Abstract
Objective:
To assess neonatal respiratory morbidity in pregnancies with and without gestational diabetes mellitus (GDM) at imminent risk of late preterm delivery in a modern U.S. cohort.
Methods:
Secondary analysis of a randomized placebo-controlled trial in which women with singleton pregnancies at high risk for delivery between 34 0/7 and 36 5/7 weeks of gestation were allocated to betamethasone or placebo. The primary outcome for the trial and this secondary analysis was a composite outcome of neonatal respiratory morbidity in the first 72 hours of life. Secondary outcomes included neonatal severe respiratory complications, neonatal intensive care unit (NICU) admission > 3 days, and hyperbilirubinemia. We examined associations between neonatal morbidities and GDM status after adjustment for baseline differences and study group allocation using modified Poisson regression. Models incorporating a product interaction term between GDM status and treatment arm (betamethasone or placebo) were also evaluated.
Results:
Of the 2831 women enrolled in the trial, 306 (10.8%) had GDM. Women with GDM were significantly older, more likely to be parous and to have hypertensive disorders of pregnancy than those without GDM, but were similar with regard to race, gestational age at randomization (35.6 weeks) and at delivery (36.1 weeks), and study group assignment. Neonates born to women with GDM were no more likely to meet the primary outcome than those without GDM even after adjusting for differences in age, parity, and hypertension disorders of pregnancy (12.1% v. 13.1%, adjusted RR 0.84; 95% CI 0.61–1.17) nor were they more likely to have severe respiratory complications or prolonged NICU admission.
Conclusion:
Maternal GDM is not associated with increased neonatal respiratory morbidity in this study population who were at high risk for late preterm birth.
Precis:
Among pregnancies at high risk for late preterm birth, maternal gestational diabetes mellitus is not associated with increased neonatal respiratory morbidity.
Introduction
In the 1970’s, studies suggested an association between maternal diabetes, including gestational diabetes mellitus (GDM), and neonatal respiratory distress syndrome (RDS). Robert et al reported that the risk of RDS in infants of diabetic mothers (cohort included women with both GDM and pre-existing diabetes) was 23.7 times greater than in infants born to non-diabetic mothers (P<0.0001)1. This increased risk was postulated to be the result of delayed fetal lung maturation. Women with GDM or class A diabetes, as well as class B and C diabetes achieved lecithin to sphingomyelin ratios >2.0 in their amniotic fluid, a marker of fetal lung maturation, 1–5 weeks later in gestation than their euglycemic counterparts2. Since those initial studies, some studies suggest GDM is associated with an increased risk of RDS while other studies have found no association with poor neonatal respiratory outcomes. In 1989, a prospective cohort study of 2,204 Californian women, 97 of whom had GDM, found no difference in the rates of RDS in neonates born to women with GDM compared with neonates born to women without GDM3. More recently, a prospective Israeli study demonstrated that among neonates born prematurely, there was no increased neonatal respiratory morbidity in the offspring of women whose pregnancies had been complicated by GDM4. These studies stand in contrast to two French retrospective data studies of hundreds of thousands of women suggesting that GDM is associated with an increased odds of RDS (OR 1.1; 95% confidence interval (CI) 1.0–1.3 and OR 1.2; 95% CI 1.1–1.3) 5,6.
Because the available data are inconsistent, we sought to evaluate neonatal respiratory morbidity in pregnancies with and without GDM in a contemporary cohort of US pregnancies in which the respiratory neonatal outcomes were collected prospectively. In particular we chose to focus on pregnancies at high risk for late preterm delivery because late preterm birth is associated with significantly more neonatal respiratory morbidity than term birth.
Methods
This is a secondary analysis of the Antenatal Late Preterm Delivery Steroids study (ALPS), a multi-centred randomized controlled trial that tested the effectiveness of betamethasone compared with placebo to reduce neonatal morbidity in women at high risk for late preterm delivery7. The study was performed in 17 centers across the US in which 2831 singleton pregnancies at high risk for delivery between 34 0/7 and 36 5/7 weeks of gestation were enrolled. The parent protocol was approved by the Institutional Review Board at all participating sites and written informed consent was obtained from all participants. Women were considered to have had GDM if they were given the diagnosis at any point during their pregnancy prior to delivery. Women with pre-existing diabetes mellitus were excluded from the parent trial. Information about GDM diagnostic criteria or treatment was not collected.
