The Risk for Neonatal Hypoglycemia and Bradycardia after Beta-Blocker Use during Pregnancy or Lactation: A Systematic Review and Meta-Analysis

Beta-blockers are often used during pregnancy to treat cardiovascular diseases. The described neonatal side effects of maternal beta-blocker use are hypoglycemia and bradycardia, but the evidence base for these is yet to be evaluated comprehensively. Hence, this systematic review and meta-analysis was performed to evaluate the potential increased risk for hypoglycemia and bradycardia in neonates exposed to beta-blockers in utero or during lactation. A systematic search of English-language human studies was conducted until 21 April 2021. Both observational studies and randomized controlled trials investigating hypoglycemia and/or bradycardia in neonates following beta-blocker exposure during pregnancy and lactation were included. All articles were screened by two authors independently and eligible studies were included. Pair-wise and proportion-based meta-analysis was conducted and the certainty of evidence (CoE) was performed by standard methodologies. Of the 1.043 screened articles, 55 were included in this systematic review. Our meta-analysis showed a probable risk of hypoglycemia (CoE—Moderate) and possible risk of bradycardia (CoE—Low) in neonates upon fetal beta-blocker exposure. Therefore, we suggest the monitoring of glucose levels in exposed neonates until 24 h after birth. Due to the limited clinical implication, monitoring of the heart rate could be considered for 24 h. We call for future studies to substantiate our findings.


Introduction
Beta-blockers are often used antihypertensive agents during pregnancy to treat preexisting hypertension, pregnancy induced hypertension, pre-eclampsia and tachyarrhythmia. Labetalol and metoprolol are the most prescribed beta-blockers during pregnancy and lactation [1]. As most beta-blockers are known to cross the placenta, their in-utero exposure may affect the condition of the fetus during pregnancy or of the neonate after birth [2,3]. Previous studies have shown that the maternal use of beta-blockers is not associated with a large increase in the risk for either overall malformations or cardiac malformations for the neonate [4,5]. However, it is unknown whether exposure to beta-blockers in utero considerably increases the risk for neonatal side effects such as bradycardia or hypoglycemia. Moreover, some beta-blockers have been found in breast milk [6], which may lead to potential negative effects in the neonate as well. However, the degree of excretion of different beta-blockers into breast milk is dependent on their individual pharmacokinetic characteristics [7]. Beta-blockers such as labetalol and propranolol pass into breastmilk in low concentrations [8,9], while atenolol reaches a relatively higher breastmilk concentration [10]. The question arises as to whether beta-blocker exposure is safe for the neonate.

Mechanisms of Action and Potential Risks
Beta-blockers inhibit the beta-1 and beta-2 receptors resulting in a decrease in heart rate and heart contractility causing a lower blood pressure [11]. Maintaining heart rate within the normal range is vital during the neonatal period as their myocardium has a limited ability to compensate in response to bradycardia by virtue of increasing the stroke volume. Therefore, beta-blocker exposure in utero and through lactation could potentially harm the neonate by decreasing heart rate, which hypothetically could cause decreased cardiac output, blood pressure and eventually organ perfusion and growth. Moreover, betablockers cause inhibition of the glycogenolysis through the activation of the sympathetic nervous system [11], which could lead to hypoglycemia. In neonates, hypoglycemia is potentially dangerous, since severe or prolonged hypoglycemia can result in significant insult to the developing brain [12,13].
Therefore, it is important to evaluate the risks associated with exposure to betablockers in utero or through lactation for the outcomes of bradycardia and hypoglycemia in neonates. In the case of a distinctly increased risk for the neonate, glucose and/or heartrate monitoring are needed and may require prolonged hospital admission in order to detect and treat these potentially harmful side effects. On the other hand, if the risk for hypoglycemia or bradycardia is not increased, the neonate may not require admission for monitoring, thus mitigating the need for a longer hospital stay and exposure to painful blood collection procedures for glucose tests.

Aim of the Study
The aim of this systematic review and meta-analysis was to evaluate the risk of hypoglycemia and bradycardia in neonates exposed to beta-blockers in-utero or through lactation in comparison with neonates without any beta-blocker exposure in order to assess the need of postnatal observation including heartrate and glucose monitoring. With this systematic review clinicians can make a better risk-benefit judgement for the use of beta-blockers during pregnancy and lactation.

