Influence of antenatal corticosteroids and sex on the mortality and morbidity of extremely prematurely born infants

Abstract

Objective

To report the effect of antenatal corticosteroids (ANS) on mortality, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD) and the duration of ventilation according to sex in extremely preterm infants.

Methods

All extremely preterm infants admitted to any neonatal unit in England between 2014 and 2019.

Results

Eleven thousand seven hundred and fourteen infants (54% male) were included with a median (IQR) gestational age of 26 + 1 (24 + 6 − 27 + 1) weeks, birth weight of 809 (670 − 960) grams and birth weight z-score of −0.38 (-0.88 to 0.07). ANS were administered in 10,449 infants (89%); equally in males and females. Infants who received ANS compared to those who did not, had a lower mortality before discharge (18.7 versus 32.3%, p < .001), a lower incidence of IVH grade III–IV (14.5 versus 25.5%, p < .001) and a shorter median (IQR) duration of mechanical ventilation [10 (3–27) versus 13 (5–31) days, p < .001]. Female compared to male infants had a lower mortality (18.7 versus 21.7%, p < .001), a lower incidence of IVH grade III–IV (10.9 versus 13.9%, p < .001), a lower incidence of bronchopulmonary dysplasia (61.6 versus 68.2%, p= <.001) and a shorter median (IQR) duration of mechanical ventilation days [9 (3–26) versus 13 (4–29) days, p= <.001]. In females, the risk of dying before discharge from hospital was greater in those who did not receive ANS (odds ratio (OR) 1.81, 95% CI 1.35–2.44) than in those who did (OR 0.55, 95% CI 0.41–0.74). In males the risk of dying was also greater in those that did not receive ANS (OR 1.36, 95% CI 1.03–1.77) compared to those who did (OR 0.74, 95% CI 0.57–0.96).

Conclusion

Antenatal corticosteroids had a greater beneficial effect in female compared to male extremely prematurely born infants in reducing death before discharge.

Keywords:

• Prematurely born infants
• antenatal corticosteroids
• mortality
• IVH
• BPD

Introduction

In the early 1970s, the term ‘male disadvantage’ was used to describe the higher incidence of perinatal mortality observed in male compared to female infants [1]. There still remains differences in neonatal outcomes between male and female preterm infants [2–4]. Antenatal corticosteroids (ANS) in threatened preterm labor are effective in reducing neonatal mortality, respiratory morbidity and intraventricular hemorrhage (IVH). A recent single-center study reported that ANS had a positive effect only in male preterms [5]. The aim of this study was to report at a whole-population level the effect of antenatal corticosteroids according to sex on mortality, intraventricular hemorrhage, bronchopulmonary dysplasia (BPD) and the duration of ventilation.

Materials and methods

Data for all infants born <28 weeks of gestation admitted for neonatal care in England between 1/1/2014 and 1/1/2019 were acquired from the National Neonatal Research Database (NNRD), Imperial College London, UK. The NNRD is approved by the National Research Ethics Service (10/H0803/151) and the Confidentiality Advisory Group of the Health Research Authority (8-05[f]/2010). Infants were categorized as having received ANS if their mother received any corticosteroid prior to delivery. Birth weight z-score was calculated [6]; intrauterine growth retardation (IUGR) was defined as a birth weight <10th centile for the gestational age [7].

Statistical analysis

Differences were assessed for significance using the x² test or the Mann-Whitney U-test as appropriate. Multivariate and binomial logistic regressions were performed to identify the independent effect of ANS on the outcomes separately in male and female infants after correcting for gestational age and birth weight z-score.

Results

The 11,714 infants (54% male, 13.3% IUGR) had a median (IQR) gestational age of 26 + 1 (24 + 6–27 + 1) weeks, birth weight of 809(670–960) grams and birth weight z-score −0.38(−0.88–0.07). Eighty-nine percent of both sexes received ANS, similar proportions in both sexes. The male infants had a lower birth weight Z-score (p = .008) (Table 1). Female infants had lower mortality compared to male (18.7 versus 21.7%, p < .001), lower incidence of IVH (10.9 versus 13.9%) p < .001) and BPD (61.6 versus 68.2%, p= <.001) and a shorter median (IQR) duration of mechanical ventilation [9(3–26) versus 13(4–29) days, p < .001].

Table 1. Demographics and results according to administration of antenatal steroids.

