Abstract
OBJECTIVE:
Evaluate if odds of survival without major morbidity are higher among extremely low gestation neonates (ELGANs) born to mothers with chronic hypertension (cHTN) or hypertensive disorders of pregnancy (HDP) compared to ELGANs born to mothers without hypertension (HTN).
STUDY DESIGN:
Retrospective study of prospectively collected data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Included children had a birthweight of 401–1000 g and/or gestational age of 220/7 to 286/7 wks. The primary outcome was survival to discharge without major morbidity. Multivariable regression models were used to compare outcomes among ELGANs born to women with cHTN, HDP, and no HTN.
RESULTS:
Survival without morbidities for newborns of mothers with no HTN, cHTN and HDP (29.1%, 32.9%, 37.0% respectively) did not differ after adjustment.
CONCLUSION:
After adjusting for contributing variables maternal HTN is not associated with improved survival free of morbidity among ELGANs.
Trials Registration:
clinicaltrials.gov Identifier: NCT00063063 (generic database)
INTRODUCTION
Chronic hypertension (cHTN) that predates pregnancy and hypertensive disorders of pregnancy (HDP, gestational hypertension and preeclampsia) are associated with important maternal, fetal, and neonatal morbidity and mortality. Due to steadily increasing maternal age and maternal body mass index (BMI), the incidence of both cHTN and HDP are increasing in the United States. Currently, it is thought that approximately 1.5% of pregnant women have cHTN and an additional 6–17% develops hypertensive disorders of pregnancy [1–3].
Well known fetal and neonatal complications associated with cHTN and HDP include fetal growth restriction, low birth weight, preterm delivery, oligohydramnios, placental abruption, stillbirth, and perinatal mortality [1, 2, 4, 5]. Preterm delivery associated with cHTN and HDP is most often iatrogenic, with delivery being prompted for the well-being of the mother and fetus. In a prospective cohort study of 109,000 pregnancies, cHTN commonly led to fetal growth restriction, preeclampsia and stillbirth, and was therefore associated with an increased risk of iatrogenic preterm birth <34 weeks (OR, 4.30 CI 3.23–5.72) [4].
In light of the increasing incidence of cHTN and HDP, more newborns are born after exposure to maternal hypertensive disease and associated utero-placental insufficiency. There are limited and contradictory results on survival with and without major morbidities among extremely low gestational age newborns (ELGANs) born to mothers with cHTN or HDP compared to mothers with no HTN [6–9]. Even with contradictory results in previous studies, there is biologic plausibility to explain improved survival in preterm newborns born to women with hypertensive disorders including; (1) uteroplacental insufficiency caused by hypertension may encourage fetal maturation, and, (2) other causes of preterm birth may be more detrimental than hypertension [7, 10]. The objective of this study was to investigate if preterm newborns born to mothers with hypertensive disorders have increased odds of survival to hospital discharge without major morbidity, compared to newborns born preterm to mothers without hypertensive disorders. We hypothesized that among ELGANs, pregnancies complicated by maternal cHTN or HDP would be associated with increased odds of neonatal survival without major morbidity compared to pregnancies in which the mother had no HTN.
MATERIALS/SUBJECTS AND METHODS
This study is a retrospective cohort study of prospectively collected data from the Generic Database Registry (GDB) among the participating centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN). Infants were included if they were born at NICHD NRN centers between January 2016 and December 2018, weighed between 401–1000 grams at birth and/or were 220/7 to 286/7 weeks gestational age at delivery. Infants were excluded if they had major congenital anomalies, died in the first 12 h after birth there was no documentation of maternal hypertensive status. Three cohorts of mothers and their preterm infants were compared; mothers with cHTN (HTN prior to the pregnancy), HDP (newly diagnosed anytime during the pregnancy), or the absence of HTN. Individuals were identified as having hypertension if it was specifically recorded in the mother’s chart. The definition used for hypertension was a maternal blood pressure above 140 systolic or 90 diastolic recorded in the medical record prior to or during the present pregnancy on at least two occasions. Individuals with cHTN who later developed preeclampsia were classified in the cHTN group as subsequent maternal outcome data was not collected in this cohort. Determination of these designations was based on documentation in the medical record and not on verification of pre-specified blood pressure measurements or laboratory assessments.