Protocol and Registration
The methods of this systematic review and meta-analysis were specified in our protocol (submitted after minor revision) and registered in PROSPERO (CRD42021264269) on 27 July 2021. The PRISMA 2009 [14] reporting checklist was used.

Patient and Public Involvement
There was no patient or public involvement in the whole process of conducting this research.

Eligibility Criteria
The following inclusion criteria were applied on the articles (including abstracts) resulting from our search:

1.
Randomized controlled trials, case series, case reports and observational studies reporting the adverse effects of beta-blockers exposure during pregnancy and lactation on the neonate; 2.
The described effect on the neonate should focus on hypoglycemia and/or bradycardia (the chosen cut-off value for hypoglycemia and bradycardia could vary between studies); 3.
Studies in human subjects.
Articles were excluded when they met the following criteria:

5.
Articles studying only the effect of the disease of the mother on the neonate; 6.
Studies on the effect of beta-blockers on only the fetus and not the neonate; 7. Reviews and editorials; 8.
Letters to the Editor.

Information Sources
Electronic database searches were used to identify studies for this systematic review. A search strategy was developed in consultation with a professional librarian of the Erasmus Medical Center, using the following electronic databases: EMBASE, Medline, Cochrane Central Register of Trials and Web of Science. English-language human studies published since the inception of the databases until 21 April 2021 were included. See the Supplemental File for the search strategy and hits.

Search Strategy
Search terms on the following subjects were included (1) beta-blockers, (2) pregnancy or lactation and (3) the effect on the neonate in terms of hypoglycemia and bradycardia. Search terms in MEDLINE included, for instance, 'beta adrenergic receptor blocking agent/exp', 'hypoglycaemia/de', 'bradycardia/exp', 'perinatal drug exposure' and 'lactation/de' (see Supplemental File for the complete search strategies).

Study Selection
Two members of the study team independently reviewed the articles based on title and abstract using the above-described inclusion and exclusion criteria (RB and SF). After a selection based on the title and abstract, two reviewers independently read the full text of the selected articles (RB and SD). Any identified discrepancies between the reviewers were resolved through evaluation and discussion by GB and RF when necessary. Extracted information included the number of participants, participant demographics, study population, study design, outcome (hypoglycemia and/or bradycardia), treatment indication and type and dosage of the beta-blocker. The number of articles meeting the inclusion criteria was recorded and the reasons for exclusion were documented in accordance with the PRISMA guidelines [14].

Data Collection Process
Two authors (RB and SD) extracted the data from included studies and three other authors performed a check on all extracted data (SF, GB and VR). Disagreements were resolved by discussion between the review authors. If no agreement could be reached, the senior researchers decided (GB, RF).

Data Items
Data were extracted from each included study on (1) the characteristics of trial participants (including treatment indication, participant demographics), (2) the type and dosage of the beta-blocker (beta-blocker versus placebo or versus another antihypertensive agent or beta-blocker versus beta-blocker), and (3) the outcome measure (including hypoglycemia and/or bradycardia).

Risk of Bias Assessment
The Cochrane risk of bias tool version 2.0 was used for randomized controlled trials (RCTs) [15] and Risk Of Bias in Non-randomized Studies of intervention (ROBINS-I) for non-RCTs [16]. Two authors (VR, GB) assessed the risk of bias independently and disagreements were resolved by consulting a third author (RF). The quality of case reports was evaluated using the Checklist for Case Reports by the Joanna Briggs Institute (JBI) [17]. The quality of case series was evaluated using the Checklist for Case Series by the JBI [18]. Two authors (RB, RF) assessed the risk of bias for case reports and case series independently and disagreements were resolved by consulting a third author (GB).

Certainty of Evidence Assessment
Grading of Recommendations, Assessment, Development and Evaluations (GRADE) were used for the Certainty of Evidence (CoE) [19][20][21]. CoE was classified into four categories, namely high, moderate, low and very low. The findings of the systematic review are reported as per a modified GRADE working group recommendation [22] (Table 1).  [23]. Meta-analysis was performed by the Mantel Haenszel method and the inverse variance method for dichotomous outcomes and continuous outcomes, respectively. Heterogeneity was assessed using Cochran Q, I 2 and τ 2 values. A random effects model was utilized if the I 2 value was >50%, and if it was ascertained that the large I 2 values were not due to differences between small and large magnitude of the effect estimates. Else, a fixed effect model was utilized. A random effects meta-analysis of proportions with the Freeman-Tukey Double arcsine transformation was also used.

