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α/β- and β-Blocker Exposure in Pregnancy and the Risk of Neonatal Hypoglycemia and Small for Gestational Age
2023 Volume 87 Issue 4 Pages 569-577
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2023 Volume 87 Issue 4 Pages 569-577
Background: α/β- and β-blockers are essential in pregnant women’s perinatal congenital heart disease management. Nevertheless, data on the effects of α/β- and β-blockers on pregnant women and fetuses are limited. We examined the risks of neonatal hypoglycemia and small for gestational age (SGA) associated with maternal exposure to α/β- and β-blockers.
Methods and Results: All consecutive pregnant women with heart disease admitted to our hospital between January 2014 and October 2020 were included. Of 306 pregnancies (267 women), 32 were in the α/β-blocker group, 11 were in the β-blocker group, and 263 were in the control group. All 32 pregnancies in the α/β-blocker group were treated with carvedilol. In the β-blocker group, 4 women were treated with bisoprolol, 3 were treated with propranolol, 2 were treated with atenolol, 1 was treated with metoprolol, and 1 was treated nadolol. The incidence of neonatal hypoglycemia was higher in pregnant women taking carvedilol than in the control group (P=0.025). SGA was observed significantly more frequently in pregnant women taking β-blockers than in the carvedilol and control groups (P<0.001).
Conclusions: Carvedilol administration during pregnancy was associated with neonatal hypoglycemia; however, it did not occur in a time- or dose-dependent manner. Routine monitoring of blood glucose levels in newborns exposed to α/β- and β-blockers is essential.
The circulating blood volume in pregnant women begins to increase at five gestational weeks and reaches a maximum at 28–32 gestational weeks, becoming 1.5 times greater than that in non-pregnancy.1–3 This increase in blood volume contributes to oxygen supply to the fetus. Cardiac output (CO) peaks at 16–24 weeks gestation (at 130–150% of CO in non-pregnancy), prior to the peak in blood volume, mainly due to an increase in stroke volume in the first half of the pregnancy and an increase in heart rate in the second half.4 Increased CO stimulates the production of prostacyclin, relaxin, and nitric oxide in vascular endothelial cells and reduces systemic vascular resistance. These changes in circulating blood volume and peripheral vascular resistance significantly affect pregnant women’s hearts and blood vessels. Therefore, pregnancy with heart disease increases the risks to the mother and fetus, such as cardiovascular events during pregnancy, preterm birth, and neonatal small for gestational age (SGA).5–8
Many studies have been conducted since the 1970s on β-blockers such as labetalol and atenolol, which are often used for hypertensive disorders of pregnancy (HDP),9–13 and α/β- and β-blockers are associated with fetal hypoglycemia and SGA.14–19 However, there are conflicting data, and some articles argue that β-blockers do not directly affect the fetus but that their antihypertensive effects cause SGA.20–22
α/β- and β-blockers are not only commonly used to control arrhythmias but are also known to improve the prognosis of patients with chronic heart failure (HF) with reduced ejection fraction (EF); their use has been highly recommended in each guideline.23–25 As the prognosis of patients with congenital heart disease (CHD) has improved, the number of pregnancies with heart disease has increased, and α/β- and β-blockers play an essential role in the perinatal management of these pregnant women. Nevertheless, data are lacking on the effects of α/β- and β-blockers other than labetalol and atenolol on pregnant women and fetuses.18,26 Tanaka et al pointed out that the effects on pregnant women and fetuses may differ depending on the type of α/β-blocker and β-blocker.27 Therefore, we examined the risks of neonatal hypoglycemia and SGA associated with maternal exposure to α/β- and β-blockers. Additionally, it is widely known that α/β- and β-blockers improve left ventricular function in a dose-dependent manner in patients with chronic HF.28 In contrast, Ersbøll et al argued that the duration of treatment with β-blockers was significantly inversely associated with the relative deviation from the expected birthweight.29 Therefore, we also examined whether the complications caused by α/β- and β-blockers are time-dependent or dose-dependent.
