Objective
This secondary analysis of a randomized placebo-controlled trial was to hypothesize on mechanisms for the improved neonatal outcomes with the use of nitroglycerin (GTN) for preterm labor.
Study Design
Women in the original trial who delivered at term were excluded. A composite of severe neonatal outcomes, gestational age at delivery, and corticosteroid use in addition to Kaplan-Meier survival analysis to assess time from randomization to delivery were examined.
Results
A decrease in composite neonatal outcome (relative risk, 0.21; 95% confidence interval, 0.05–0.81; P = .018) with GTN (n = 39) compared with placebo (n = 38) was primarily due to a 23 day prolongation of pregnancy ( P = .019) and a trend ( P = .04) toward completing a course of corticosteroids in the subgroup randomized prior to 28 weeks’ gestation.
Conclusion
We hypothesize that GTN has a gestational age–dependent reduction in neonatal outcomes as a result of pregnancy prolongation and corticosteroid administration.
Preterm birth and its sequelae are a major global health problem. Despite advances in our understanding of the physiology of labor and perinatal medicine in general, the incidence of preterm birth continues to rise. The primary goal of tocolytic therapy is to reduce neonatal morbidity and mortality by delaying birth, allowing for corticosteroid administration and maternal transfer to a tertiary care center.
Tocolytics in general have poor efficacy, have not been shown to increase antenatal corticosteroid administration, may cause significant maternal/fetal adverse events, and have not improved neonatal outcomes. However, the Canadian Preterm Labor Nitroglycerin Trial demonstrated that transdermal nitroglycerin (GTN), compared with placebo patches, significantly decreased the risk of severe neonatal morbidity and mortality. This was despite no difference in overall gestational age at delivery or corticosteroid use between the groups. Given what we know about the etiology of preterm labor and the potential duration for any effect, women who deliver at term (>37 weeks’ gestation) likely represent subjects who were not in true preterm labor. Therefore, exclusion of these subjects for secondary analysis may help with hypothesis generation and power calculation for future studies.
The objective of this secondary analysis of the data was to determine the possible mechanism(s) by which the use of transdermal nitroglycerin for preterm labor improves neonatal outcome by examining only the women in the trial who delivered preterm.
Materials and Methods
Characteristics of the trial have previously been described at length. In brief, based on clinical determinants of preterm labor (clinical diagnosis of at least 4 painful uterine contractions per 20 minutes and evidence of cervical change [change in Bishop score or Bishop score >6]), women between 24 and 32 weeks and zero days’ gestation were randomized to receive either transdermal nitroglycerin or an identical appearing placebo patch. Subjects were stratified by center and gestational age (GA; 24 0 to 28 0 , 28 1 to 32 0 ).
For this secondary analysis, women were excluded if they delivered at term (>37 weeks and zero days GA). As previously described and defined, the primary outcome measure was a composite of significant neonatal morbidity (the occurrence of ≥1 of chronic lung disease, necrotizing enterocolitis [NEC], significant (grade 3 or 4) intra-ventricular hemorrhage [IVH], peri-ventricular leukomalacia [PVL]), and perinatal mortality. Secondary outcomes included overall GA at delivery and prolongation of pregnancy, GA at delivery and prolongation of pregnancy, and corticosteroid use by GA stratification at randomization.
The analysis was based on intention to treat. The primary and secondary outcomes were compared between the 2 groups. The χ 2 test was used to compare dichotomous variables with Fisher’s exact where appropriate and the Student t test to compare continuous variables. Because this is a secondary analysis and randomization may not hold true, multiple logistic regression analysis was also carried out to assess neonatal outcomes.
Kaplan-Meier survival analysis was used to assess whether the time from randomization to delivery differed in premature babies by GA stratification between the 2 arms. Statistical significance was defined as P < .05. Results are presented as relative risk, adjusted relative risk, and risk difference with 95% confidence intervals. A Cochrane-Armitage test for trend was also carried out. SAS 9.1 (SAS Institute, Cary, NC) was used for data analyses.
Results
One hundred fifty-eight women were originally recruited (n = 77 GTN; placebo n = 81) and analyzed by intention to treat. Exclusion of women who delivered at term resulted in 39 women who received GTN and 38 who received placebo for subanalysis. There was no difference in baseline characteristics between treatment groups nor between those women excluded from subanalysis ( Table 1 ).
| Characteristic | GTN (n=39) | Placebo (n=38) |
|---|---|---|
| Mean age (SD) (y) | 29.5 (5.9) | 28.7 (5.2) |
| Race, % | ||
| Black | 10.3 | 2.6 |
| White | 84.6 | 89.5 |
| Asian | 0 | 5.3 |
| Continental European | 5.1 | 0 |
| Other | 0 | 2.6 |
| Educational level, % | ||
| Grade school | 5.1 | 7.9 |
| High school | 28.2 | 21.1 |
| Post-secondary | 66.7 | 71.1 |
| Marital status, % | ||
| Married/common-law | 76.9 | 84.2 |
| Single | 23.1 | 15.8 |
| Smoking history, % at randomization | ||
| Yes | 6 | 9 |
| No | 94 | 91 |
| Alcohol use, % | 12.8 | 7.9 |
| Street drug use, % | 5.1 | 5.3 |
| Social support, % | ||
| Other adult in the household | 86.8 | 89.9 |
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