Study Selection
The PRISMA flow is shown in Figure 1, starting with 1462 identified articles from our search in EMBASE, Medline, Cochrane Central Register of Trials and Web of Science. After removal of duplicates, 1043 articles remained. Screening the titles and abstracts using the inclusion and exclusion criteria led to excluding 911 articles. Subsequently, 132 articles were screened based on the entire content of the article. The reviewers (RB, SD, SF) had discrepancies about four articles [24][25][26][27] and these were resolved through evaluation and discussion by GB and RF. Two of these [26,27] articles were included. The two excluded articles [24,25] did not report sufficiently on the occurrence of hypoglycemia and bradycardia in neonates exposed to beta-blockers in utero or through lactation. Two articles were not electronically available and were therefore excluded as well. This led to a total of 776 articles being excluded and 55 articles being included in this systematic review, of which 15 are case reports. Table 2 shows the details of 40 of the included studies. The 15 case reports are described in Section 3.6. All included studies provided information about possible neonatal effects after in utero exposure or through lactation. Few studies provided information about the neonatal outcome after beta-blocker use during lactation; see paragraph 3.5. Moreover, Table 3 shows the type and dosage of the used beta-blocker in each study. The case reports were not included in the meta-analysis. Furthermore, two other studies were excluded from the meta-analysis since these focused on the short-term use of beta-blockers during pregnancy for the induction of anesthesia or labor instead of its use for cardiovascular diseases [28,29].

Hypoglycemia and bradycardia
Davis RL, 2011 [39] Women older than 15 years delivering an infant, who had been continuously enrolled with prescription drug coverage for ≥1 year prior to delivery n = 584 cases (full-term infants exposed to beta blockers), n = 804 controls (full-term infants exposed to calcium-channel blockers) and >75,000 unexposed infants

United States Cohort study
To study risks for perinatal complications and congenital defects among infants exposed to beta blockers in utero Not described in article Hypoglycemia    To investigate atenolol's ability to cross the human placental barrier and to study the excretion of atenolol in breast milk.

Hypertension in pregnancy Bradycardia
Livingstone I, 1983 [55] Pregnancy-associated hypertension treated with propranolol or methyldopa n = 14 cases and n = 14 controls Australia RCT To compare propranolol with methyldopa in hypertensive pregnancy A blood pressure of 140/90 or above, on two consecutive readings at least twenty-four hours apart.

Hypoglycemia and bradycardia
Dubois D, 1983 [26] High-risk pregnancies with hypertension using beta blockers n = 125 France Case series To investigate the outcome of beta blocker use in high-risk pregnancies