We compared pregnancy outcomes between those diagnosed with GDM (exposed pregnancies) and those without a GDM diagnosis (unexposed). The primary outcome was a composite of neonatal respiratory morbidity identical to that of the primary study. The composite included significant respiratory morbidity (continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation), stillbirth, or neonatal death within the first 72 hours of life. Secondary outcomes included severe neonatal respiratory complications, neonatal intensive care unit (NICU) admission lasting longer than 3 days, and neonatal hyperbilirubinemia. Severe neonatal respiratory complications was defined as any of the following: CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth or neonatal death within the first 72 hours of life. Hyperbilirubinemia was considered present if the peak total neonatal bilirubin was at least 15 mg% or if the neonate was treated with phototherapy.
Significant additional maternal and neonatal data were collected on each participant. These data were collected by local research staff members at each site but was reviewed centrally for consistency. Data were also available regarding study group assignment (betamethasone or placebo). All study staff was blinded to the original study intervention, betamethasone or placebo. Study staff, including the neonatal care team, were aware of a woman’s GDM status.
The relative risk of the primary outcome was assessed using modified Poisson regression 8. Relative risks were adjusted for covariates that differed significantly in univariable analysis (p<0.05) between pregnancies complicated by GDM and those that were not. Models incorporating a product interaction term between GDM status and treatment arm (betamethasone or placebo) were also evaluated. Analyses were conducted using the SAS System version 9.3 (SAS Institute, Cary NC).
A power calculation, after the primary study, but prior to performing this secondary analysis, was performed and revealed 80% power to detect a 38% difference between neonatal respiratory morbidity in pregnancies exposed to GDM and those unexposed. The ALPS trial had a cumulative respiratory morbidity incidence of 13% and so we assumed a baseline respiratory morbidity incidence of 13% in the majority of ALPS pregnancies that were not complicated by GDM and anticipated being able to detect a difference if the rate of respiratory morbidity in pregnancies complicated by GDM was 18% or greater.
Results
GDM data were collected on all 2831 participants in the parent trial who delivered between October 2010 and February 20157. In total, 306 of the 2831 (10.8%) pregnancies were complicated by GDM. Among pregnancies with GDM, an equal number of women were randomized to betamethasone and placebo. Compared with women whose pregnancies were not complicated by GDM, women with GDM were older, more likely to be parous, and more often developed hypertensive disorders of pregnancy (Table 1). At the time of study enrollment, women with GDM were less likely to have preterm labor or premature rupture of membranes compared with women without GDM. There was no difference between women with GDM and those without with regard to race, gestational age at randomization, or study group assignment. The mean gestational age at delivery was similar for women with and without GDM (36.1 weeks).
Table 1:
Characteristics
| Gestational Diabetes (GDM) n=306 | No GDM n=2,525 | P-valuea | |
|---|---|---|---|
| Maternal age (years) | 31±6 | 28±6 | <0.001 |
| Race or ethnic group | 0.27 | ||
| Black | 70 (23) | 687 (27) | |
| White | 186 (61) | 1442 (57) | |
| Other | 50 (16) | 396 (16) | |
| Nulliparous | 80 (26) | 825 (33) | 0.02 |
| Smoking | 31 (10) | 359 (14) | 0.05 |
| Hypertensive disorder | 142 (46) | 733 (29) | <0.001 |
| Gestational age at randomization (weeks) | 35.6±0.8 | 35.5±0.8 | 0.22 |
| Gestational age at delivery (weeks) | 36.1±1 | 36.1±1.1 | 0.36 |
| Indication for trial entry | <0.001 | ||
| Preterm labor | 53 (17) | 739 (29) | |
| Ruptured membranes | 59 (19) | 561 (22) | |
| Gestational hypertension or preeclampsia | 113 (37) | 614 (24) | |
| Fetal growth restriction | 3 (1) | 87 (4) | |
| Oligohydramnios | 9 (3) | 81 (3) | |
| Other | 69 (23) | 443 (18) | |
| Betamethasone received | 153 (50) | 1276 (51) | 0.90 |
Data are mean ± standard deviation or n (%) unless otherwise specified.