This was a single-center retrospective study of 267 consecutive pregnant women with heart disease between January 2014 and October 2020. We studied 306 pregnancies in 267 women during the study period. The patients were identified based on their prescription histories, and their hospital records were examined. This was a retrospective analysis of data collected for routine clinical care and was approved by the institutional ethics committee. Because α/β- and β-blocker therapy in pregnant women is off-label, we obtained approval from the institutional ethics committee and received written informed consent from all patients.
Data collection included baseline characteristics before pregnancy, such as age at pregnancy, cardiac diagnosis, New York Heart Association (NYHA) functional class before pregnancy, surgical history, gestational age, primiparity, delivery mode (cesarean, painless, normal vaginal, or vacuum or forceps), anesthesia mode (general, spinal, or none), and complications during pregnancy (gestational diabetes mellitus [GDM], HDP, HF, arrhythmia, obstetric complications, and others). GDM was diagnosed using the modified criteria of the International Association of Diabetes and Pregnancy Study Groups according to the general diagnostic method in Japan.30,31 In Japan, hypertension that develops during pregnancy was previously known as pregnancy-induced hypertension (PIH), but in 2018, it was revised to HDP to define and classify diseases reflecting the prognosis of both the mother and the baby. HDPs have been newly classified into four disease types: (1) preeclampsia, (2) gestational hypertension, (3) superimposed preeclampsia, and (4) chronic hypertension. In HDP, the definition of hypertension is blood pressure ≥140/90 mmHg, and the definition of proteinuria is ≥300 mg/24 h or a protein/creatinine ratio >0.3 mg/mg in spot urine.32,33 Patients diagnosed with “arrhythmia” included atrial arrhythmias (premature atrial contraction, atrial fibrillation [AF], atrial tachycardia, and paroxysmal supraventricular tachycardia [PSVT]), ventricular arrhythmias (premature ventricular contraction [PVC] and ventricular tachycardia), and severe sinus tachycardia and bradycardia.
HF was defined by ≥10% reduction in systemic ventricular EF, ≥100 pg/mL elevation in brain natriuretic peptide (BNP) levels, or deterioration of valvular disease during pregnancy, which required intervention. Depending on the medication during pregnancy, women were classified into the α/β-blocker group (those who were prescribed carvedilol), the β-blocker group (those who were prescribed bisoprolol, propranolol, atenolol, metoprolol, or nadolol), and the control group (who did not take any of the α/β-blockers and β-blockers). The α/β- and β-blocker groups included patients who were administered α/β- or β-blockers before pregnancy and those who were first introduced to α/β- or β-blockers during pregnancy, respectively. For patients who took α/β- or β-blockers before pregnancy, the administration period was calculated from the date of establishment of pregnancy to that of delivery or discontinuation (whichever occurred first). The cumulative dose was calculated from the period and the daily dose. We also collected data on neonatal birth weight, Apgar score (1 and 5 min), umbilical artery pH, heart rate (when entering the neonatal intensive care unit [NICU] or neonatal room), hypoglycemia at birth, SGA, and CHD.
Cardiovascular DiseaseThe maternal cardiovascular diseases were divided into six groups: (1) CHD and pulmonary hypertension (PH); (2) aortic disease (including Marfan syndrome); (3) valvular disease; (4) coronary artery disease and acute coronary syndrome; (5) cardiomyopathy and HF; and (6) arrhythmia based on the European Society of Cardiology (ESC) guidelines.34 The CHD and PH group included patients with atrial septal defect, ventricular septal defect, atrioventricular septal defect, coarctation of the aorta, tetralogy of Fallot (TOF), transposition of the great arteries (TGA), congenitally corrected TGA, and Fontan circulation. The aortic disease group included patients with Marfan syndrome, aortic valve stenosis, including bicuspid aortic valve, aortic regurgitation, and arteritis. The valvular disease group included patients with mitral stenosis, mitral regurgitation, and pulmonary valve stenosis. The coronary artery disease and acute coronary syndrome group included patients with coronary artery aneurysm with Kawasaki disease, vasospastic angina, and anomalous left coronary artery from the pulmonary artery. The cardiomyopathy and HF group included patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), a history of myocarditis, and tachycardia-induced cardiomyopathy. The arrhythmia group included patients with bradyarrhythmias such as sick sinus syndrome and atrioventricular block and tachyarrhythmias such as Wolff-Parkinson-White syndrome, paroxysmal AF, PVC, and long QT syndrome (LQTS).