Hypertension in pregnancy Hypoglycemia
Boutroy MJ, 1982 [56] Children born from hypertensive pregnant women treated with acebutolol n = 31 France Case series To determine the pharmacokinetics of acebutolol in the mother, as well as its placental transfer, and the pharmacokinetics in the fetus Chronic or pregnancy-associated hypertension, after failure of strict bed rest and methyldopa with or without hydralazine Bradycardia    [29] 2 mg Kayser A, 2020 [30] 1.25-10 mg/day 12-400 mg/day Kumar N, 2020 1,2 [31] Mazkereth R, 2019 2 [32] X X X Easterling T, 2019 [33] 200 mg/day (max. 600 mg/day) Thewissen L, 2017 [34] X Bateman BT, 2016 2 [35] X X X X X X X X X X Singh R, 2016 3 [58] 100-400 mg Garden A, 1982 [59] 200 mg Dumez Y, 1981 [60] 200-800 mg/day  [37]. 5 Davis RL et al. [39] did not mention the types of beta-blockers which they included in their study. 6 A 20 mg intravenous bolus dose was followed by 40 mg if not effective within 20 min, followed by 80 mg every 20 min up to a maximum dose of 300 mg (five doses) [40]. 7 Before induction of anesthesia, 20 mg of labetalol was administered intravenously as a bolus followed by 10 mg increments every 2 min until the diastolic blood pressure was below 100 mmHg or the mean arterial pressure fell by 20% from baseline values [28]. 8 The dosage of the drug was altered as clinically indicated to maintain a sitting diastolic BP at or below 80 mm Hg [63].
Abbreviations: Y = Yes; N= No; U = Unclear; N/A not applicable. Q1 Were patient's demographic characteristics clearly described? Q2 Was the patient's history clearly described and presented as a timeline? Q3 Was the current clinical condition of the patient on presentation clearly described? Q4 Were diagnostic tests or assessment methods and the results clearly described? Q5 Was the intervention(s) or treatment procedure(s) clearly described? Q6 Was the post-intervention clinical condition clearly described? Q7 Were adverse events (harms) or unanticipated events identified and described? Q8 Does the case report provide takeaway lessons? 1 This case report concerned a neonate in the first days of life. There was no information available about the neonates' medical history, previous treatment and past diagnostic test results. 2 This case report concerned a neonate in the first days of life. There was no information available about the patients' medical, family and psychosocial history (including relevant information, as well as relevant past interventions and their outcomes). 3 Diagnosis, treatment/medication and medical history of the mother were described, but not of the neonate.

Beta-Blocker vs. Control Group without a Beta-Blocker
Seven of the included articles [28,32,34,35,37,43,49] studied the heart rate of neonates exposed to a beta-blocker compared to a control group without beta-blocker exposure. These controls had mothers with hypertensive diseases and were exposed to antihypertensive drugs other than beta-blockers. However, in these studies not a specific other agent, such as methyldopa, was compared to the beta-blocker group. Two of these seven articles [32,35] showed that bradycardia occurred significantly more in neonates exposed to a beta-blocker in-utero. Mazkereth et al. [32] showed that 3.9% of the neonates of mothers treated with propranolol, labetalol or metoprolol experienced bradycardia, while bradycardia did not occur in the control group (p = 0.03). The six neonates with documented bradycardia were asymptomatic and were discharged following 24 h of non-bradycardic heart monitoring [32]. None of the neonates needed to be admitted to the neonatal intensive care unit [32]. Bateman et al. [35] observed a 30% increase in the risk of neonatal bradycardia in infants born to mothers using beta-blockers. The other five articles [28,34,37,43,49] showed no significant difference in the occurrence of bradycardia. In one of these studies the mother received labetalol solely as a short-term pretreatment for anesthesia prior to cesarean section [28].

Beta-Blocker vs. Placebo
One of four studies comparing a beta-blocker exposed group with a placebo group observed that bradycardia occurred more often in neonates exposed to atenolol when compared with the placebo group (39.1 vs. 10.3 %, p < 0.01) [53]. In none of the cases was treatment for bradycardia needed [53]. The three other studies did not find a significant difference between the beta-blockers exposed group and the placebo group [45,51,81].

Beta-Blocker vs. Methyldopa
Six articles [30,33,38,52,55,60] studied the difference in the heart rate of neonates exposed to either a beta-blocker or methyldopa in utero. One of these studies [60] found a significantly lower heart rate in neonates exposed to acebutolol when compared to those exposed to methyldopa (see Table 8) and therefore concluded that acebutolol has a longlasting neonatal hemodynamic effect. However, another study comparing acebutolol to methyldopa found no signs of bradycardia in both groups [52].

Beta-Blocker vs. Hydralazine
Three articles [40,47,59] studied the effects of beta-blockers compared to hydralazine on the heart rate of neonates after being exposed in utero. Vigil et al. [40] observed a significantly higher rate of bradycardia in neonates exposed to labetalol compared with neonates exposed to hydralazine. In the study of Garden et al. [59] all three infants in the labetalol group were born with a bradycardia compared to none of the three neonates who were exposed to hydralazine. All three infants in the labetalol group were growthretarded [59]. On the other hand, Mabie et al. [47] found no differences between both groups (40 cases labetalol vs. 20 hydralazine controls) regarding neonatal bradycardia.

