Association between antenatal steroids for lung maturation and hypoglycaemia in the first 48 hours in premature infants between 26 and 34 weeks of gestational age

Introduction

Hypoglycaemia is a frequent condition in neonatal care units, and its importance lies in its relationship with alterations in neurode-velopment [1–6]. The values defining it are still controversial, with the definitions proposed by the Paediatric Endocrinology Society and by the American Academy of Paediatrics being the most used. [7–10]. The maternal risk factors which may trigger it include, among others: gestational diabetes, maternal obesity, the use of beta-blockers or hypoglycaemic agents, and associated hypertensive disorders in pregnancy [1, 3, 11, 12]. Neonatal risk factors include low weight, intrauterine growth restrictions, small foetus for gestational age, prematurity, infections, respiratory distress syndrome, or inborn errors of metabolism, among others [3, 9, 12–14].
The benefits of the use of maternal prenatal steroids in preterm infants are well documented; with a decrease in the incidence of respiratory distress syndrome, necrotising enterocolitis, periventricular leukomalacia, or persistent ductus arteriosus, among others, as well as lower mortality and hospitalisation time [15–19]. However, other publications find side effects of the use of prenatal steroids, especially from multiple cycles: Bevilacqua et al., in their meta-analysis published in 2010, reported lower foetal weight and lower ce-phalic circumference, findings that were also described in other publications [15, 18, 20]. In turn, Mazunder et al. reported shorter stat-ure at six months of postnatal life [16].
On the other hand, Gyamfi-Bannerman et al. reported that when applying antenatal corticosteroids between weeks 34 and 36 of gestation, newborns improved respiratory outcomes, although they presented a greater number of instances of hypoglycaemia in patients exposed to betamethasone [21], Alrais et al. indicated a higher frequency of admission to neonatal intensive care secondary to low glu-cose values among preterm infants exposed to the steroid prenatally but without finding significant differences related to the length of stay in the unit [22]. In contrast, studies by Koivisto et al. and Pettit et al. did not describe this association [23, 24].

Aim of the study

This study seeks to evaluate whether there is a relationship between the incidence of neonatal hypoglycaemia and the use of antenatal corticosteroids for lung maturation in preterm infants between 26 and 34 weeks of gestational age.

Material and methods

This is a prospective closed-cohort study. The procedures followed the principles of the Declaration of Helsinki. The Ethics Com-mittees of the University Hospital of Santander (HUS) and the Industrial University of Santander endorsed the protocol.
Neonates between 26 and 34 weeks of gestational age, born at the HUS, Colombia between 2016 and 2017 were analysed. They were divided into two cohorts: one to those exposed to antenatal betamethasone for lung maturation and one another to those who were not exposed. Neonates with identifiable genetic syndromes, adrenal insufficiency, suspicion of multiple deficit of pituitary hor-mones, and those exposed to steroids for causes other than lung maturation were excluded. Those for whom data collection was incom-plete were also excluded. The data was obtained from the medical records of the newborns. When there was missing information, it was checked directly with the mother or with the manual nursing records.The main outcome was the presence in the first 48 hours of hypo-glycaemia according to the parameters of the Paediatric Endocrine Society (central glucose or capillary glucose < 50 mg/dl). The recol-lection of the information finished when the neonates complete 48 hours of life or when an episode of hypoglycaemia was identified during that period of time.
Variables were analysed in proportions or measures of central tendency and dispersion, according to their nature. Differences were established between the two cohorts using the chi-square test or Mann-Whitney U test, considering the value of p < 0.05 as signif-icant. The overall incidence was calculated for each cohort with their respective 95% confidence intervals. Two multivariate models were performed: in the first, binomial regression was performed to estimate the relative risk (RR) of hypoglycaemia; in the second, a Cox model was proposed for estimating the difference in the two cohorts in terms of incidence density. In both, the assumptions of the model were verified. Finally, Kaplan-Meier hypoglycaemia-free survival curves were explored, including whether there were differences in the incidence of hypoglycaemia according to maternal age and primiparity.

