Effect of antenatal betamethasone on fetal heart rate short-term variability in growth restricted fetuses

Introduction

Preterm birth remains a leading cause of perinatal morbidity and mortality, with risk increasing with the earlier onset of the birth. Birth before 32 weeks of gestation requires prolonged neonatal intensive care, primarily due to pulmonary immaturity. When birth before 34 weeks of gestation is imminent, antenatal corticosteroid (GCS) therapy is administrated in order to reduce the risks of neonatal respiratory distress syndrome [1], 2]. One of the most common causes of medically indicated preterm delivery is fetal growth restriction (FGR). We proceed with delivery when fetal status is assessed as critically compromised, posing a threat of irreversible damage of intrauterine death. In early gestation, the aim is to prolong pregnancy to improve the chances of healthy survival. The decision to deliver due to suspected fetal hypoxia is based on the assessment of fetal status, which relies mainly on indirect methods, including ultrasound and cardiotocography (CTG). CTG recording interpretation is at least partly subjective and particularly challenging in early gestation due to the gestational age-dependent maturity of the autonomic nervous system (ANS), which coordinates the fetal heart rate. For this reason, the use of computerized CTG (cCTG) and short-term (beat-to-beat) variability (STV) of the fetal heart rate is recommended in cases of FGR [3], 4]. Low STV values of the fetus, considering gestational age, can indicate fetal compromise as a result of hypoxia and is an indication for immediate delivery regardless of gestation [5]. STV is regulated by the autonomic nervous system (ANS) through a negative feedback loop, in which sympathetic precedes parasympathetic maturation. During fetal hypoxia, sympathetic dominance occurs. GCS have a similar effect on the ANS as hypoxia, which can lead to misinterpretation of the STV and possibly an inappropriate decision to deliver. The effect of maturation therapy with corticosteroids on STV is not fully understood, and data on the effect of GCS on FGR fetuses are limited. An initial transient increase in STV following GCS administration is documented; however, findings regarding a subsequent decrease in STV after completing the therapy are inconsistent [6], 7]. Moreover, short-term variability (STV) thresholds indicative of fetal hypoxia – and thus indicating the need for immediate delivery – vary across established international guidelines [3], 8].

Our study aimed to evaluate the magnitude and duration of the effect of antenatal GCS therapy with betamethasone on STV in FGR fetuses and to compare these findings with appropriate for gestational age (AGA) fetuses. Stress-related metabolism resulting from impaired oxygenation and/or nutrient supply in FGR may accelerate the maturation of the fetal autonomic nervous system, which could lead to a different physiological response to exogenous corticosteroid administration compared to AGA fetuses, therefore contributing to observed differences in treatment response between both groups. A better understanding of the impact of antenatal betamethasone on STV could improve clinical interpretation of fetal status during and after GCS administration, which could help to avoid misclassification of fetuses as hypoxic – leading to potentially unnecessary early delivery – as opposed to those whose condition still permits expectant management aimed at prolonging gestation and increasing fetal maturity.

Results

A total of 41 fetuses who received betamethasone therapy for the risk of preterm delivery were included in the study. Twenty-one of them were FGR, and 20 were AGA. Among the 21 FGR fetuses, 11 had an EFW and/or AC below the 3rd percentile, 10 had an EFW and/or AC between the 3rd and 10th percentile accompanied by an umbilical artery pulsatility index (UA-PI) above the 95th percentile. Of the 205 planned cCTG recordings, 188 were completed and analyzed. The 17 missing recordings included one recording 6–12 h after the first betamethasone dose (AGA fetus who subsequently underwent the next scheduled recording), two recordings on the day after the first dose (both in FGR fetuses), five recordings on the day after the second dose (three in FGR fetuses and two in AGA fetuses); and nine recordings two days after the second dose, which were missed due to delivery (seven in FGR and two in AGA fetuses).