Neonatal Hypoglycemia and SGANeonatal blood glucose levels were measured within 1 h after birth in all cases of premature birth, infants weighing less than 2,500 g, small for dates, heavy for dates, and concomitant GDM. According to our NICU criteria, hypoglycemia was defined as a blood glucose level <30 mg/dL in low-birth-weight infants and a blood glucose level <40 mg/dL in mature infants. The infants’ birth weights were evaluated using the new standard value of physique at birth by gestational age proposed by the Neonatal Committee of the Japanese Society of Pediatrics in 2010.35 This standard value is based on information regarding 143,370 newborns obtained from 147 institutions from 2003 to 2005, excluding multiple births, stillbirths, hydrops fetalis, severe congenital malformations, gestational age, sex unknown, children born after 42 weeks of gestation, and children whose measured values at birth were clearly outliers. All babies born in Japan after January 1, 2011 were evaluated using this standard value.
Statistical AnalysisData are expressed as the means±standard deviations or percentages. Continuous and categorical variables were compared between the groups using the Kruskal-Wallis test. If there was a significant difference in the Kruskal-Wallis test, the Tukey-Kramer test was added. In the results of the Tukey-Kramer test described in the tables, the α/β-blocker group was defined as group A, the β-blocker group was defined as group B, and the control group was defined as group C. In addition, multivariable logistic regression analysis was performed in three groups to assess the risk of neonatal hypoglycemia and SGA. All statistical analyses were performed using SPSS Statistics (version 25.0; IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05.
Of 306 pregnancies, 32 were in the α/β-blocker group, 11 were in the β-blocker group, and 263 were in the control group. The maternal backgrounds are summarized in Table 1. There were no between-group differences regarding maternal age. Regarding the type of cardiac disease, there were fewer cases of CHD and PH in the β-blocker group than in the control group (P=0.002), and there were significantly more cardiomyopathy and HF patients in the α/β-blocker group than in the control group (P=0.002). In contrast, the number of cases of arrhythmia was higher in the β-blocker group than in the other two groups (P<0.001). The number of patients taking medications other than α/β-blockers or β-blockers was significantly higher in the α/β-blocker group than in the control group (P<0.001), including angiotensin-converting enzyme (ACE) inhibitors, diuretics, and antiplatelet drugs. ACE inhibitors were discontinued when pregnancy was confirmed in the patients. The number of NYHA class cases was significantly higher in the α/β-blocker group than in the control group (P=0.025), which was more common in patients with cardiomyopathy. Regarding surgical history, 75.9% of patients in the α/β-blocker group had undergone intracardiac repair, which was a significantly higher percentage than that in the β-blocker group (P=0.010). The number of patients undergoing cardioverter defibrillator implantation was significantly higher in the β-blocker group than in the other two groups (P=0.001).
