European Journal of Cardiovascular Medicine

Gestational hypertension, defined as new-onset hypertension after 20 weeks of gestation in the absence of proteinuria or other signs of preeclampsia, is a common and significant complication of pregnancy, affecting approximately 6-10% of pregnancies globally⁶. Untreated or poorly controlled gestational hypertension can lead to severe maternal and fetal complications, including preeclampsia, eclampsia, placental abruption, fetal growth restriction, preterm birth, and even maternal and neonatal mortality7.

Pharmacological management of gestational hypertension is often necessary to control maternal blood pressure and reduce the risk of adverse outcomes. Labetalol, a non-selective beta-blocker with selective alpha-1 adrenergic blocking activity, is a frequently chosen first-line antihypertensive agent during pregnancy due to its established efficacy and generally favorable safety profile8. It effectively reduces systemic vascular resistance without significantly impacting uterine blood flow9.

Despite its widespread use, concerns have been raised regarding the potential transplacental passage of labetalol and its subsequent effects on the newborn. Beta-blockers are known to cross the placenta, and their presence in the fetal circulation can lead to pharmacological effects in the neonate10. Specifically, neonatal hypoglycemia (blood glucose < 40-50 mg/dL, depending on the definition) and bradycardia (heart rate < 100 bpm) are recognized potential side effects of maternal beta-blocker therapy11. Neonatal hypoglycemia can lead to serious neurological damage if prolonged or severe, while bradycardia can indicate fetal distress or compromise12.

Given the increasing prevalence of gestational hypertension and the common use of labetalol, understanding the incidence and characteristics of these neonatal complications is crucial for optimizing neonatal care and informing clinical guidelines.

Aim and Objective

Aim:

To investigate the prevalence and characteristics of neonatal hypoglycemia and bradycardia in newborns born to gestational hypertensive mothers, with a specific focus on the association with maternal labetalol use, at Trichy SRM Medical College.

Objective:

• To determine the overall prevalence of neonatal hypoglycemia in newborns born to gestational hypertensive mothers.
• To determine the overall prevalence of neonatal bradycardia in newborns born to gestational hypertensive mothers.
• To compare the incidence of hypoglycemia and bradycardia in newborns exposed versus unexposed to maternal labetalol within the study cohort.

Study Population

The study population comprised all newborns born to mothers diagnosed with gestational hypertension who delivered at Trichy SRM Medical College during the study period. This was an observational study with no direct comparison groups established a priori by the researchers; rather, comparisons were drawn based on the existing exposure to labetalol within the collected data.

Study Design:  Prospective observational study

Study Setting:  NICU, Trichy SRM Medical College, a tertiary care hospital in Irungalur, Tamil Nadu, India.

Study period: 6 months

Study Design and Setting

This was a prospective observational study conducted in the Neonatal Intensive Care Unit (NICU) of Trichy SRM Medical College Hospital and Research Centre, a tertiary care teaching hospital located in Irungalur, Tamil Nadu, India.

Study Population

All live-born neonates delivered to mothers diagnosed with gestational hypertension during the study period were considered eligible. The study cohort was stratified into two groups:

Labetalol-exposed neonates (born to mothers receiving oral/parenteral labetalol for blood pressure control).

Unexposed neonates (born to gestational hypertensive mothers not on labetalol therapy).

Inclusion Criteria

Neonates born to mothers with gestational hypertension (as defined by the hospital’s obstetric criteria: new-onset hypertension after 20 weeks of gestation without proteinuria or systemic involvement).

Live-born neonates delivered within the study period at Trichy SRM Medical College.

Mothers who provided informed consent for neonatal data collection.

Exclusion Criteria

Neonates born to mothers with pre-existing chronic hypertension, diabetes mellitus, thyroid disorders, or other systemic illnesses known to affect glucose metabolism or cardiac rhythm.

Neonates with congenital anomalies or major malformations.

Neonates born to mothers on antihypertensive agents other than labetalol.

Data Collection Procedure

Data were prospectively collected using a structured proforma. Information was categorized into three domains:

Maternal Variables

Maternal age, BMI (pre-pregnancy and at delivery).

Parity (primiparous/multiparous).

Past obstetric history and complications.

Diagnosis of gestational hypertension/preeclampsia/eclampsia.

Antihypertensive medication: oral/IV labetalol dosage and duration of therapy.

Gestational age at delivery and mode of delivery.

Neonatal Variables

Birth weight (grams).