No Control Group
Three articles [27,56,62] studied the effect of in utero exposure to beta-blockers on neonatal heart rate without comparison to a control group. Boutroy et al. [56] observed bradycardia, defined as a basal heart rate of less than 120 beats/minute and lasting longer than one hour, in twelve of the 31 neonates exposed to atenolol. O'Hare et al. [62] detected bradycardia, also defined as less than 120 beats/minute, in six of the twelve neonates who were exposed to sotalol in utero. The heart rate in these neonates was in a range from 90 to 120 beats/minute and stayed present for up to 25 h after birth in five neonates [62]. The neonates did not suffer from any negative symptoms of the bradycardia [62]. Another study [64] noted bradycardia in one of the twelve neonates exposed to propranolol in utero. This neonate was born only 29 min after the last dose of propranolol [64].   [64] Propranolol (no control group) 1/12 (8.3%) N N Abbreviations: N: is not described in article; NS: not significant; bpm: beats per minute. 1 PS-matched: Propensity scores were estimated using a logistic regression model in which exposure was the dependent variable and was estimated on the basis of 5 groups of potential confounders of the planned analysis: demographic characteristics, medical conditions, obstetrical conditions, maternal medications, and measures of healthcare use [35]. 2 As regards other outcome variables, namely, the Apgar score, respiratory and heart rate at delivery, hypoglycemia and jaundice during the first 24 h-the differences between the two treatment groups were inconsistent and non-significant [44]. 3 Hypotension, bradycardia and transient tachypnea were observed in one infant. The article does not describe if there were any other cases of bradycardia. 4 For the analyses, the material was divided into two categories. The first group gives data for all the 161 patients whom it was the intention to treat. In the calculation of cause-and-effect, 26 patients were withdrawn from the original group of 161: in 5 patients of C-group, DBP exceeded 110 mmHg and they were then treated with antihypertensive drugs; one patient in T-group admitted that she had not taken the prescribed drugs; 6 patients gave birth to malformed or stillborn children and their data were not used for the calculation of Apgar scores, birth weights or other vitality signs. Eight patients in the T-group and 6 in the C-group gave birth within 2 weeks after admission to the study, and these 14 women were excluded from the cause-and-effect analyses because of the short treatment period [50]. 5 One infant in the placebo group had a bradycardia in the first 12 h of life. The article does not describe if there were any other cases of bradycardia. 6 Bradycardia was only investigated in one of the seven infants [27]. At no time did this infant have bradycardia or any other clinical sign of beta-blockade [27].

Beta-Blocker vs. Control Group without a Beta-Blocker
Eight articles [28,32,35,37,39,41,43,49] studying the blood glucose levels in neonates compared a group exposed to beta-blockers with a control group of neonates non-exposed to beta-blockers in utero. Five out of these eight articles [32,35,39,41,43] showed a significantly higher risk for hypoglycemia in neonates exposed to beta-blockers in utero (Table 10). For example, in the article of Mazkereth et al. [32] hypoglycemia occurred more often in the beta-blocker exposed neonates than in the non-exposed neonates (30.7% vs. control 18.3%, p = 0.016). Darcie et al. [41] showed that 65% of the neonates who were exposed to beta-blockers in utero developed hypoglycemia when compared to only 28,5% of the non-exposed neonates in the control group (p < 0.05). Kumar et al. [31] found out that the odds of neonatal hypoglycemia are 1.75 times higher when the baby was exposed to beta-blockers in utero. Kumar et al. [31] reported that the risk for developing neonatal hypoglycemia was 3.15 times higher when the maternal beta-blocker usage was combined with maternal diabetes during pregnancy. The study of Ramanathan et al. [28] did not find an increased risk for hypoglycemia. However, in this study labetalol was prescribed for short-term use solely for the induction of anesthesia [28].

Beta-Blocker vs. Placebo
Four articles [29,44,45,53] compared neonates exposed in utero to beta-blockers with neonates exposed to a placebo. None of these articles found a significant difference regarding hypoglycemia between the two study groups. However, in the study of Bigelow et al. [29] mothers received propranolol solely short term for the induction of labor.