| α/β-blocker group (A) n=32 |
β-blocker group (B) n=11 |
Control group (C) n=263 |
Kruskal-Willis P value |
Tukey-Kramer P value | |||
|---|---|---|---|---|---|---|---|
| (A)–(B) | (A)–(C) | (B)–(C) | |||||
| Maternal age, years | 33.0±4.3 | 33.6±5.5 | 33.0±4.6 | 0.968 | – | – | – |
| BMI | 23.1±2.5 | 23.1±1.8 | 23.8±2.7 | 0.332 | – | – | – |
| Smoking | 0 | 0 | 1.5 (4) | 0.719 | – | – | – |
| Type of cardiac disease, % (n) | |||||||
| CHD and PH | 56.3 (18) | 18.2 (2) | 44.5 (117) | *0.002 | 0.056 | 0.424 | *0.002 |
| Aortic disease | 9.4 (3) | 9.1 (1) | 6.5 (17) | 0.792 | – | – | – |
| Valvular disease | 0 | 0 | 10.6 (28) | 0.081 | – | – | – |
| CAD and ACS | 6.3 (2) | 0 | 2.3 (6) | 0.356 | – | – | – |
| Cardiomyopathy and HF | 15.6 (5) | 9.1 (1) | 2.7 (7) | *0.002 | 0.614 | *0.002 | 0.544 |
| Arrhythmia | 12.5 (4) | 63.6 (7) | 9.1 (24) | *<0.001 | *<0.001 | 0.823 | *<0.001 |
| Other | 0 | 0 | 1.5 (4) | 0.719 | – | – | – |
| Medication other than α/β-blocker or β-blocker, % (n) | |||||||
| All medication | 53.1 (17) | 54.5 (6) | 10.6 (28) | *<0.001 | 0.078 | *<0.001 | 0.253 |
| Diuretics | 3.1 (1) | 18.1 (2) | 0.4 (1) | *<0.001 | *<0.001 | 0.372 | *<0.001 |
| NYHA class before pregnancy, % (n) | |||||||
| Class I | 87.5 (28) | 100.0 (11) | 97.0 (255) | *0.027 | 0.154 | *0.025 | 0.865 |
| Class II | 12.5 (4) | 0 | 3.0 (8) | *0.027 | 0.154 | *0.025 | 0.865 |
| Class III | 0 | 0 | 0 | – | – | – | – |
| Class IV | 0 | 0 | 0 | – | – | – | – |
| Surgical history, % (n) | |||||||
| ICR | 75.9 (22) | 25.0 (2) | 51.0 (134) | *0.011 | *0.010 | 0.095 | 0.102 |
| PMI | 9.4 (3) | 0 | 2.3 (6) | 0.069 | – | – | – |
| ICD | 3.1 (1) | 18.2 (2) | 0 | *<0.001 | *<0.001 | 0.171 | *<0.001 |
Data are percentage (number). ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CHD, congenital heart disease; HF, heart failure; ICD, implantable cardioverter defibrillator; ICR, intracardiac repair; NYHA, New York Heart association; PMI, pace maker implantation. *P<0.05.
All 32 pregnancies in the α/β-blocker group were treated with carvedilol (0.3125–30 mg/day). The administration period of carvedilol was 194.4±91.3 days, and the cumulative dose of carvedilol was 1,474.5±1,760.5 mg. No patients received labetalol. CHD accounted for 56.3% of the α/β-blocker group, including three cases after the Fontan procedure (tricuspid atresia [2], single right ventricle [1]), seven cases of TGA after intracardiac repair (atrial switch [5], Rastelli [1], and Jatene procedures [1]), and two cases of congenitally corrected TGA after the double-switch procedure. These patients were given an α/β-blocker because of an increased risk of atrial arrhythmia, systemic ventricular dysfunction, or both. Cardiomyopathy cases included DCM in three cases and HCM in one.
The breakdown of the β-blocker group was as follows: bisoprolol was administered in four cases (1.25–5.00 mg/day), propranolol in three (30–60 mg/day), atenolol in two (30–50 mg/day), and metoprolol (120 mg/day) and nadolol (60 mg/day) in one case each. Bisoprolol was administered for total anomalous pulmonary venous return, Marfan syndrome, HCM, and LQTS in one patient each, while propranolol was administered to LQTS in two and catecholaminergic polymorphic ventricular tachycardia (CPVT) in one. Atenolol was administered for atrial tachycardia suppression in a patient with congenital tricuspid valve regurgitation and another with LQTS. Metoprolol was administered to a patient with CPVT, and nadolol was administered to a patient with LQTS.