FGR fetuses had, as expected, significantly lower weight (1310.90 ± 431.26 g vs. 1717.47 ± 449.06 g; p=0.006) and a smaller AC for gestational age (236.73 ± 29.95 mm vs. 253.10 ± 60.07; p=0.016) and the average AU-PI was significantly higher (1.31 ± 0.38 vs. 1.02 ± 0.19; p=0.002). Similarly, the percentile values of the measurements were also significantly lower in FGR (Table 1). The average gestational age did not differ significantly between them. The groups did not differ significantly in maternal characteristics (Table 1).

Maternal body temperature (p=0.252), arterial pulse (p=0.401) and mean arterial pressure (p=0.072) did not differ significantly between FGR and AGA fetuses at all times of cCTG recordings, and none of them received antidepressants or anxiolytics (Figure 1).

Figure 1:

Maternal biometric measurements during the time of cCTG (computerized cardiotocogram) recording in the group of growth restricted (FGR) and appropriate-for-gestational age (AGA) fetuses considering betamethasone application.

Before the first dose of betamethasone, the STV value was significantly affected by the type of fetal growth (p=0.038) and the gestational age of the fetus (p=0.001) in the regression model, independently of other confounding variables (Table 2) FGR fetuses had an average of 4.3 m s lower STV values at any gestation compared with fetuses with normal growth. With each day of gestation, the STV value was, on average, 0.12 m s higher, regardless of the type of fetal growth.

STV increased 6–12 h after the first dose of betamethasone by an average of 5.05 m s in the FGR group and 4.52 m s in the AGA group. Following this transient elevation, STV decreased by 4.00 m s, 0.81 m s, and 1.06 m s in the FGR group and by 3.24 m s, 1.48 m s, and 0.95 m s in the AGA group. STV values did not differ significantly between the two groups at any time (Table 3).

The increase in STV observed 6–12 h after the first dose of betamethasone was statistically significant compared to baseline in both groups (p < 0.001). STV remained significantly elevated one day after the first dose in the FGR group (p=0.018). Meanwhile, it was not significantly elevated in the AGA group. The difference between the two groups was not statistically significant at that time point. Furthermore, there was no significant difference in STV between baseline (before the first dose of betamethasone) and the measurements taken on the second day after the first dose (48 h) or the third day after the second dose (72 h) in either group (Table 4, Figure 2).

Figure 2:

Fetal heart rate short-term variability (STV) before and after two doses of Betamethasone 24 h apart in growth restricted (FGR) (blue line) and appropriate-for-gestational age (AGA) fetuses (red line) before and after adjustement for gestational age. STV showed a significant increase in both groups 6–12 h after the first application, which remained increased in FGR fetuses after 24 h. After 24 and until 72 h, STV decreased to levels not significantly different from before application. Adjusted for gestational age, STV was significantly lower in FGR fetuses at all times of cCTG recordings (two-way analysis of variance; p=0.031).

When adjusted for gestational age, which was significantly associated with STV, STV differed significantly between the two groups and was lower in the FGR compared to the AGA group at all times of cCTG recordings (p=0.031) (Figure 2).

Discussion

The study aimed to assess the magnitude and duration of the effect of antenatal betamethasone on STV in FGR fetuses and to compare this response with that of AGA fetuses. In our study, antenatal betamethasone significantly affected STV in both fetal groups. Following the initial increase in STV after the first dose of betamethasone, STV declined – at different rates in the two groups – and returned to levels that did not differ significantly from baseline. The elevation in STV persisted longer in FGR fetuses than in AGA fetuses.