Data were collected for maternal characteristics including age, race, pre-pregnancy body mass index (BMI), marital status, maternal health insurance, education level, diabetes prior to pregnancy, gestational diabetes, acute histological chorioamnionitis, clinical chorioamnionitis, prolonged rupture of membranes (>18 h), mode of delivery, multiple births, antenatal steroid administration (none, any, completed course), and delivery center. Baseline neonatal characteristics collected included birth weight, length, head circumference, gestational age, sex, Apgar scores, delivery room interventions (positive pressure ventilation, continuous positive airway pressure [CPAP], endotracheal intubation, chest compressions, and epinephrine), and length of hospital stay among survivors. Neonatal data were collected until death, discharge or 120 days of age, whichever occurred first.
The primary outcome was survival to hospital discharge without major morbidity, defined as the absence of all of the following: grade III or IV intracranial hemorrhage (ICH), cystic periventricular leukomalacia (cPVL), late-onset (>day 3 of age) culture positive sepsis (LOS), necrotizing enterocolitis (NEC, Bell’s stage ≥2) [11], bronchopulmonary dysplasia (BPD, supplemental oxygen use at 36 weeks corrected age), or treated retinopathy of prematurity (ROP, received surgery/Bevacixumab or other anti-VEGF medication). Secondary outcomes included: (1) survival to hospital discharge without major morbidity, excluding the most common morbidity, BPD, (2) all cause in-hospital mortality in the first 120 days, (3) survival to hospital discharge without an individual major morbidity including major neurologic morbidity (grade III or IV ICH, cPVL), BPD, treated ROP, NEC, and, LOS, and (4) length of hospital stay among survivors. For infants who remained in the hospital for greater than 120 days neonatal data was collected at day of life 120 however the length of stay was not truncated at 120 days and included all days in the hospital.
Maternal and infant characteristics of each group (no HTN, cHTN, and HDP) were compared using independent t tests and Mann–Whitney U-test for continuous variables and Fisher’s exact test or chi-square tests for categorical variables. All comparisons were two-sided. Primary and secondary outcomes were evaluated using Generalized Linear Mixed models with adjustment for variables that differed between groups before or at birth including center, which was treated as a random effect. Results were expressed as an odds ratio and 95% confidence interval. For a number of secondary outcomes, covariate adjustment changed the direction of the odds for survival without individual morbidities. Thus, a sensitivity analysis was conducted examining a series of models with and without selected covariates, in addition to examining interactions. Covariates were introduced one by one into generalized linear mixed models and the unadjusted and adjusted odds ratios were compared to find which covariate accounted for the change in direction of the odds ratio.
RESULTS
There were 5994 newborns born at NRN centers between January 2016 and December 2018 and of these 913 met exclusion criteria, leaving 5081 for inclusion in this study (Fig. 1). The cohort included 3460 (68%) newborns born to mothers with no HTN, 771 (15%) with cHTN, and 850 (17%) with HDP.
Fig. 1. Participant exclusion and inclusion.
Number of patients included for analysis and excluded including reasons for exclusion.
Maternal and infant characteristics differed based on maternal HTN status (Table 1). Differences were also present between groups for intra-partum variables of histologic chorioamnionitis, singleton pregnancy, mode of delivery, and antenatal steroids. Similarly, multiple differences were present among infants in the three maternal groups (Table 2). Differences were present for infant characteristics (gestational age, sex, birth weight and other growth parameters), interventions used at birth for stabilization (use of CPAP, intubation and chest compressions in the delivery room) and Apgar scores at 5 min. Differences were present in major morbidities among the 3 groups including severe ICH, cPVL, BPD, LOS, and treated ROP.
Table 1.
Maternal characteristics categorized by hypertensive status.