Maternal OutcomesTable 2 describes the maternal outcomes. Gestational age was significantly shorter in the α/β-blocker group than in the other two groups (P<0.001). As for the mode of delivery, the α/β-blocker group had more cesarean sections (C/S; P<0.001) and less normal vaginal delivery (P<0.001) than the control group. Concomitantly, general anesthesia was applied predominantly in the α/β-blocker group compared to the control group (P<0.001). As complications during pregnancy, arrhythmia occurred significantly in each of the α/β- (P<0.001) and β-blocker groups (P=0.016) compared to the control group. There were no between-group differences in the incidences of GDM and HDP. One patient in the β-blocker group had HDP compared to eight patients in the control group. Of the HDP patients in the control group, two patients had preeclampsia and six had gestational hypertension.
| α/β-blocker group (A) n=32 |
β-blocker group (B) n=11 |
Control group (C) n=263 |
Kruskal-Willis P value |
Tukey-Kramer P value | |||
|---|---|---|---|---|---|---|---|
| (A)–(B) | (A)–(C) | (B)–(C) | |||||
| Gestational age, weeks | 30.8±5.3 | 35.7±2.5 | 35.4±4.7 | *<0.001 | *0.018 | *<0.001 | 0.965 |
| Primiparity, % (n) | 56.3 (18) | 72.7 (8) | 62.7 (165) | 0.599 | – | – | – |
| Delivery mode, % (n) | |||||||
| Cesarean | 93.8 (30) | 72.7 (8) | 52.1 (137) | *<0.001 | 0.498 | *<0.001 | 0.290 |
| Cardiovascular indication | 96.7 (29) | 100.0 (8) | 65.0 (89) | – | – | – | – |
| Obstetrics indication | 3.3 (1) | 0 | 33.6 (46) | – | – | – | – |
| Fetal indication | 0 | 0 | 1.5 (2) | – | – | – | – |
| Painless | 6.3 (2) | 9.1 (1) | 12.5 (33) | 0.559 | – | – | – |
| Cardiovascular indication | 100.0 (2) | 100.0 (1) | 51.5 (17) | – | – | – | – |
| Obstetrics indication | 0 | 0 | 0 | – | – | – | – |
| Fetal indication | 0 | 0 | 1.1 (3) | – | – | – | – |
| Patients’ request | 0 | 0 | 39.4 (13) | – | – | – | – |
| Normal vaginal | 0 | 9.1 (1) | 33.1 (87) | *<0.001 | 0.826 | *<0.001 | 0.183 |
| Vacuum or forceps | 0 | 9.1 (1) | 2.3 (6) | 0.221 | – | – | – |
| Anesthesia mode, % (n) | |||||||
| General | 31.3 (10) | 9.1 (1) | 6.8 (18) | *<0.001 | 0.068 | *<0.001 | 0.964 |
| Spinal | 68.8 (22) | 72.7 (8) | 57.4 (151) | 0.304 | – | – | – |
| None | 0 | 18.2 (2) | 35.7 (94) | *<0.001 | 0.484 | *<0.001 | 0.418 |
| Complications during pregnancy, % (n) | |||||||
| GDM | 6.3 (2) | 0 | 9.1 (24) | 0.507 | – | – | – |
| HDP | 0 | 9.1 (1) | 3.0 (8) | 0.297 | – | – | – |
| HF | 15.6 (5) | 0 | 6.1 (16) | 0.087 | – | – | – |
| Arrhythmia | 25.0 (8) | 18.2 (2) | 1.5 (4) | *<0.001 | 0.579 | *<0.001 | *0.016 |
| Obstetric complication | 9.4 (3) | 0 | 11.0 (29) | 0.494 | – | – | – |
Data are mean±SD or percentage (number). GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; HF, heart failure. *P<0.05.