Beta-Blocker vs. Methyldopa
Seven articles [30,33,38,52,55,60,63] studied neonates born after in utero exposure to either a beta-blocker or methyldopa. Gallery et al. [63] showed that the blood sugar levels of neonates exposed to methyldopa in utero were significantly lower than those of neonates exposed to oxprenolol. None of the neonates in the oxprenolol group of this study were clinically hypoglycemic, meanwhile two neonates in the methyldopa group were clinically hypoglycemic [63]. The studies of Verma and Easterling et al. [33,38] showed no significant differences in neonatal hypoglycemia after labetalol or methyldopa exposure in utero.

Beta-Blocker vs. Hydralazine
Four articles [36,40,46,47] studied the difference in effect of in utero exposure to a beta-blocker and in utero exposure to hydralazine on neonates. None of these articles found a significant difference in occurrence of hypoglycemia in these neonates [36,40,46,47]. In the study of Ashe et al. [46] one neonate was diagnosed with hypoglycemia; however, this neonate was severely growth-retarded, which is a known risk factor for hypoglycemia.    [65] Propranolol (no control group) 0/22 (0%) N N N: is not described in article. NS: not significant. 1 PS-matched: Propensity scores were estimated using a logistic regression model in which exposure was the dependent variable and was estimated on the basis of 5 groups of potential confounders of the planned analysis: demographic characteristics, medical conditions, obstetrical conditions, maternal medications, and measures of healthcare use [35]. 2 Hypoglycemia was grouped under endocrine and metabolic disturbances specific to newborns, which included neonatal hypoglycemia [39]. 3 As regards other outcome variables, namely, the Apgar score, respiratory and heart rate at delivery, hypoglycemia and jaundice during the first 24 h-the differences between the two treatment groups were inconsistent and non-significant [44]. 4 Blood glucose levels were mostly within the normal reported range of 2.0-5.0 mmol/L for term infants, but they all tended towards the lower limit, with a range of 1.8-4.2 mmol/L, with a median of 3.2 mmol/l. No infant was clinically hypoglycemic at any time [49]. 5 For the analyses, the material was divided into two categories. The first group gives data for all the 161 patients for whom it was the intention to treat. In the calculation of cause-and-effect, 26 patients were withdrawn from the original group of 161: in 5 patients of C-group, DBP exceeded 110 mmHg and they were then treated with antihypertensive drugs; one patient in the T-group admitted that she had not taken the prescribed drugs; 6 patients gave birth to malformed or stillborn children and their data were not used for the calculation of Apgar scores, birth weights or other vitality signs. Eight patients in the T-group and 6 in the C-group gave birth within 2 weeks after admission to the study, and these 14 women were excluded from the cause-and-effect analyses because of the short treatment period [50]. 6 There were no abnormal changes in heart frequency, P-glucose, P-bilirubin and maturity of the lungs of the new-born infants in groups A and B in comparison with group C, in which no adrenergic beta-blocking agent was used [58].

No Control Group
Seven articles [26,54,57,61,62,64,65] examined the effect of beta-blockers on the neonate without comparing with a control group. Dubois et al. [26] found one neonate with a low cord blood glucose level who was exposed to acebutolol in utero. Another study done by O'Hare et al. [62] showed that one of the small for gestational age (SGA) infants suffered an episode of hypoglycemia one hour after birth after being exposed to sotalol in utero. This neonate responded well to a single dose of dextrose [62]. They found no additional symptoms suggesting an adverse effect of sotalol in the twelve infants included in the study and therefore did not adjust or discontinue the use of sotalol by the mothers [62]. In the study of Pruyn et al. [64], three of the twelve neonates who were in utero exposed to propranolol were diagnosed with hypoglycemia. One of those neonates was small for their gestational age, one was delivered by Cesarean section for fetal distress and one was the result of a precipitous delivery 29 min after the last dose of propranolol [64]. Eliahou et al. [65] measured the blood sugar in thirteen of the neonates who were in utero exposed to propranolol and these were all normal.

Meta-Analyses for the Outcome Hypoglycemia
A moderate CoE from meta-analyses of cohort studies indicated that beta-blockers were probably associated with a significantly higher risk of hypoglycemia when compared to placebo, no therapy or other drugs (RR, 95% CI: 3.01, 2.79-3.25) ( Figure 6, Table 9). A sub-group analysis also revealed that beta-blockers were possibly associated with a higher risk of hypoglycemia when compared to placebo or no therapy (RR, 95% CI: 3.05, 2.82-3.29) and calcium channel blockers (RR, 95% CI: 2.42, 1.47-4.00), but not when compared with methyldopa (RR, 95% CI: 1.84, 0.48-7.03) ( Figure 6).