| Characteristic n/N(%), or mean (SD) | No hypertension N = 3460 | Chronic hypertension N = 771 | Hypertensive disorders of pregnancy N = 850 | P value* |
|---|---|---|---|---|
| Maternal age (years) | 28.25 (6.0) | 31.43 (5.8) | 28.51 (6.3) | <0.0001 |
| Maternal race | 1189/3340 (35.6) | 398/755 (52.7) | 298/830 (35.9) | <0.0001 |
| Black | ||||
| White | 1907/3340 (57.1) | 315/755 (41.7) | 459/830 (55.3) | <0.0001 |
| Other | 244/3340 (7.3) | 42/755 (5.6) | 73/830 (8.8) | 0.0470 |
| Medicaid insurance | 2013/3457 (58.2) | 480/771 (62.3) | 432/850 (50.8) | <0.0001 |
| Diabetes | 90/3459 (2.6) | 120/771 (15.6) | 24/850 (2.8) | <0.0001 |
| Pre-existing | ||||
| Gestational | 139/3420 (4.1) | 60/764 (7.9) | 45/843 (5.3) | <0.0001 |
| Maternal BMI | 88/2304 (3.82) | 6/498 (1.20) | 17/566 (3.00) | 0.0113 |
| Underweight (BMI < 18.5) | ||||
| Obese (BMI ≥ 30) | 734/2304 (31.9) | 315/498 (63.3) | 228/566 (40.3) | <0.0001 |
| Histologic chorioamnionitis | 1888/3230 (58.5) | 199/728 (27.3) | 91/807 (11.3) | <0.0001 |
| Singleton | 2411/3460 (69.7) | 654/771 (84.8) | 704/850 (82.8) | <0.0001 |
| Cesarean delivery | 2112/3454 (61.1) | 650/771 (84.3) | 784/849 (92.3) | <0.0001 |
| Antenatal Steroids | 3197/3455 (92.5) | 718/768 (93.5) | 820/849 (96.6) | 0.0001 |
| Complete course of antenatal steroids | 2296/3187 (72.0) | 565/715 (79.0) | 661/819 (80.7) | <0.0001 |
P value refers to overall significance among the three groups without any adjustment for covariates.
Chi-square test was used for categorical data, and Nonparametric Wilcoxon test for continuous data.
Table 2.
Neonatal characteristics at birth and morbidities by maternal hypertension status.
| Characteristic N(%), or Mean (SD) | No hypertension N = 3460 | Chronic hypertension N = 771 | Hypertensive disorders of pregnancy N = 850 | P value* Unadjusted |
|---|---|---|---|---|
| Gestational age (weeks) | 25.91 (2.0) | 26.50 (1.9) | 27.16 (1.9) | <0.0001 |
| Sex, male | 1821/3460 (52.6) | 358/771 (46.4) | 368/850 (43.3) | <0.0001 |
| Apgar score 1 min, more than median of 4 | 1888/3460 (54.6) | 413/771 (53.6) | 492/850 (57.9) | 0.1531 |
| Apgar score 5 min, more than median of 7 | 2029/3460 (58.6) | 480/771 (62.3) | 573/850 (67.4) | <0.0001 |
| DR CPAP | 1869/3459 (54.0) | 484/771 (62.8) | 580/850 (68.2) | <0.0001 |
| DR endotracheal intubation | 2158/3459 (62.4) | 426/771 (55.3) | 391/850 (46.0) | <0.0001 |
| DR chest compression | 171/3460 (4.9) | 24/771 (3.1) | 15/850 (1.8) | <0.0001 |
| DR epinephrine | 61/3460 (1.8) | 11/771 (1.4) | 10/850 (1.2) | 0.4319 |
| Birth weight (grams) | 878.45 (242.9) | 820.86 (232.0) | 815.28 (216.5) | <0.0001 |
| Birth weight <10th percentile (SGA) | 273/3460 (7.9) | 188/771 (24.4) | 291/850 (34.2) | <0.0001 |
| Birth length (cm) |
N = 3353 33.70 (3.5) |
N = 757 33.08 (3.5) |
N = 829 33.31 (3.2) |
<0.0001 |
| Birth head circumference (cm) |
N = 3393 23.66 (2.4) |
N = 758 23.56 (2.4) |
N = 847 23.83 (2.1) |
0.0107 |
| Neonatal morbidities | ||||
| BPD | 1503/2982 (50.4) | 338/695 (48.6) | 345/770 (44.8) | 0.0206 |
| Severe ICH | 568/3377 (16.8) | 75/754 (10.0) | 61/830 (7.4) | <0.0001 |
| PVL | 157/3387 (4.6) | 25/754 (3.3) | 23/834 (2.8) | 0.0244 |
| Treated ROP | 358/2962 (12.1) | 74/693 (10.7) | 68/763 (8.9) | 0.0402 |
| NEC | 320/3456 (9.3) | 65/771 (8.4) | 72/849 (8.5) | 0.6478 |
| LOS | 650/3341 (19.5) | 117/747 (15.7) | 109/834 (13.1) | <0.0001 |
DR delivery room, CPAP continuous positive airway pressure, BPD bronchopulmonary dysplasia, ICH intracranial hemorrhage, PVL periventricular leukomalacia, ROP retinopathy of prematurity, NEC necrotizing enterocolitis, LOS late-onset sepsis
P value refers to overall significance among the three groups without any adjustment for covariates.