Table 3 shows the neonatal outcomes. The weight of the infants in the α/β-blocker group was significantly lower than those in the control group (P<0.001). In the α/β-blocker group, which had more general anesthesia, there were more sleeping babies; therefore, the 1- and 5-min Apgar scores in this group were significantly lower than those in the other two groups (P<0.001). Although there were no significant between-group differences regarding the umbilical artery’s pH and neonatal heart rate, the incidence of hypoglycemia was higher in the α/β-blocker group than in the control group (P=0.025). Glucose was promptly injected intravenously into neonates with hypoglycemia, and none of the children’s prognoses were impacted due to hypoglycemia. On the contrary, SGA was observed significantly more frequently in the β-blocker group than in the other two groups (P<0.001). Neither the α/β-blocker group nor the β-blocker was involved in the prevalence of CHD in infants.
| α/β-blocker group (A) n=32 |
β-blocker group (B) n=11 |
Control group (C) n=263 |
Kruskal-Willis P value |
Tukey-Kramer P value | |||
|---|---|---|---|---|---|---|---|
| (A)–(B) | (A)–(C) | (B)–(C) | |||||
| Birth weight, g | 2,299.6±586.5 | 2,451.9±387.9 | 2,712.2±539.5 | *<0.001 | 0.699 | *<0.001 | 0.262 |
| Apgar score (1 min) | 5.8±2.9 | 8.1±0.5 | 7.7±1.7 | *<0.001 | *<0.001 | *<0.001 | 0.750 |
| Apgar score (5 min) | 7.1±2.4 | 8.9±0.3 | 8.6±1.1 | *<0.001 | *<0.001 | *<0.001 | 0.749 |
| Umbilical artery pH | 7.31±0.05 | 7.30±0.08 | 7.30±0.08 | 0.654 | – | – | – |
| Heart rate, bpm | 133.4±11.4 | 126.8±14.1 | 133.6±12.3 | 0.337 | – | – | – |
| Hypoglycemia, % (n) | 54.5 (12) | 27.3 (3) | 14.4 (38) | *0.028 | 0.826 | *0.025 | 0.642 |
| SGA, % (n) | 12.5 (4) | 25.5 (5) | 6.0 (15) | *<0.001 | *0.002 | 0.458 | *<0.001 |
| CHD, % (n) | 9.4 (3) | 9.1 (1) | 2.7 (7) | 0.057 | – | – | – |
Data are mean±SD or percentage (number). CHD, congenital heart disease; SGA, small for gestational age. *P<0.05.
Next, we examined the relationship between hypoglycemia and the timing of α/β-blocker treatment in the α/β-blocker group (Figure 1). Although most patients had been on α/β-blockers before pregnancy, only seven cases were administered α/β-blockers during pregnancy due to increased BNP or ventricular arrhythmia (PVC or nonsustained ventricular tachycardia). There was no difference in the development of hypoglycemia in infants between the group who received continuous α/β-blockers before pregnancy and those who were administered α/β-blocker during pregnancy (P=0.535). Similarly, we examined the relationship between SGA and the timing of β-blocker treatment in the β-blocker group; five patients in this group developed SGA, and all were administered β-blocker therapy before pregnancy. Only one patient was administered β-blocker therapy during pregnancy. The small number of patients prevented us from statistically examining SGA and the timing of β-blocker treatment initiation. Although most patients had been on β-blockers before pregnancy, only one case with Marfan syndrome was administered β-blocker during pregnancy due to PSVT. There was no difference in the development of SGA in infants between the group who received continuous β-blockers before pregnancy and those who were administered β-blocker during pregnancy (P=0.545).
Relationship between hypoglycemia and the timing of α/β-blocker treatment in the α/β-blocker group.
Figure 2A and 2B show the relationship between hypoglycemia and the administration period of α/β-blocker and the cumulative α/β-blocker dose. There was no clear association between hypoglycemia and the administration period of α/β-blocker (P=0.173) and the cumulative dose of α/β-blocker (P=0.902). Identically, Figure 2C show the relationship between SGA and the administration period of β-blocker. There was no clear association between SGA and the administration period of β-blocker (P=0.121).
(A) Relationship between hypoglycemia and the administration period of α/β-blocker in the α/β-blocker group. (B) Relationship between hypoglycemia and the cumulative α/β-blocker dose in the α/β-blocker group. (C) Relationship between small for gestational age (SGA) and the administration period of β-blocker in the β-blocker group.
