Objective
To test whether 17 alpha-hydroxyprogesterone caproate (17P) will reduce neonatal morbidity by increasing gestational age at delivery in triplet pregnancies.
Study Design
Double-blind, randomized clinical trial. Mothers carrying trichorionic-triamniotic triplets were randomly assigned (in a 2:1 ratio) to weekly injections of 250 mg of 17P or placebo, starting at 16-22 weeks and continued until 34 weeks. Primary outcome was composite neonatal morbidity.
Results
Fifty-six women were randomized to 17P and 25 to placebo. Composite neonatal morbidity occurred with similar frequency in the 17P and placebo groups (38% vs 41%, respectively; P = .71). Mean gestational age at delivery was not affected by 17P (31.9 vs 31.8 weeks; P = .36). There were 13 midtrimester fetal losses with 17P vs none with placebo ( P < .02).
Conclusion
In triplet pregnancy, prophylactic treatment with 17P did not reduce neonatal morbidity or prolong gestation but was associated with increased midtrimester fetal loss.
Triplet pregnancy carries a high risk of severe neonatal morbidity because of a high rate of very early preterm birth. In the United States, the rate of preterm birth (before 37 weeks of gestation) among triplets exceeds 92% and the rate of very preterm birth (before 32 weeks) exceeds 36%. Infant mortality among triplets approaches 60 per 1000 live births, nearly 10 times the rate of singletons, primarily because of complications of prematurity.
In 2003, 2 large clinical trials showed that prophylactic progestins can substantially reduce the risk of recurrent preterm birth when given to women with a singleton pregnancy and a history of prior preterm birth. Later that year, the American College of Obstetrics and Gynecology reviewed those trials and other literature and concluded that progesterone is beneficial for a “select group of very high-risk women,” presumably meaning those with a history of prior preterm birth, but that “further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestation….” A trial reported in 1980 had studied whether 17 alpha-hydroxyprogesterone caproate (17P) might reduce prematurity in twin pregnancy. That study found no benefit of 17P, but the drug was not started until a mean gestational age of 29 weeks. At the inception of the current study, there were no other reports on the use of progestins to prevent preterm birth in multiple gestations.
We hypothesized that 17P might reduce the rate of very preterm birth when given to women with triplet pregnancy and might thereby reduce the risk of neonatal mortality and serious morbidity. This current study was undertaken to test this hypothesis.
Materials and Methods
The study was performed by the Obstetrix Collaborative Research Network, a consortium of maternal-fetal medicine practices across the United States. The participating practices and personnel are listed in the Appendix . In most cases, subjects were enrolled and followed-up on an outpatient basis antenatally, with delivery and neonatal management at an appropriate hospital. The study was approved by the Institutional Review Board at each site. The trial was conducted under Investigational New Drug (IND) approval Number 69-536, assigned by the United States Food and Drug Administration (FDA). The trial was registered at www.clinicaltrials.gov , NCT00163020 . An independent Data and Safety Monitoring Board (DSMB) supervised the trial, reviewed adverse event reports, and conducted an interim analysis of efficacy.
Potential subjects were screened for eligibility at 15-23 weeks of gestation after a detailed second-trimester ultrasound examination had been performed showing trichorionic-triamniotic triplet pregnancy with normal amniotic fluid volume and no major fetal anomalies. Women were excluded if they had symptomatic uterine contractions, rupture of the fetal membranes, any contraindication to interventions intended to prolong the pregnancy (including amnionitis, preeclampsia, severe growth delay, or imminent fetal death), a preexisting medical condition that might be worsened by progesterone (including asthma requiring medications, impaired liver function, renal insufficiency, seizure disorder, ischemic heart disease, active cholecystitis, or history of breast cancer, thromboembolism, or depression requiring hospitalization), or a preexisting medical condition carrying a high risk of preterm delivery (including refractory hypertension, diabetes with retinopathy or nephropathy, active lupus). Women were also excluded if they were less than 18 years of age, had an allergy to 17P or the oil vehicle, had taken any progesterone-derivative medication after 15 weeks of gestation, or had undergone placement of cervical cerclage for treatment of cervical change in the current pregnancy. We did not exclude women with a history of prior preterm birth, women who had undergone multifetal pregnancy reduction in the current pregnancy, or those who had undergone prophylactic cerclage because of a history suggestive of cervical insufficiency.