Chi-square test was used for categorical data, and Nonparametric Wilcoxon test for continuous data.
In unadjusted analysis, survival without severe neonatal morbidities was lowest for infants of mothers with no HTN and highest for infants of mothers with HDP (29.1% vs. 37%, p < 0.0001) (Table 3). After adjusting for differences between groups prior to or at birth (maternal race, Medicaid insurance, maternal BMI as fixed effects, chronic maternal diabetes, antenatal steroids, singleton pregnancy, mode of delivery, histologic chorioamnionitis, gestational age, infant sex, and center as a random effect) survival without severe morbidities did not differ (p = 0.1575) between groups. Removal of the most common morbidity of prematurity, BPD, did not change the result; adjusted survival to discharge without severe morbidities excluding BPD for infants of mothers with no HTN, cHTN and HDP was 43.4%, 46.9% and 54.1%, respectively, (p = 0.2382). Adjusted mortality for infants of mothers with no HTN, cHTN and HDP (14.3%, 10.2%, and 9.6% respectively) also did not differ (Table 3).
Table 3.
Infant morbidity and mortality by maternal hypertension status.
| Characteristic N(%), or mean (SD) | No hypertension N = 3460 | Chronic hypertension N = 771 | Hypertensive disorders of pregnancy N = 850 | P value unadjusted analysis* | P value adjusted analysis** |
|---|---|---|---|---|---|
| Survival without severe morbidities (including BPD) | 998 (29.1) | 251 (32.9) | 310 (37.0) | <0.0001 | 0.1575 |
| Secondary Outcomes | |||||
| Mortality | 492 (14.3) | 78 (10.2) | 81 (9.6) | <0.0001 | 0.5530 |
| Survival without severe morbidities, excluding BPD | 1491 (43.4) | 360 (46.9) | 455 (54.1) | <0.0001 | 0.2382 |
| Survival without major neurologic morbidity (ICH+ and PVL) | 1813 (52.6) | 427 (55.5) | 530 (62.6) | <0.0001 | 0.1397 |
| Survival without BPD | 1241 (36.1) | 309 (40.4) | 364 (43.2) | 0.0002 | 0.0235 |
| Survival without treated ROP | 1901 (55.2) | 447 (58.3) | 537 (63.6) | <0.0001 | 0.0098 |
| Survival without NEC | 1909 (55.2) | 438 (56.8) | 537 (63.2) | 0.0001 | 0.0349 |
| Survival without LOS | 1793 (51.8) | 420 (54.5) | 519 (61.1) | <0.0001 | 0.0171 |
| Length of hospital stay among survivors | 107.06 (52.0) | 108.87 (61.5) | 102.88 (59.5) | <0.0001 | 0.0334 |
ICH intracranial hemorrhage, PVL periventricular leukomalacia, BPD bronchopulmonary dysplasia, ROP retinopathy of prematurity, NEC necrotizing enterocolitis, LOS late-onset sepsis.
P value refers to overall significance among the three groups without any adjustment for covariates.
P value refers to overall significance among the three groups after adjustment for maternal race, socioeconomic status, chronic maternal diabetes, gestational age, sex, antenatal steroids, singleton, mode of delivery, histologic chorioamnionitis, and maternal BMI as fixed effects; adjusted for center as a random effect.
ICH III or IV.
In contrast, there were differences for the secondary outcomes of adjusted survival with the individual morbidities of BPD, NEC, ROP and LOS (Table 3). These findings prompted pairwise comparisons between groups to localize differences (Table 4). Unadjusted comparisons of outcomes among infants born to mothers with HDP versus infants born to mothers without HTN indicated significantly increased odds of survival without BPD, NEC, LOS, or ROP. However, after adjustment the odds of survival with each of the morbidities were significantly reduced. As part of a sensitivity analysis, removal of gestational age as a covariate for each analysis (survival free of BPD, NEC, LOS, and ROP) resulted in the absence of differences for infants exposed to maternal HDP compared to no HTN. No interactions were found between gestational age and each of the exposures using gestational age as either a continuous or categorical variable. Unadjusted comparisons of outcomes among infants born to mothers with cHTN versus no HTN were significant only for survival without BPD. This difference was not present after adjustment for covariates. Adjusted analyses indicated no differences for any outcome among infants born to mothers with HDP versus cHTN (data not shown).