The main findings of this study are summarized as follows: (1) the incidence of neonatal hypoglycemia was higher in pregnant women taking carvedilol than in the control group (P=0.025). (2) There was no clear association between hypoglycemia and the carvedilol start time (P=0.535), the administration period of carvedilol (P=0.173), and the cumulative dose of carvedilol (P=0.902). (3) SGA was observed significantly more frequently in pregnant women taking β-blockers (bisoprolol, propranolol, atenolol, metoprolol, and nadolol) than in the carvedilol and control groups (P<0.001). To the best of our knowledge, this is the first study to show that the administration period and cumulative dose of carvedilol do not affect neonatal hypoglycemia.
The United States Food and Drug Administration (FDA) changed the previously used classification system for counseling pregnant women and nursing mothers requiring drug therapy in 2015. The former A-X categories have been replaced by the Pregnancy and Lactation Labelling Rule, which provides a descriptive risk summary and detailed information on animal and clinical data. The 2018 ESC guidelines for managing cardiovascular diseases during pregnancy also included the former A-X categories (ranging from “safest” [A] to “known danger: do not use!” [Z]), because they would be present in the literature for a more extended period.34 Bisoprolol, carvedilol, labetalol, metoprolol, nadolol, and propranolol are classified as category C (no well-controlled studies have been conducted in humans; animal studies have demonstrated an adverse effect on the fetus), and only atenolol is classified as category D (evidence of human risk exists; however, the benefits may outweigh the risks in certain situations) in the former FDA categories. In the ESC guidelines, carvedilol is described as having “no adequate human data regarding bradycardia and hypoglycemia in the fetus; use only if the potential benefit outweighs the potential risk.” All β-blockers, such as bisoprolol and propranolol, are listed as causing “bradycardia and hypoglycemia in the fetus.34 ”
Although α/β- and β-blockers are associated with neonatal hypoglycemia and SGA,14–19 other than labetalol and atenolol, which are often used for HDP,9–13 data are limited regarding their effects in pregnant women and fetuses.18,26
Bateman et al suggested that the risk of neonatal hypoglycemia associated with β-blockers was inconclusive, with a wide confidence interval (CI) in the pooled estimate (relative risk, 0.81; 95% CI, 0.44–1.49) and argued that labetalol exposure is associated with a 1.8-fold increased risk of hypoglycemia.19 Although it is well known that β-blockers affect glucose and lipid metabolisms, no studies have described the mechanism by which β-blockers cause neonatal hypoglycemia. Vasodilating β-blockers (carvedilol, labetalol, and nebivolol) are known to have more favorable effects on glucose and lipid profiles than non-vasodilating β-blockers (atenolol, metoprolol, and propranolol).36 Additionally, differences in each drug’s placental permeability and the number of patients studied may have contributed to the results of a previous study in which carvedilol caused neonatal hypoglycemia and other β-blockers did not.
Tanaka et al reported that neonatal hypoglycemia 2 h after birth was evident 2 of 13 (15%) cases in which the mother was taking carvedilol;27 however, in the present study, an intravenous line containing 10% glucose was routinely placed in all low-birth-weight and preterm newborns soon after birth. Thus, they pointed out that the neonatal hypoglycemia rate might not be accurate.27 All children with hypoglycemia in this study were immediately treated with glucose solution, and none had any residual long-term sequelae. Although the literature on the effects of neonatal hypoglycemia on long-term neurodevelopment is limited, brain imaging studies have suggested that the developing brain may be vulnerable to hypoglycemia.37,38 Therefore, our findings suggest that the routine monitoring of blood glucose levels in newborns exposed to α/β- and β-blockers is essential.
