While the effectiveness of tocolytic agents is somewhat controversial, it is thought that with earlier diagnosis and treatment, significant prolongations of gestation can be achieved in many cases. In a meta-analysis of the literature on tocolytic treatment, researchers from the University of North Carolina, Duke University and the Research Triangle Institute supported by the Agency for Healthcare Quality in Research demonstrated that all tocolytics, except ethanol, were effective in extending births to term as compared with placebo/no tocolytic treatment, with odds ratios ranging from 1.62 to 2.48.27
    In the present study, while ultimate pregnancy outcomes were similar, women treated with 17P had a lower incidence of hospitalization for preterm labor, a reduced incidence of preterm labor diagnosis and less-frequent tocolytic treatment compared to women observed with dPNS. This underscores the presumptive role of 17P as preventive therapy. In addition to the reduction in preterm birth, the parallel reduction in hospitalization and tocolytic use is an important secondary benefit of 17P use. This difference is unlikely to be due to chance as the 2 risk groups were carefully matched. It is also unlikely to be due to overdiagnosis of preterm labor in the dPNS group as this has never been reported in any prospective, randomized trial of this intervention.1 As hospitalization was defined as an inpatient length of stay of at least 24 hours, observation visits of <24 hours did not affect the rate of hospital admission in either group. Although 17P appears to reduce the overall incidence of preterm labor, almost 45% of the women receiving 17P were still diagnosed with preterm labor, and one third delivered prematurely as a result. The lower incidence of hospitalization for PTL and less frequent tocolytic use in the 17P group suggest that these 2 interventions (17P and dPNS) work through different, possibly complementary, mechanisms. Combining 17P with a program for early detection and treatment of preterm labor may further enhance preterm birth prevention efforts for some patients. Further investigations of 17P used in combination with dPNS, as well as comparison to patients receiving neither 17P nor dPNS, are required.
    
References
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From the Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, and Department of Clinical Research, Matria Healthcare (now Alere, Women's and Children's Health), Marietta, Georgia.

Presented at the American College of Obstetrics and Gynecology 54th Annual Clinical Meeting, Washington, D.C., May 6–10, 2006.

Address correspondence to: Roger B. Newman, M.D., Department of Obstetrics and Gynecology, Medical University of South Carolina, 96 Jonathan Lucas Street, Room 634, Charleston, SC 29425 (newmanr@musc.edu).

Financial Disclosure: The Department of Obstetrics and Gynecology, Medical University of South Carolina, received a 2-year grant from the South Carolina Department of Health and Human Services. Matria Healthcare (Marietta, Georgia) was the vendor for many of the services provided in this grant. The data base used in this study is that of Matria Healthcare.  Dr. Newman was previously on a Speaker's Bureau list for Matria Healthcare. The grant was completed in December 2007, and there is currently no relationship ongoing between the investigators, the department and Matria Healthcare. Mses. Istwan and Rhea and Dr. Stanziano are employees of Matria Healthcare (now Alere, Women's and Children's Health).



  
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