Table 4.
Infant morbidities and mortality by maternal hypertension status.
| Outcome | cHTN vs. no HTN | HDP vs. no HTN |
|---|---|---|
| Survival without bronchopulmonary dysplasia | aOR, (95% CI) | aOR, (95% CI) |
| Unadjusted analysis | 1.20 (1.02,1.41) | 1.35 (1.16,1.57) |
| Adjusted analysisa | 0.81 (0.61,1.08) | 0.70 (0.53,0.91) |
| Adjusted analysis without GA | 0.97 (0.76,1.24) | 1.15 (0.91,1.44) |
| Survival without treated retinopathy of prematurity | ||
| Unadjusted analysis | 1.13 (0.97,1.33) | 1.42 (1.21,1.65) |
| Adjusted analysisa | 0.79 (0.60,1.05) | 0.67 (0.51,0.87) |
| Adjusted analysis without GA | 0.98 (0.77,1.24) | 1.13 (0.90,1.42) |
| Survival without necrotizing enterocolitis | ||
| Unadjusted analysis | 1.07 (0.91,1.25) | 1.39 (1.19,1.63) |
| Adjusted analysisa | 0.78 (0.59,1.02) | 0.74 (0.57,0.95) |
| Adjusted analysis without GA | 0.95 (0.75,1.20) | 1.17 (0.94,1.47) |
| Survival without late-onset sepsis | ||
| Unadjusted analysis | 1.11 (0.95,1.30) | 1.46 (1.25, 1.70) |
| Adjusted analysisa | 0.79 (0.60,1.04) | 0.70 (0.54,0.91) |
| Adjusted analysis without GA | 0.96 (0.76,1.21) | 1.14 (0.92,1.42) |
| Length of hospital stay among survivors | Estimate, (95% CI) | Estimate, (95% CI) |
| Unadjusted analysis | 1.81 (−2.89,6.51) | −4.19 (−8.71,0.34) |
| Adjusted analysisa | 9.51 (3.29,15.73) | 10.36 (4.53,16.20) |
| Adjusted analysis without GA | 7.08 (−0.15,14.31) | 0.46 (−6.28,7.20) |
GA Gestational Age.
aOR adjusted odds ratio, CI confidence interval, cHTN chronic hypertension, HTN hypertension, HDP hypertensive disorders of pregnancy.
Adjusted for center, maternal race, socioeconomic status (maternal Medicaid insurance), chronic maternal diabetes, sex, antenatal steroids, singleton, mode of delivery, histologic chorioamnionitis, maternal BMI, and gestational age at delivery.
Odds ratios and 95% confidence intervals were calculated for categorical outcomes using Generalized Linear Mixed models and for continuous outcomes, adjusted estimates were obtained using Generalized Linear models.
The length of hospital stay (107 ± 52, 109 ± 62 and 103 ± 60 days for infants of mothers without HTN, cHTN and HDP, respectively) differed after covariate adjustment. Compared to infants born to mothers without HTN, both groups of infants born to mothers with HTN (cHTN and HDP) had a longer hospital stay.
DISCUSSION
Our study demonstrates that after adjusting for maternal variables and infant gestational age and sex, there was no difference in survival without severe morbidities among ELGANs whose mothers had no HTN, cHTN or HDP. Furthermore, recognizing that BPD is the most common morbidity among extremely preterm infants, removal of BPD did not change the primary outcome. To our knowledge, previous literature has not explored the relationship between maternal HTN and ELGANs survival without severe morbidities. Our data also demonstrates, after adjusting for contributing variables, no difference in mortality between groups, no difference in survival without major neurological morbidity, and a decreased odds of survival without four major morbidities individually (BPD, ROP, NEC, LOS) among ELGANs whose mothers had HDP compared to no HTN. A similar difference among infants whose mothers had cHTN compared to no HTN was not found. The sensitivity analysis supported the importance of gestational age in understanding associations with survival free of specific morbidities.