Results

Of 3480 infants born alive in the HUS during the collection period, 173 fulfilled the inclusion criteria, 152 (87.9%) of whom re-ceived pulmonary maturation treatment. The median maternal age was 24 years for both cohorts, with six (28.6%) and 52 (34.1%) among those not exposed and exposed, respectively (p = 0.608). No significant differences were found when performing the analysis of maternal comorbidities between the two cohorts (Table 1). The median gestational age of the newborns was 33 weeks for both cohorts (p = 0.301). In exposed infants, the distribution by sex was 76 women (50.3%) versus 11 women (52.4%) in the unexposed, and the median birth weight was 1910 g and 1725 g (p = 0.730), respectively. There were no significant differences when comparing Apgar score and glucose infusion rate (Table 1).
The incidence of hypoglycaemia in the first 48 hours was 29 episodes per 100 newborns not exposed to antenatal steroids and 25 episodes per 100 newborns exposed to it (p = 0.725). The presentation speed was 8.80 and 6.36 events/1000 person-hours, respec-tively, a difference that is not statistically significant either (p = 0.468). No significant differences were found according to the time in which they were exposed (two hours before birth or more hours), gestational age, weight, and number of doses of the steroid. There was no significant difference in the incidence of hypoglycaemia with respect to gestational age, weight, time of steroid application, and betamethasone cycles.
The binomial model indicated that exposure to foetal lung maturation with steroids was not associated with hypoglycaemia in newborns (RR 0.852, 95% CI: 0.411–1.771), value adjusted for maternal age, primiparity, maternal diabetes, and gestational age. The same phenomenon occurred with the Cox model, where the hazard ratio (HR) was 0.721 (95% CI: 0.310–1.710).
The analysis of survival revealed that the onset speed of hypoglycaemia is higher in the first 8.8 hours of life; but there are no differences between those who did or did not receive the prenatal steroids even after adjusting the data for maternal age and primiparity (Figure 1A). A higher rate of hypoglycaemia was found in the offspring of women older than 35 years of age with respect to the off-spring of women aged 35 years or younger, as well as among primiparous women (Figure 1B, C). However, the binomial or Cox mod-els did not support this finding, either for those older than 35 years (RR 1.323, 95% CI: 0.585–2.992, HR 1.198, IC95%: 0.472–3.039) or for primiparous women (RR 1.439, 95% CI: 0.847–0.2444; HR 1.456, IC95%: 0.799–2.659).

Discussion

The general incidence of hypoglycaemia in preterm infants exposed to antenatal steroids was 25%, with no significant differences between exposed with those unexposed. This incidence is within the ranges already reported in the literature and varies according to the reference values used, the additional risk factors of the newborn (being higher in those small for gestational age), and adherence to local guidelines [14, 25–28].
Kuper et al. [28] published a study in 2018 in which they evaluated the incidence of hypoglycaemia in neonates whose mothers did or did not receive antenatal steroids, in an age range similar to that used in this study (23 to 34 weeks of gestational age). They in-cluded 635 patients, of whom an incidence was reported in the first 48 hours of life of 23.0% (exposed) versus 16.1% (not exposed), without this difference being significant (OR 1.3, IC95%: 0.5–3.6), as was found in the present study.
In the late preterm group, the relationship between neonatal hypoglycaemia and exposure may be more frequent, as reported by Gyamfi-Bannerman et al. in 2016. Recent recommendations of the American College of Obstetricians and Gynaecologists, regarding the application of steroids for lung maturation in this group of neonates, or, as another publication proposes, in late preterm infants with a high risk of morbidity and mortality, may be controversial because this measure has been associated with possible short-term compli-cations such as hypoglycaemia and subsequent neurological alterations [29, 30]. Alrais et al. reported a higher risk of hypoglycaemia in late preterm infants and indicated higher admission to the neonatal intensive care unit secondary to low glucose values, but with no sig-nificant difference between the length of stay [22]. Vaibhavi reported in his retrospective cohort study higher rates of hypoglycaemia and hyperbilirubinaemia in late preterms in whom the steroid was not applied according to the exact criteria of the American College of Ob-stetricians and Gynaecologists (single pregnancy, is likely to remain pregnant 12 hours, no previous treatment with steroids, no pregestational diabetes, no signs of infection or other contraindications) [31]. Prospective studies are necessary to clarify the association between this exposure and hypoglycaemia.
The time for the appearance of hypoglycaemia is variable; Stark et al. report that 50% of hypoglycaemia in neonates with risks factors occurs between the first 2 hours and 20 minutes of life [25]. However, it would be necessary to analyse these data cautiously because it has been described that the physiological nadir in preterm and term neonates occurs in the first three hours of life [32]. In our case, the speed of onset was greater in the first 8.8 hours of life, which became more evident when adjusting the variable for maternal age and primiparity. This result had already been documented by Pettit et al. who reported a higher risk of presenting hypoglycaemia (OR 1.60, 95% CI: 1.24–2.07) when the variables were adjusted for gestational age, maternal age of 35 years, nulliparity, race, and dia-betes [24]; however, more studies are needed to define their association.
We recognise that one of the weaknesses of the study is the size of the sample of the cohorts, which could explain the absence of differences in the incidences. Despite this, the characteristics of the population were similar, thereby making the information obtained relevant, although a larger sample might be needed to show statistically significant differences.

Conclusions

There are no significant differences in the incidence of hypoglycaemia between infants exposed in utero to steroids for lung matura-tion and those not exposed between week 26 and 34 of gestational age. Although the incidence of hypoglycaemia is similar to the values previously reported in the literature, efforts must be made to reduce it, due to the long-term neurological impact of this condition.
More studies are needed to clarify the aetiological relationship between exposure to antenatal steroids for lung maturation and neonatal hypoglycaemia. Despite differences in results, the positive impact on neonatal mortality and morbidity with the use of the ster-oids cannot be denied. By studying this relationship, we intend to reinforce the importance of identifying risk factors and controlling glycaemic values in this population in order to take timely measures to avoid it.

Acknowledgement

The authors highlight the contribution of professor Luis Alfonso Díaz Martínez. MD, Pediatrician and MSc Epidemiology of In-dustrial University of Santander.

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