Based on t-test, Fisher exact or chi square test
Composite respiratory morbidities were not significantly different among neonates born to women with GDM compared to those born to women without GDM (12.1% v. 13.1%; adjusted RR 0.84, 95% CI 0.61–1.17) nor were severe respiratory complications or prolonged NICU admission (Table 2). Neonates born to women with GDM were more likely to have hyperbilirubinemia (15.0% compared to 10.3%, p=0.04). This association persisted after adjustment for age, parity, and hypertension disorders of pregnancy (relative risk 1.39 [95% CI 1.03–1.88]). The occurrence of cesarean delivery among women with GDM and those without was 37% v 31%, p=0.02. When we included mode of delivery in the model, GDM still was not associated with an increased risk of RDS (0.81; 95% CI 0.56–1.18). We also did not include indication for trial entry in the principle adjusted model because these diagnoses occurred temporally after the diagnosis of GDM and likely represent modifiers rather than confounders. However, as a precaution, we performed additional models in which they were included and no significant difference in results was found. Finally, there were no significant differences in the association between GDM and the composite and secondary outcomes by initial study intervention arm (betamethasone or placebo) (P> 0.05 for interaction for all comparisons).
Table 2:
Neonatal complications
| Gestational diabetes (GDM) n=306 | No GDM n=2,525 | Unadjusted P-value | Adjusted relative riska (95% CI) | |
|---|---|---|---|---|
| Respiratory support in first 72 hours | 37 (12.1) | 330 (13.1) | 0.70 | 0.84 (0.61–1.17) |
| Severe respiratory complications | 30 (9.8) | 253 (10.0) | 0.78 | 0.91 (0.63–1.31) |
| Neonatal intensive care unit admission of >3 days | 114 (37.3) | 874 (34.6) | 0.52 | 1.03 (0.88–1.21) |
| Hyperbilirubinemia (>15mg/dl) | 46 (15.0) | 261 (10.3) | 0.04 | 1.39 (1.03–1.88) |
Data are n (%) unless otherwise specified.
Adjusted for age, parity, and hypertension
Discussion
The original ALPS trial demonstrated that for pregnancies at high risk of late preterm delivery, antenatal steroids reduced neonatal respiratory complications. In this secondary analysis, we found that pregnancies complicated by GDM at high risk for late preterm delivery had similar neonatal respiratory outcomes as pregnancies without GDM. GDM was not associated with an increased risk of the composite neonatal respiratory morbidity, nor was it associated with prolonged NICU admission or severe neonatal respiratory complications. The equivalent neonatal respiratory morbidity frequencies suggest that women with GDM delivering in the late preterm interval should be managed under the same guidelines as those without GDM. The original ALPS study suggested that 25 women at risk for late preterm labor must be treated with antenatal steroids to prevent one case of neonatal respiratory morbidity. Our findings suggest that the number needed to treat in women with GDM is similar to that required in women without GDM.