Our findings also suggest that taking carvedilol during pregnancy may cause neonatal hypoglycemia. The infants from the α/β-blocker group showed significantly lower birth weight than the control group, and even after adjusting for SGA, we found a significantly increased risk of neonatal hypoglycemia in the α/β-blocker group, confirming the known premise that low birth weight infants are prone to neonatal hypoglycemia.39 Similarly, after adjusting for GDM, we yet again found that carvedilol significantly increased the risk of neonatal hypoglycemia. However, after adjusting for preterm birth, the significance of carvedilol was no longer observed. Therefore, we consider that preterm birth may have affected the risk of neonatal hypoglycemia.
A search of the PubMed database using the words “pregnancy,” “carvedilol,” and “neonatal hypoglycemia” yielded no results for studies that discussed the relationship between the administration period and cumulative dose of carvedilol and neonatal hypoglycemia. Our study showed that the timing of carvedilol administration, carvedilol administration period, and cumulative carvedilol dose were not associated with neonatal hypoglycemia. Although further research is needed, our data suggest that it would be beneficial to use a sufficient dose of carvedilol to prevent the deterioration of heart disease in pregnant women, given that appropriate attention is paid to neonatal hypoglycemia.
Regarding the relationship between SGA and HDP, several articles reported an association between mean treatment-induced falls in mean arterial pressure (MAP) and impaired fetal growth, arguing that this relationship could not be explained by the type of hypertension, type of antihypertensive agent, or mean therapy duration since none of these were related to mean difference in MAP.20–22
Although there is little data on the association between β-blockers (other than atenolol) and SGA, a prospective observational cohort study was reported in Germany for bisoprolol. A comparison of the 339 patients in the bisoprolol cohort group with the 678 patients in the control group reported no increased risk of spontaneous abortions and fetal malformations but a high probability of preterm birth and SGA.26 On the contrary, Tanaka et al argued that SGA was observed in the propranolol, metoprolol, and atenolol groups; however, no SGA was observed with bisoprolol administration in five patients.27 Our study included four cases administered bisoprolol, three cases administered propranolol, two cases administered atenolol, one case administered metoprolol, and one case administered nadolol; however, similar to the report by Tanaka et al,27 the number of cases was too small to discuss the differences between the types of β-blockers. In any case, β-blockers have been suggested to be associated with SGA, which should be noted. Even after adjusting for HDP, GDM, and maternal heart disease, the results of the multivariate analysis indicated that the use of β-blockers increased the risk of SGA.
Previous studies have reported that β-blockers are associated with neonatal bradycardia and congenital malformations,19,40,41 but in this study, neonatal bradycardia and congenital malformations were not observed in either the α/β-blocker group or the β-blocker group.
Study LimitationsThis study’s limitations include its single-center, retrospective design and the small number of patients included in the analysis. In addition, we had insufficient information regarding maternal cardiac disease, such as indices of CO other than LVEF and the severity of cyanosis, to be able to examine the possibility that these factors affected neonatal hypoglycemia and SGA. Furthermore, outcomes from our tertiary center with high-volume care for CHD cannot necessarily be extrapolated to other settings. However, we believe that our cohort is representative of contemporary tertiary practice.
Our study demonstrated that carvedilol administration in pregnant women was associated with neonatal hypoglycemia; however, this did not occur in a time- or dose-dependent manner. No hypoglycemic newborns with long-term residual sequelae were observed, and the routine monitoring of blood glucose levels in newborns exposed to α/β- and β-blockers is essential. Conversely, SGA was observed significantly more frequently in pregnant women taking β-blockers (bisoprolol, propranolol, atenolol, metoprolol, and nadolol) than in the carvedilol and control groups. However, we believe that if the benefits outweigh the risks of fetal complications, pregnant women with heart disease should be given α/β- or β-blockers without hesitation. Information on α/β- and β-blockers for pregnant women with heart disease is still insufficient; thus, further accumulation of cases is warranted in the future.
Not applicable.
None.
The authors declare no conflict of interest. K.I. is a member of Circulation Journal’s Editorial Team.
Institutional review board of Tokyo Women’s Medical University (Approval Number: 2021-0203).
The deidentified participant data will not be shared.