Lactation
Most of the included studies reported no specific information regarding the type of feeding of the neonate. Only the study by Kumar et al. [31] included the type of feeding into their multiple regression analysis. Interestingly, they showed that formula feeding was a risk factor for hypoglycemia (p < 0.001) and not breast milk [31]. Moreover, Boutroy et al. [48] described a case with symptoms of bradycardia and hypotension. This child was exposed to high concentrations of acebutolol through breast milk [48]. Another study in children exposed to sotalol showed no bradycardia in the child with the highest concentration in breast milk [62]. In the study of Liedholm et al. [27] no signs of beta blockade were observed after exposure to atenolol. O'Hare [62] and Liedholm [27], found a ratio of maternal plasma concentrations versus breast milk concentrations of 1:5.4 (sotalol) and 1:4.5 (atenolol). Although the concentrations in breast milk are higher than in maternal plasma, the corresponding expected serum concentrations in infants would be less than the daily dose for hypertensive patients in general [27,58]. However, according to O'Hare et al. [62] the expected plasma concentration in a breastfed infant for sotalol is expected to be within the therapeutic dose range.

Case Reports
Fifteen case reports [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] were included in this systematic review (Table 11). Eleven case reports [67,68,70,[72][73][74][75][76][77][78][79] reported the occurrence of both hypoglycemia as well as bradycardia in a neonate. Two other articles [66,80] reported hypoglycemia in a neonate exposed to a beta-blocker in utero. Moreover, two other case reports [69,71] reported bradycardia after beta-blocker exposure in utero.  The heart rate remained low for 72 h, and frequent short episodes of bradycardia occurred that were not associated with apnea and that resolved spontaneously [72]. 2 At the time of conception, the mother was placed on a regimen of 160 mg/day. Three weeks prior to term, the propranolol dosage was reduced to 60 mg/day in preparation for the delivery [74]. 3 In case 1, the mother was receiving propranolol 20 mg for times a day at time of delivery [77]. 4 The bradycardia persisted for most of the first 36 h of life, and the heart rate remained between 100 to 120 per minute for most of the second 36 h [77]. 5 Frequent episodes of bradycardia during the first 24 h of life and occasional episodes over the next 48 h [77]. 6 The infant had occasional episodes of bradycardia (heart rate 80 to 90/minute) during the first 48 h of life, but his heart rate generally ranged between 100 to 120/minute [77]. 7 The day prior to the Cesarean section, she received 60 mg propranolol every six hours and 60 mg was given orally six hours before surgery; an additional 3 mg was given intravenously one hour before the operation [78]. 8 The mother was taking 240 mg/day at the time of conception. The dose was decreased to 160 mg/day in the fourth month of pregnancy [79].