A systematic review and meta-analysis by Razak et al reported that pregnancy induced hypertension (PIH) was associated with lower mortality in preterm infants born less than 37 week gestation [6]. Similarly, McBride et al used 88,275 births between 2008–2011 in the Vermont Oxford Network and reported that preterm infants (220/7–296/7 wks) born to hypertensive mothers had significantly lower mortality compared to preterm infants born to mothers without HTN [7]. A cohort from the International Network for Evaluating Outcomes of Neonates (iNeo) database from 2007–2010 reported that HDP was associated with lower odds of infant mortality (aOR 0.77; 95%,CI 0.67–0.88) [12]. Chen et al. also reported lower mortality in infants born at lower gestational ages to mothers with HTN but higher mortality in term infants born to mothers with HTN [8]. In contrast, data from the Neonatal Research Network of Japan reported higher mortality among nearly 19,000 very low birthweight infants associated with maternal pre-eclampsia but the results were not adjusted for covariates [13]. Gagliardi, et al used a different comparison group and reported that infants born less than 28 weeks to mothers with HTN had an increased mortality compared to mothers with chorioamnionitis. It was postulated that uteroplacental insufficiency may cause more fetal compromise than acute inflammation [9]. Overall, these findings differ from our report of no difference in mortality and may reflect multiple considerations. First, the cohort reported in the current study is more contemporary and there may be differences in obstetric and neonatal care (e.g., thresholds for interventions) compared to cohorts from more than a decade ago. Second, mortality among ELGANs is heavily influenced by gestational age at birth [14] and each study differed in the gestational age distribution among studied population. Third, the NRN is not population-based but a consortium of large academic regional centers in the United States. As such, lower risk infants born to mothers with HTN may be cared for in hospitals outside of an NRN center but within the region served by the NRN center. Finally, many of these studies have either excluded patients with cHTN or grouped cHTN and HDP together as one variable. These differences may account for differences in the association between maternal HTN and mortality between our current data and other published reports.
Among specific neonatal morbidities, there are multiple reports to support an association between maternal HTN and higher rates of BPD among preterm infants. Data from three neonatal networks, Canadian (<29wks), Portuguese (240–300wks), and Italian (230–300wks), all report increased BPD among infants born to mothers with HTN [9, 15, 16]. These data lend support to the role that HTN may play in the developing lung. Animal data have identified that HTN can impair alveolarization in the developing lung and inhibit vascular growth, contributing to abnormal lung structure in BPD [17, 18]. The pathogenesis may even extend to the placenta since chorionic plate vascularization may also play a role in the development of BPD in extremely premature neonates [19] with some data reporting that vascular placental pathology amplifies the risk of BPD in neonates exposed to maternal HTN [20]. These publications are consistent with the findings of the current report of reduced odds of survival without BPD when infants born to HDP were compared to those born in the absence of maternal HTN. An association between cHTN and more BPD was not present in the current report and could reflect differences in antecedent events in the fetus and newborn involving maternal HDP compared to cHTN. Alternatively, the results in the current report may be limited by sample size since the odds ratio for survival without BPD when chronic hypertension was compared to no hypertension is in the same direction as for comparison of HDP and no hypertension. However, not all observations were consistent with an increase in BPD among mothers with HTN. O’Shea et al reported the absence of a change in risk of BPD in an Australian cohort of extremely premature or extremely low birthweight infants (<28weeks or <1000grams) in the presence of preeclampsia [21]. A retrospective study based on the Korean Neonatal Network reported that the odds of BPD associated with pregnancy induced HTN were not increased for gestations <27 weeks but were increased for gestational ages of 27–29 weeks [22]. These latter two cohorts represent infants born from 5–20 years prior to the infants in the current study and differences in categorization of maternal HTN (cHTN, gestational hypertension, preeclampsia and superimposed preeclampsia) can make it difficult to directly compare prior reports. Furthermore, as the definition of BPD is evolving [23] using more contemporary definitions may lead to different conclusion.
Similar to BPD, survival free of other major morbidities (NEC, ROP, LOS) was reduced among infants born to mothers with HDP compared to mothers without cHTN. The odds ratio for survival with each individual morbidity shifted from increased to reduced in adjusted regressions. A sensitivity analysis supported the conclusion that gestational age was responsible for the change in odds ratio and highlights the importance of gestational age in understanding associations of neonatal morbidities with maternal HTN. Relative to the associations between maternal HTN and BPD in published reports, there is more heterogeneity of associations between maternal HTN and the outcomes of NEC, ROP, and LOS [6, 15, 16, 24]. These morbidities may be affected by local practice, such as the impact of breast milk on NEC [25], or supplemental oxygen on ROP [26]. Since these morbidities are lower in frequency relative to BPD, local practice may make it more difficult to determine consistent associations with maternal HTN.