One possible explanation for the rapid increase of STV in FGR following the first dose of betamethasone is its effect on glucocorticoid receptors in the brain, which, via the hypothalamic suprachiasmatic nucleus, contributes to the suppression of the normal fetal diurnal rhythm. The inhibitory effect of betamethasone predominantly targets the sympathetic component of autonomic heart rate regulation, increasing STV [15], 16]. An increase in STV within 24 h after the first dose of betamethasone has been previously described in other studies, both in FGR fetuses and mixed cohorts. However, in contrast to our findings, several studies have reported a significant decrease in STV following the initial transient rise within the first 24 h, with the suppression lasting up to 72 h after the first dose of betamethasone [7], 17], 18]. Schneider et al. similarly observed suppression of overall fetal heart rate variability, not specifically short-term variability, following betamethasone administration using magnetocardiotocography [15]. Knaven et al. reported, in contrast to the present study’s results, that the STV increase was limited to the first 24 h after the initial dose in both the preeclampsia and FGR groups, as well as in the remaining study population [17]. The observed discrepancies between our findings and previous reports may reflect heterogeneity in fetal and maternal characteristics, differences in study design, and variability in corticosteroid protocols. In particular, the gestational age at administration and the degree of placental dysfunction in FGR fetuses likely influence the duration and direction of STV changes after antenatal corticosteroid administration. That is to say, in the study of the association between fetal heart rate variability and FGR, Zizzo et al. [19] found that while during fetal respiratory movements, FGR fetuses preserved vagal activity at similar levels as seen in AGA fetuses, during quiescence, they presented lower RMSSD and HF power, which is consistent with a suppressed cardiac vagal activity and an increased sympatho‐vagal balance, implying an activated stress response due to chronic hypoxia. The addition of exogenous GCS to an environment with elevated levels of endogenous corticosteroids may result in a prolonged initial suppressive effect on the sympathetic component of autonomic heart rate regulation. Due to the iatrogenically increased STV in FGR fetuses that persists longer than in AGA fetuses, cCTG cannot be a reliable measure for assessing fetal wellbeing during the first 48 h after the first application of betamethasone.

Based on the findings of our study, STV values in FGR fetuses measured 48 h after the first dose of betamethasone likely reflect the actual fetal condition rather than a residual pharmacologic effect of betamethasone. These results are in line with the conclusions of Knaven et al., who reported that the decline in STV 24 h after betamethasone administration was less than 1 m s, suggesting that any observed decrease in STV should be interpreted as a sign of fetal compromise rather than a persistent corticosteroid effect [17]. The decrease in STV values after 24 h from the first dose of betamethasone in our study ranged between 0.81 and 1.06 m s in FGR and between 1.48 and 0.95 m s in AGA fetuses. Based on these results, STV may be considered a reliable parameter for fetal assessment 48 h after betamethasone administration in FGR and 24 h after administration in AGA fetuses. In this context, STV threshold values should still be interpreted primarily as indicators of fetal hypoxia rather than as transient effects of antenatal corticosteroids.

The present study also found that the STV was significantly lower in FGR at any gestational age than in AGA fetuses. Ghi et al. observed a similar finding in a study on the association between fetal size and the incidence of reduced STV after antenatal betamethasone administration. They found that compared with fetuses with normal STV values, fetuses with persistently lower STV values ​​had lower body weight estimates and birth weight [20]. Nijhuis et al. found that in FGR fetuses, the basal heart rate was generally higher, and the fetal heart rate variability was lower compared with the control group [21]. The lower fetal heart rate variability may be caused by an altered hypothalamic-pituitary-adrenal axis (HPA) characteristic of fetuses with growth retardation. Changes in HPA axis function lead to, among other things, reduced fetal and placental growth [22], 23].

Conclusions

Our study confirms that the increased STV observed in FGR fetuses during the first 48 h after the initial dose of betamethasone does not reflect actual fetal condition. This transient elevation in STV can be considered corticosteroids’ direct pharmacologic effect. Therefore, alternative monitoring methods should be used to assess fetal well-being accurately during this period. The reliability of STV as an indicator of fetal well-being in FGR fetuses is restored 48 h after the first application of betamethasone when values no longer differ significantly from baseline measurements obtained before betamethasone administration. In AGA fetuses, STV is restored to baseline measurements after 24 h. At all times of cCTG recordings, FGR fetuses have significantly lower STV in comparison to AGA fetuses. Our findings should be verified in a larger cohort, possibly with different doses of betamethasone.