Discussion
There is an ongoing debate as to whether exposure to beta-blockers in utero and through lactation negatively affects the neonate, whereas beta-blockers are often used in pregnant women with cardiovascular diseases. As it is unknown to what extent betablockers harm the neonate, best clinical practice about heart rate and glucose monitoring is inconclusive. In this systematic review and meta-analysis, the occurrence of the postnatal neonatal side effects of hypoglycemia and bradycardia among neonates exposed to betablockers in utero or during lactation were evaluated systematically. Our overall aim was to assess the need of postnatal monitoring and observation of the neonate. Moreover, differences in neonatal risk between the different types of beta-blockers were studied. To the best of our knowledge, this is the first systematic review and meta-analysis evaluating the neonatal outcomes associated with fetal beta-blocker exposure.
Our meta-analysis showed that in utero exposure to beta-blockers possibly results in a higher risk for neonatal bradycardia. While our sub-group analysis of RCTs revealed that the risk of bradycardia was possibly higher with beta-blockers when compared to placebo or no therapy, this risk was possibly similar when compared to methyldopa, suggesting other causal factors for bradycardia rather than the beta-blocker exposure. Another explanation could be that methyldopa might be associated with neonatal bradycardia as well. Bradycardia has been reported as a side-effect of methyldopa with an unknown incidence [81]. This possibly explains the lack of difference between both groups of antihypertensive drugs. Future studies regarding the effect of the maternal use of methyldopa on the neonate are needed. However, clinical harm could not be excluded for the use of beta-blockers. Importantly, even if beta-blockers induce a higher risk for neonatal bradycardia, the clinical relevance of this in terms of hypotension and the required treatment and hospital stay need to be elaborated further in future studies. The treatment for resulting hypotension was not described in any of the reports and neither were other serious adverse events. The majority of case reports reported bradycardia after beta-blocker exposure. However, there is a possibility of publication bias being associated with evidence from case reports.
Regarding hypoglycemia, our meta-analysis indicated that in utero exposure to betablockers was probably associated with a significantly higher risk of hypoglycemia when compared to placebo, no therapy or other drugs than beta-blockers. However, no difference was found in comparison to methyldopa exposure. Yet again, the effects of methyldopa on the neonate need to be studied. Since beta-blocker exposure was probably associated with a higher risk for hypoglycemia, which is dangerous if untreated, we do suggest blood glucose monitoring during the first 24 h after birth for all beta-blockers.
Regarding the different types of beta-blockers, propranolol, metoprolol (combined with hydralazine) and labetalol had the lowest risk for bradycardia and sotalol had the highest risk of possibly being associated with bradycardia in neonates. Moreover, metoprolol and labetalol had the lowest risk for hypoglycemia and atenolol had the highest risk of possibly being associated with hypoglycemia in neonates. Fortunately, labetalol and metoprolol are more often prescribed than sotalol and atenolol during pregnancy and lactation [1]. Fetal and neonatal drug exposure and effects following maternal pharmacotherapy are influenced by multiple drug specific characteristics, i.a. lipophilicity, neonatal half-life, different dosages, the duration of maternal exposure as well as via lactation, the aspects of placental passage of beta-blockers, intra-and inter-patient variability in disposition, and their varying potency on neonatal bradycardia and hypoglycemia. Generally, fetal and neonatal exposure and effects are increased for drugs with a longer neonatal elimination half-life, more lipophilic drugs (leading to increased placental passage as well as disposition to breastmilk), increased dosages, and an increased duration of maternal treatment. This profile has not yet been reported for each beta-blocker used in clinical practice and requires further investigation. Moreover, future research may focus on neonatal effects after exposure to beta-blockers through lactation, as available literature is sparse.
The strength of this systematic review and meta-analysis is its clinically relevant scope along with the use of a robust search strategy, assessment of the overall CoE with the GRADE system, rating risks of biases using standard tools and conducting metaanalyses for the studied outcomes. However, this review has its limitations. Firstly, the definitions used for bradycardia and hypoglycemia were widely variable between the studies. For example, some studies defined bradycardia as a heart rate of less than 100 beats per minute while others used 120 beats per minute as the cut-off. Some other studies did not mention the definition at all. The same yielded true for the cut-off value for defining hypoglycemia. Unfortunately, since most studies only provided the occurrence of bradycardia or hypoglycemia instead of the raw data, we were unable perform any meta-regression. Secondly, only a few studies provided data on lactation. It could be that exposure through breastfeeding contributed to the positive findings in some studies as transmission of various beta-blockers to breastmilk has been reported [7,[82][83][84]. Finally, we were unable to take into account the time of initiation of beta-blocker treatment, the total dose and duration of exposure, the exact indication and different gestational ages of the neonates due to lack of information.

Conclusions
Our meta-analysis determined a probable risk of hypoglycemia and possible risk of bradycardia in neonates upon neonatal beta-blocker exposure in utero or through lactation. As the CoE was moderate for the outcome of hypoglycemia, we suggest monitoring glucose levels in beta-blocker-exposed neonates until 24 h after birth irrespective of the type of used beta-blocker. Monitoring of the heart rate could be considered for 24 h, although the clinical implication of this needs to be evaluated in future studies. The necessity for heart rate monitoring may be adjusted according to the type of beta-blocker neonates are exposed to, which is most relevant for sotalol, and less for propranolol and labetalol.