Full cohort n = 11,714
		AN steroids N = 10,449	No AN steroids N = 1265	p Value	Male N = 6324	Female N = 5390	p Value
Gender male:	6324 (54%)	5647 (54%)	677 (53.4%)	.429	n/a	n/a	n/a
Gestational age (weeks)	26.0 (24.85−27.14)	26.14 (24.86−27.14)	25.71 (24.28−27.0)	<.001	26.0 (24.85−27.14)	26 (24.85−27.0)	.285
Birth weight (gr)	809 (670−960)	810 (675−960)	800 (656−964)	.212	835 (698−990)	780 (648−923)	<.001
Birth weight z-score	−0.38 (−0.88−0.07)	−0.40 (-0.90−0.05)	−0.23 (−0.70−0.18)	<.001	−0.398 (−0.908–0.063)	−0.366(-0.848–0.073)	.008
AN steroids	10449 (89.2%)	n/a	n/a	n/a	5647 (89.3%)	4802 (89.1%)	.429
Death	2360 (20.1%)	1951 (18.7%)	409 (32.3%)	<.001	1373 (21.7%)	987 (18.3%)	<.001
IVH	1843 (15.7%)	1520 (14.5%)	323 (25.5%)	<.001	1116 (17.6%)	727 (13.5%)	<.001
Survivors only, n = 9354
		AN steroids N = 8498	No AN steroids N = 856		Male N = 4951	Female N = 4403
MV (days)	11 (3−27) (range 0–276)	10 (3−27) (range 0−276)	13 (5–31) (range 0–121)	<.001	13 (4–29) (range 0–217)	9 (3−26) (range 0–276)	<.001
BPD	6088 (65.1%)	5509 (64.8%)	579 (67.6%)	.151	3375 (68.2%)	2713 (61.6%)	<.001
IVH	1170 (12.5%)	996 (11.7%)	174 (20.3%)	<.001	688 (13.9%)	482 (10.9%)	.001

Data are presented as N (%) or median (IQR).

Lack of ANS (32 versus 19% in ANS, p < .001) and male gender (22 versus 18% females, p < .001) were associated with higher risk of death. In the ANS group, females had lower mortality: males 20.2% versus females 16.9% (p= <.001). Female infants had an odds ratio for mortality of 1.81(95% CI 1.35–2.44) if they had not received ANS, but the OR was 0.55(95% CI: 0.41–0.74) in those that received ANS. In males the OR was 1.36(95% CI: 1.03–1.77) in those that did not receive ANS versus 0.74(95% CI: 0.57–0.96) in those that received ANS.

A larger proportion of infants who did not receive ANS developed IVH (25.5 versus 14.5% in the ones that received ANS, p = .001). Additionally, more male infants had IVH (26.6 versus females 22.3%, p = .001). Regression analysis demonstrated that risk factors for IVH included male sex (OR 1.46; CI: 1.31–1.64) and younger gestational age. The infants that received ANS had a lower risk for IVH (OR 0.42;95% CI: 0.42–0.58).

Lower gestational age, lower birth weight Z-score and increased duration of MV were independently associated with increased risk of developing BPD after adjusting for ANS and gender. Male infants were more likely to develop BPD than females (OR 1.29;95% CI:1.16–1.45). Administration of ANS was not associated with the outcome of BPD at 36 weeks.

Lower gestational age and birth weight z-score were associated with longer duration of MV. The infants that received ANS had a shorter duration of ventilation by 2.3 days (p < .001) compared to the ones that did not receive ANS, and female infants had a shorter course of ventilation by 2.8 days compared to males (p < .001)

Discussion

We have demonstrated that antenatal corticosteroids were associated with a greater reduction in mortality in female compared to male infants. We reported significantly worse outcomes in male compared to female infants. Infants of both sexes had a positive response to ANS. The influence of sex on the effect of ANS in preterm infants has not been widely examined. A meta-analysis of 2000 infants [8] reported similar beneficial effects of ANS in both sexes in reducing IVH and mortality. The influence of sex, however, was not examined in two other meta-analyses of the effects of ANS [9]. The pathophysiological basis of the female advantage to antenatal steroids is not completely understood. Animal studies have demonstrated that ANS upregulated airway sodium and potassium pump activity, which facilitated lung fluid removal [10]. In a rat model, male pups had lower rates of alveolar sodium channels than females [11] which possibly contributed to the increased risk of respiratory distress syndrome in male compared to female infants, despite ANS exposure [12]. In a sheep model, administration of ANS in females was associated with greater improvements in compliance, conductance and arterial oxygen partial pressure compared to males [13]. Although this was a large whole-population study, we should acknowledge as a limitation the absence of data on the completeness and timing before delivery of the corticosteroids course. The study period, however, was within the period of the consensus guidance from the Royal College of Obstetricians and Gynecologists [14] and the subsequent NICE guideline [15] recommending a standardized approach to antenatal corticosteroids for preterm labor.

In conclusion, we have demonstrated that antenatal corticosteroids were more effective in reducing mortality in female compared to male, extremely preterm infants.

Ethical approval

As the study used data held in an existing database, participation did not require approval from individual Trusts, but only from the NHS Trust holding the database (Chelsea and Westminster NHS Foundation Trust) which was obtained, Research Ethics Committee (REC reference: 19/WM/0172) and the UK Health Research Authority (HRA) (IRAS project ID: 259225)

Geolocation information

London, United Kingdom

Author contributions

RL, AG and TD designed the study. All authors designed the statistical analysis and analyzed the data. All authors were involved in the preparation of the manuscript and approved the final manuscript as submitted.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data will be made available on request.

Additional information

Funding

This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Center at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.