This study has several strengths. First, the data were prospectively collected using pre-defined variables allowing for consistency between data collected from different healthcare systems. Second the data were derived from contemporary cohort (2016–2018) at large academic centers in the United States making the data more generalizable to today’s neonatal resuscitation and treatment practices. And thirdly, the size of this sample allowed adjustment of multiple confounders for neonatal outcomes. Despite these strengths there are several limitations to acknowledge. First, the diagnosis of HTN was based on documentation by the care team in the maternal medical records and was not confirmed with specific criteria, such as laboratory values or primary data collection of blood pressure from the maternal health record. Those patients who had hypertension prior to pregnancy were classified as having cHTN and those who developed hypertension during pregnancy were classified as having HDP. These definitions differ from those of ACOG which define cHTN as hypertension that develops prior to 20 weeks gestation. Additionally, it was not possible with the available data to identify women with chronic HTN who develop superimposed preeclampsia, the cHTN group includes both women with cHTN with and without superimposed preeclampsia. Similarly, there was no way to distinguish preeclampsia from gestational hypertension and superimposed preeclampsia. These limitations in classification of hypertension could lead to misclassification bias and change the nature of our results. Although we recognize that our classification is different than ACOG we believe this is unlikely to change our results since comparisons between each hypertensive group (hypertension developing before pregnancy or during pregnancy) is with the no hypertension group. Our initial hypothesis was based on prior proposed biological plausibility that uteroplacental insufficiency promotes fetal maturation and we would expect those with the longest exposure to HTN (those diagnosed prior to conception) to have potential survival benefit compared to those with HTN diagnosed during pregnancy. Our data demonstrated that those with cHTN (which in our cohort included those diagnosed prior to pregnancy) did not have a survival benefit. Second, the available data did not allow an assessment of the severity of maternal HTN. Third, the database provides infant morbidities only during hospitalization and only up to 120 days of life even if hospitalization continued after that time point. Although neonatal morbidities are not a clear predictor of long-term outcome, previous studies have demonstrated lower rates of poor long-term neurodevelopmental outcome among preterm infants who survive to 36 weeks postmenstrual age free of BPD, brain injury, LOS and severe ROP [27, 28]. Fourth, approximately 0.9%of neonates in the original cohort were excluded due to missing data on maternal HTN, which may lead to selection bias, although this is a very small number. Additionally, it is important to note that although some differences in maternal characteristics, such as maternal age, are statistically significant, they likely do not represent an important biologic effect. Finally, this study is observational and causal inferences cannot be drawn.
Biologic plausibility has been proposed for putative improved survival in preterm neonates born to women with hypertensive disorders based on (1) uteroplacental insufficiency promoting fetal maturation via acceleration of endogenous corticosteroid secretions [8, 29], and (2) other causes of preterm birth, often associated with a pro-inflammatory environment, which maybe more deleterious than HTN [7, 8, 24]. If these hypotheses were correct, we would anticipate a graded effect in which cHTN with its long exposure would be the most protective, while HDP would result in some neonatal benefit, but likely less than cHTN. Results of this study do not support such a hypothesis.
With increasing rates of cHTN and HDP, information regarding outcomes of ELGANs following these pregnancies is needed to inform providers who are responsible for balancing maternal risk with expectant management and neonatal risk with preterm delivery. Data from this study support the absence of an association between maternal HTN and survival without severe morbidity for ELGANs. However, HDP was associated with lower odds of survival without individual major morbidities and longer hospital stays.
Supplementary Material
ACKNOWLEDGEMENTS
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Center for Advancing Translational Sciences (NCATS) provided grant support for the Neonatal Research Network’s Generic Database Study through cooperative agreements. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government. Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, RTI International had full access to all of the data in the study, and with the NRN Center Principal Investigators, takes responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.
FUNDING
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Footnotes
COMPETING INTERESTS
The authors declare no competing interests.
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41372-023-01631-6.
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DATA AVAILABILITY
Data from this active and ongoing registry study can be requested at: https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data from this active and ongoing registry study can be requested at: https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.