Each eligible subject was offered preliminary enrollment. After informed consent was obtained, a trial injection of 1 mL of castor oil was given intramuscularly (IM) and the subject was asked to return for an enrollment-completion visit approximately 1 week later. Those who returned were randomly assigned to receive either 17P (250 mg in 1 mL castor oil) or identical-appearing placebo (1 mL castor oil) and were given the first dose of medication at that visit. Randomization was allowed at 16 weeks of gestation or later, but before 24 weeks.
Randomization was performed according to a computer-generated scheme kept at McGuff Pharmaceuticals (Santa Ana, CA), the central compounding pharmacy. The scheme called for 2 subjects to be assigned to 17P for every 1 subject assigned to placebo, stratified so that each study site would have a similar ratio. Progesterone or identical-appearing placebo was compounded by the pharmacy according to the IND specifications, shipped in advance to each study site in coded, prenumbered kits, and replenished as needed to keep a fresh supply at each site. To randomize a consenting, eligible subject, the research nurse contacted the central pharmacy by telephone or fax to obtain the code number for the kit assigned to that patient. Subjects, physicians, and study personnel remained blinded as to group assignment until after completion of the trial. The assigned medication was repeated weekly until 34.0 weeks of gestation or delivery, whichever occurred first.
Patients were given the option to return to the study site for weekly repeat injections or to have a partner give the injections at home. Those who chose home injections were asked to bring their partner for training regarding medication handling, injection technique, and biohazards disposal. An injection diary was used to record each dose given. Each subject answered a detailed side effects questionnaire for each injection. To assess compliance, we reviewed these diaries and also measured the unused medication returned by the patient at the conclusion of her dosing. Analysis was by the “intention-to-treat” principle. Accordingly, outcomes for each patient were tabulated according to the assigned group (17P vs placebo) regardless of her compliance.
At 24-26 weeks of gestation, a cervicovaginal swab was obtained for fetal fibronectin testing and a transvaginal ultrasound was performed for cervical length assessment. These procedures were not part of routine clinical care of triplets at most of the study sites and subjects at those sites were not charged for these assessments. Other than this visit, the subjects received standard clinical care for triplets. For guidance regarding standard care, the protocol outlined a synopsis of the relevant Educational Bulletin of the American College of Obstetrics and Gynecology.
After delivery, maternal and newborn data were abstracted from the medical records, recorded on standardized forms, and entered into a secure online database by study personnel who remained blinded to each subject’s group assignment. Neonatal data included follow-up until hospital discharge or 28 days of life, whichever occurred earlier.
The primary study outcome was composite neonatal morbidity, defined as 1 or more of: perinatal death (stillbirth, neonatal death, miscarriage), respiratory distress syndrome, use of oxygen therapy at 28 days of life, neonatal sepsis proven by blood culture, pneumonia, intraventricular hemorrhage (grade 3 or 4), periventricular leukomalacia, necrotizing enterocolitis requiring surgery, retinopathy of prematurity, or newborn asphyxia (ischemic injury of vital organ with pH <7.0 from umbilical artery or newborn artery). Secondary outcomes included the individual neonatal morbidities listed before, gestational age at delivery, birthweight, and maternal side effects.