The strengths of this study lie primarily with the large sample size as well as the detailed definition of the outcome data prior to initiation of the parent study. Trained research nurses collected the data, which was regularly and iteratively audited for completeness and accuracy. However, the parent study did not include women with preexisting diabetes, only those with GDM. Another limitation was the study designnot examining GDM as an independent variable, or collecting data about each participant’s glucose control, diabetes treatment, or timing of diagnosis. Therefore, we cannot perform any sub-analyses assessing GDM severity and risk of respiratory morbidities. It is quite possible that the degree of dysglycemia affects neonatal respiratory morbidity and this study was unable to detect those differences. Based on the data available, it is likely that the women in this study represent a typical cross section of women with GDM; many needed no medication to achieve euglycemia, some used insulin and some used oral hypoglycemic. Women with GDM in this study population had an increased frequency of common risk factors for GDM (age, parity, and hypertensive disorders) compared to the non-GDM group3,9. Neonates born to women with GDM in this cohort also had an increased risk of neonatal hyperbilirubinemia compared with neonates born to women without GDM, a well-established and consistent neonatal complication of maternal hyperglycemia10. This study was also limited by a pre-determined sample size as it was a secondary analysis and therefore we may not have been powered to detect differences in all confounders (e.g. racial/ethnic differences). The final limitation of this study is that neonatal care providers were not blinded to the women’s GDM status, which could result in bias, but would likely be in favor of interventions, such as supplemental O2, in the GDM-affected neonates.
Currently in the US, 7.6% of pregnancies are complicated by GDM11. As the burden of GDM grows, it is vital that clinical management be guided by high quality evidence in order to optimize maternal and neonatal outcomes. In this contemporary cohort, GDM was not associated with a clinically significant difference in neonatal respiratory outcomes. This suggests that evidence based interventions known to reduce morbidity (e.g induction at 37 weeks for preeclampsia without severe features and induction at 39 weeks for low risk women), should be considered in all women regardless of their GDM status.
Supplementary Material
Acknowledgments
FUNDING: Supported by grants (HL098554 and HL098354) from the NHLBI, by grants (HD21410, HD27915, HD27917, HD27869, HD34116, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD53097, HD53118, HD68268, HD68258, HD68282, and HD36801) from the NICHD, and by a grant (UL1 TR000040) from the National Center for Advancing Translational Sciences, National Institutes of Health. The comments and views expressed in this article are those of the authors and do not necessarily represent the views of the National Institutes of Health.
The authors thank Felecia Ortiz, RN, BSN and Sabine Bousleiman, RNC, MSN, MPH for protocol development and coordination between clinical research centers, Kathleen Jablonski, PhD for protocol and data management, and Ronald Wapner, MD, Elizabeth A. Thom, PhD, Carol Blaisdell, MD, and Catherine Spong, MD for protocol development and oversight.
Dr. Rouse, Associate Editor (Obstetrics) of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.
Footnotes
Financial Disclosure
The authors did not report any potential conflicts of interest.
Each author has confirmed compliance with the journal’s requirements for authorship.
See Appendix 1, available online at http://links.lww.com/xxx, for a list of other members of the NICHD MFMU Network
Contributor Information
Erika F. Werner, Brown University, Providence, RI.
Megan E. Romano, Dartmouth College, Lebanon, NH.
Dwight J. Rouse, Brown University, Providence, RI.
Grecio Sandoval, George Washington University Biostatistics Center, Washington, DC.
Cynthia Gyamfi-Bannerman, Columbia University, New York, NY.
Sean C. Blackwell, University of Texas Health Science Center at Children’s Memorial Hermann Hospital, Houston, TX.
Alan T.N. Tita, University of Alabama at Birmingham, Birmingham, AL.
Uma M. Reddy, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
Lucky Jain, Emory University, Atlanta, GA.
George R. Saade, University of Texas Medical Branch, Galveston, TX.
Jay D. Iams, Ohio State University, Columbus, OH.
Erin A.S. Clark, University of Utah Health Sciences Center, Salt Lake City, UT.
John M. Thorp, Jr., University of North Carolina at Chapel Hill, Chapel Hill, NC.
Edward K. Chien, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH.
Alan M. Peaceman, Northwestern University, Chicago, IL.
Geeta K. Swamy, Duke University, Durham, NC.
Mary E. Norton, Stanford University, Stanford, CA.
Brian M. Casey, University of Texas Southwestern Medical Center, Dallas, TX.
Steve N. Caritis, University of Pittsburgh, Pittsburgh, PA.
Jorge E. Tolosa, Oregon Health and Science University, Portland, OR.
Yoram Sorokin, Wayne State University, Detroit, MI.
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