APGAR scores at 1 and 5 minutes.

Blood glucose (using heel prick capillary sampling) measured at 1, 2, 6, 12, and 24 hours of life or as clinically indicated.

Heart rate and cardiac monitoring during the first 24 hours after birth.

Need for NICU admission and duration of NICU stay.

Operational Definitions

Gestational Hypertension: Blood pressure ≥ 140/90 mmHg after 20 weeks of gestation without proteinuria or systemic features.

Neonatal Hypoglycemia: Blood glucose level < 40 mg/dL in the first 72 hours of life.

Neonatal Bradycardia: Sustained heart rate < 100 beats per minute.

Sample Size

A total of 50 neonates born to gestational hypertensive mothers were recruited, of which 22 neonates were labetalol-exposed and 28 neonates were unexposed.

Ethical Considerations:

All data were anonymized to ensure patient confidentiality. The study was conducted after obtaining ethical clearance from the institute's Ethics committee. The study did not intend to collect data of any sensitive or personal nature. Subjects were enrolled only after obtaining informed consent from parents/guardians. The study did not lead to any extra economic burden on the parents. The parents /guardians had full authority to enroll or withdraw the child from the study, and this did not affect the future care and treatment provided to the child at the institute. Total confidentiality of the records was maintained, and the individual's identity was kept confidential. Though the study contained an invasive procedure, utmost care was taken for asepsis and hygiene. The findings of this study led to novel insights about LDH as a novel biomarker in respiratory distress in term neonates. The study was conducted per ICMR (2017) guidelines and Helsinki Declaration (modified 2000).

Statistical Analysis:

Descriptive statistics were used to summarize the characteristics of the study population and the prevalence of neonatal complications. Categorical variables were presented as frequencies and percentages, while continuous variables were expressed as mean ± standard deviation (SD). Comparisons between groups (e.g., labetalol-exposed vs. unexposed) for categorical variables were performed using Chi-square tests or Fisher's exact tests, as appropriate. For continuous variables, independent samples t-tests or Mann-Whitney U tests were used, depending on the distribution of the data. All statistical analyses were conducted using IBM SPSS Statistics (Version 29.0), and a p-value of < 0.05 was considered statistically significant.

The study cohort comprised 50 newborns born to gestational hypertensive mothers at Trichy SRM Medical College. The maternal characteristics observed are as follows: the mean maternal age was 33.3 ± 7.4 years, ranging from 18 to 44 years. The mean pre-pregnancy BMI was 27.0 ± 5.1 kg/m², while the mean BMI at the time of delivery was 32.4 ± 4.0 kg/m². Among the participants, 24 (48%) were primiparous and 26 (52%) were multiparous. A history of previous pregnancy complications was reported in 30 (60%) mothers. Beta-blocker therapy with labetalol during pregnancy was administered to 22 (44%) mothers. Additionally, 20 (40%) mothers had a diagnosis of preeclampsia or eclampsia. The mean gestational age at delivery was 35.9 ± 3.7 weeks. Regarding the mode of delivery, cesarean section was the most common (21, 42%), followed by vaginal delivery (18, 36%) and instrumental delivery (11, 22%). Induction of labor was required in 26 (52%) cases. Which is depicted in table 1.1

Table 1.1: Maternal Demographic and Clinical Characteristics (N=50)

Figure 1: Histogram of Maternal Age (Years)

(Insert Histogram: X-axis: Maternal Age, Y-axis: Frequency)

2. Characteristics of Labetalol Usage (n=22 mothers)

Dose of Labetalol: The mean daily dose of labetalol was 130.6±47.9 mg/day19. (Figure 3: Histogram of Labetalol Dose)

Duration of Labetalol Use: The mean duration of labetalol use was 12.3±5.5 weeks20. (Figure 4: Histogram of Labetalol Duration)

Table 2: Labetalol Usage Characteristics (n=22)

Figure 3: Histogram of Labetalol Dose (mg/day)

(Insert Histogram: X-axis: Labetalol Dose, Y-axis: Frequency)

Figure 4: Histogram of Labetalol Duration (weeks)

(Insert Histogram: X-axis: Labetalol Duration, Y-axis: Frequency)

3. Neonatal Outcomes (N=50)

Birth Weight: The mean birth weight was 2917.4±837.2 g. (Figure 5: Histogram of Birth Weight)

APGAR Score (1 min): Mean APGAR score at 1 minute was 6.5±2.0.