Statistical analysis of the primary outcome (composite neonatal morbidity) and secondary neonatal outcomes used a repeated measures approach (generalized estimating equations for dichotomous variables with an exchangeable correlation structure and a mixed linear model for continuous variables using a compound symmetry correlation structure) where each infant was considered the repeated measure. Odds ratios (ORs), 95% confidence intervals (CIs), and P values were determined from the repeated measures models. Differences between treatment groups in baseline maternal characteristics and maternal delivery characteristics and complications were determined using a χ 2 test or Fisher’s exact test for dichotomous variables and a Wilcoxon-rank sum test for continuous or ordinal variables. ORs and 95% CI (using either the normal approximation or an exact method) were provided for maternal complications. Pregnancy prolongation (time from randomization to delivery) was analyzed using a staggered entry Kaplan-Meier analysis (adjusting for gestational age at randomization) and differences between the treatment groups was determined using the log-rank test. All analyses were performed using SAS 9.2 (SAS Institute Inc, Cary, NC). All statistical tests appear as 2-sided P values.
We estimated that the primary outcome rate would be 60% for the placebo group based on estimates from the Pediatrix Medical Group neonatal database of 2155 triplet newborns from 124 centers nationwide. We calculated that a sample of 243 newborns (162 in the 17P group and 81 placebo) would yield a power of 80% to detect a reduction of neonatal morbidity to 40% in the 17P group using an alpha level of .05. To obtain this number of newborns, we planned to enroll 81 mothers (roughly 54 in the 17P group and 27 placebo).
A planned interim analysis of the primary outcome was conducted on completion of 50% of the case reports. A second interim analysis was planned at 75% completion, but at that time the trial had already enrolled all but 2 of the total number of subjects. Accordingly, the Data Safety and Monitoring Board concluded that an interim analysis would be moot and recommended that it not be performed. To correct for the planned interim analysis, the alpha level for the primary outcome was adjusted to .0488 based on the O’Brien-Fleming spending function. For all other analyses, no adjustments were made and an alpha level of .05 is used.
Results
Recruitment occurred at 18 sites from November 2004 through June 2008. We identified 248 women with triplets, of whom 147 were eligible for trial inclusion ( Figure 1 ). Of these, 89 (61%) gave consent and were given the trial injection. Of these, 81 (91%) returned for random treatment allocation, 56 of whom were assigned to 17P and 25 to placebo. Outcome data were available for all 81 mothers and 243 offspring.
Baseline characteristics of the subjects in the 2 treatment groups were similar ( Table 1 ). At the 24-26 week visit, sonographic cervical length evaluation was performed in 86% of subjects (70/81) and fetal fibronectin screening in 84% (68/81). There was no significant difference between the groups in the percentage with cervix length less than 2.5 cm (8/47 [17%] in the 17P group vs 8/23 [35%] in the placebo group, P = .13) or with positive fibronectin (5/46 [11%] vs 2/22 [9%], respectively, P > .99).
| Characteristic | 17-hydroxyprogesterone (n = 56) | Placebo (n = 25) |
|---|---|---|
| Maternal age, y | 33.4 ± 5.0 | 33.6 ± 5.4 |
| Gestational age at randomization, wk | 19.3 ± 2.3 | 20.0 ± 2.3 |
| Prepregnancy weight, lbs | 148 ± 31 | 158 ± 32 |
| Nulliparous, n (%) | 24 (43) | 13 (52) |
| Progestins used before 15 wk | 35 (63) | 14 (56) |
| Method of conception, n (%) | ||
| In vitro fertilization | 34 (61) | 12 (48) |
| Other assisted reproduction | 16 (29) | 9 (36) |
| Spontaneous | 5 (9) | 2 (8) |
| Unknown | 1 (2) | 2 (8) |
| Married, living with partner | 53 (95) | 25 (96) |
| Ethnicity, n (%) | ||
| White | 39 (70) | 17 (68) |
| Hispanic | 10 (18) | 7 (28) |
| Asian/Pacific Islander | 5 (9) | 0 |
| African American | 2 (4) | 1 (4) |
| Education, n (%) | ||
| College | 39 (70) | 17 (68) |
| High school or less | 12 (21) | 6 (24) |
| Unknown | 5 (9) | 2 (8) |
| Substance use during pregnancy | ||
| Alcohol, rare, n (%) | 17 (30) | 13 (52) |
| Alcohol, more than rare | 0 | 0 |
| Tobacco | 0 | 0 |
| Other | 1 (2) | 0 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