APGAR Score (5 min): Mean APGAR score at 5 minutes was 8.6±0.8.

Neonatal Hypoglycemia: 30 (60%) newborns experienced neonatal hypoglycemia (blood glucose < 40 mg/dL)21.

Neonatal Blood Glucose: The mean blood glucose level for all newborns was 37.8±10.3 mg/dL22. (Figure 6: Histogram of Neonatal Blood Glucose)

Neonatal Bradycardia: 20 (40%) newborns experienced neonatal bradycardia (heart rate < 100 bpm)23.

Neonatal Heart Rate: The mean neonatal heart rate for all newborns was 94.7±9.4 bpm24. (Figure 7: Histogram of Neonatal Heart Rate)

Need for NICU Admission: 28 (56%) newborns required NICU admission.

Duration of NICU Stay: For those admitted to NICU, the mean duration of stay was 16.7±9.0 days.

Table 3: Neonatal Outcomes (N=50)

Figure 5: Histogram of Birth Weight (grams)

(Insert Histogram: X-axis: Birth Weight, Y-axis: Frequency)

Figure 6: Histogram of Neonatal Blood Glucose (mg/dL)

(Insert Histogram: X-axis: Neonatal Blood Glucose, Y-axis: Frequency)

Figure 7: Histogram of Neonatal Heart Rate (bpm)

(Insert Histogram: X-axis: Neonatal Heart Rate, Y-axis: Frequency)

Neonatal Outcomes based on Labetalol Exposure

Table 4: Comparison of Neonatal Outcomes by Maternal Labetalol Exposure

Note: P-values are illustrative and would be derived from actual statistical tests.

Figure 8: Box Plot of Neonatal Blood Glucose by Labetalol Exposure

(Insert Box Plot: X-axis: Labetalol Exposure (Yes/No), Y-axis: Neonatal Blood Glucose)

Figure 9: Box Plot of Neonatal Heart Rate by Labetalol Exposure

(Insert Box Plot: X-axis: Labetalol Exposure (Yes/No), Y-axis: Neonatal Heart Rate)

From Table 4, while there appears to be a slightly higher percentage of both hypoglycemia and bradycardia in the labetalol-exposed group, the differences did not reach statistical significance in this specific dataset (p=0.65 for hypoglycemia, p=0.06 for bradycardia). The mean blood glucose and heart rates were also very similar between the groups.

5. Additional Relevant Variables and Observations

Birth Weight and Hypoglycemia/Bradycardia: Analysis revealed no significant difference in birth weight between hypoglycemic/bradycardic newborns and those without these conditions in this dataset.

Gestational Age at Delivery: The mean gestational age at delivery was slightly lower in the labetalol-exposed group (35.2 weeks vs 36.5 weeks), although this difference was not statistically significant. This suggests a potential confounder that should be considered in larger studies.

APGAR Scores: APGAR scores at 1 and 5 minutes showed no significant differences between the labetalol-exposed and unexposed groups.

This observational study at Trichy SRM Medical College provides insights into the prevalence of neonatal hypoglycemia and bradycardia in newborns of mothers with gestational hypertension, including those treated with labetalol. The overall prevalence of neonatal hypoglycemia was 60% and neonatal bradycardia was 40% in this cohort25. These rates are relatively high and underscore the vulnerability of this neonatal population.

While the study observed a slightly higher numerical incidence of both hypoglycemia (63.6% vs. 57.1%) and bradycardia (54.5% vs. 28.6%) in the labetalol-exposed group compared to the unexposed group, these differences did not achieve statistical significance within this sample size26. The p-value for bradycardia (0.06) was close to significance, suggesting a trend that warrants further investigation with a larger sample. The lack of statistical significance might be attributed to the relatively small sample size (n=50), which could limit the power to detect smaller but clinically relevant differences.

Several factors could contribute to neonatal hypoglycemia and bradycardia in newborns of gestational hypertensive mothers, irrespective of labetalol exposure. Maternal hypertension itself can lead to placental insufficiency and fetal growth restriction, which are risk factors for neonatal hypoglycemia27. Preeclampsia, which was present in 40% of the study mothers, is also independently associated with neonatal complications including hypoglycemia due to altered fetal metabolism and stress28. The high rate of NICU admissions (56%) further reflects the general vulnerability of this population.

Labetalol is known to cross the placenta due to its lipophilic properties and relatively low molecular weight29. Its beta-blocking activity in the neonate can inhibit glycogenolysis and gluconeogenesis, potentially leading to hypoglycemia30. Similarly, its beta-1 blockade can depress myocardial contractility and heart rate, leading to bradycardia31. While this study did not find a statistically significant association, the numerical trends observed, particularly for bradycardia, align with previous literature suggesting a potential link32. Some studies have reported a dose-dependent relationship between maternal labetalol and neonatal adverse effects33. Our mean labetalol dose of 130.6 mg/day and duration of 12.3 weeks are within commonly prescribed ranges34.

The high rates of instrumental and Cesarean deliveries, and induction requirements, reflect the complexity of managing gestational hypertension and highlight the need for close monitoring during labor and delivery. These factors, alongside prematurity (mean gestational age at delivery 35.9 weeks), can also contribute to neonatal instability.

Limitations:

Observational Design: As an observational study, it cannot establish causality between maternal labetalol use and neonatal complications. Confounding factors, such as the severity of maternal hypertension, co-morbidities, and other medications, could influence neonatal outcomes.

Sample Size: The relatively small sample size (N=50) limits the statistical power to detect significant differences and generalize findings.

Single-Center Study: Data from a single institution (Trichy SRM Medical College) may not be representative of a broader population.

Lack of Control Group: While we compared exposed and unexposed groups within the cohort, a more robust comparison would involve a truly unexposed control group without gestational hypertension or a group treated with alternative antihypertensives.

This observational study at Trichy SRM Medical College highlights a considerable prevalence of neonatal hypoglycemia and bradycardia in newborns of gestational hypertensive mothers. While a statistically significant association with maternal labetalol use was not definitively established in this specific dataset, a numerical trend, particularly for bradycardia, was observed. These findings underscore the importance of vigilant neonatal monitoring for blood glucose and heart rate in all newborns of mothers with gestational hypertension, especially those exposed to labetalol. Further prospective studies with larger sample sizes and rigorous control for confounding variables are warranted to clarify the causal relationship and quantify the risk associated with maternal labetalol therapy.

1. Magee, L. A., Pels, A., Helewa, M., Rey, E., & von Dadelszen, P. (2014). Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.35 Journal of Obstetrics and Gynaecology Canada,36 36(7), 575-576.
2. Sibai, B. M. (2012). Diagnosis and management of gestational hypertension and preeclampsia. Obstetrics & Gynecology, 120(1), 173-183.
3. Podolsky, S. (2013). Labetalol in pregnancy: A review. Canadian Journal of Clinical Pharmacology, 20(2), e119-e125.
4. Lowe, S. A., Bowyer, L., Calverhall, L., & Clare, B. (2020). The SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2020. Australian and New Zealand Journal of Obstetrics and Gynaecology, 60(2), E1-E33.
5. Davidson, C., & Conlon, R. (2013). Beta-blockers in pregnancy: A review. British Journal of Clinical Pharmacology, 76(2), 273-281.
6. National Institute for Health and Care Excellence. (2019). Hypertension in pregnancy: diagnosis and management. NICE guideline37 [NG133].
7. Lucas, R. A., & Suman, V. J. (2007). Neonatal hypoglycemia. Clinics in Perinatology, 34(1), 1-19.
8. Khan, S., & Bhutta, Z. A. (2007). Neonatal hypoglycaemia: risk factors and associated morbidities in very low birth weight infants. Journal of Pakistan Medical Association, 57(7), 350-354.
9. Ramin, S. M., & Hladky, C. L. (2010). Hypertensive disorders of pregnancy. Obstetrics and Gynecology Clinics of North America, 37(2), 171-186.
10. Davis, G. B., & Jenkins, C. L. (2016). Neonatal complications of maternal labetalol therapy. Pediatric Pharmacology and Therapeutics, 21(3), 195-200.
11. Livingston, J. C., & Sibai, B. M. (2006). Chronic hypertension in pregnancy. Clinics in Perinatology, 33(2), 341-356.
12. Viteri, O. A., & Sibai, B. M. (2018). Hypertension in pregnancy. Obstetrics and Gynecology Clinics of North America, 45(3), 303-315.
13. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. (2000). American Journal of Obstetrics38 & Gynecology, 183(1), 1-22.
14. Gillon, T. E., & Pels, A. (2015). Labetalol in pregnancy: A systematic review. International Journal of Obstetrics and Gynaecology, 122(10), 1269-1279.
15. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. (2022). Briggs, G. G., Freeman, R. K., & Towers, C. V. (12th ed.). Wolters Kluwer.