Authors: Rosalie de Bruin, Sarah L. van Dalen, Shamaya J. Franx, Viraraghavan V. Ramaswamy, Sinno H. P. Simons, Robert B. Flint, Gerbrich E. van den Bosch
Categories: Systematic Review, beta-blockers, bradycardia, hypoglycemia, lactation, neonate, pregnancy
Source: International Journal of Environmental Research and Public Health
Authors: Rosalie de Bruin, Sarah L. van Dalen, Shamaya J. Franx, Viraraghavan V. Ramaswamy, Sinno H. P. Simons, Robert B. Flint, Gerbrich E. van den Bosch
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.
Beta-blockers are often used antihypertensive agents during pregnancy to treat pre-existing 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.
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, beta-blockers 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 beta-blockers 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.
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.
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.
There was no patient or public involvement in the whole process of conducting this research.
The following inclusion criteria were applied on the articles (including abstracts) resulting from our 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;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);Studies in English;Studies in human subjects.
Articles were excluded when they met the following 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.
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 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 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).
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].
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 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).
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).
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).
R software (version 3.6.2, R Foundation for Statistical Computing, Vienna, Austria) was utilized for data analysis [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.
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].
Amongst the 18 RCTs included, 15 were classified as having a high risk of overall bias [28,36,38,41,42,44,45,46,47,50,51,53,55,59,63], two had some concerns [33,40] and one low risk [29]. Most of the RCTs had some concerns for the domains of the randomization process since the process of allocation concealment was not mentioned, which describes deviations from the intended interventions and bias due to selection of the reported results with an absence of an a priori registered trial protocol. The risk of bias in the RCTs is shown in Table 4.
Amongst the 13 non-RCTs, four had critical [32,39,54,60], six had serious [31,34,43,49,52,58] and three had a moderate risk of overall bias [30,35,37]. Most of the studies had issues of confounding, selection bias, bias in classification of interventions and selective reporting. Table 5 shows the risk of bias in non-randomized controlled trials. Table 6 shows the quality of the nine case series [26,27,48,56,57,61,62,64,65]. Table 7 shows the quality of the 15 case reports [66,67,68,69,70,71,72,73,74,75,76,77,78,79,80].
Forty-one of the fifty-five included articles examined whether bradycardia was found in neonates exposed to beta-blockers either in utero or during lactation [27,28,30,32,33,34,35,37,38,40,43,44,45,47,48,49,50,51,52,53,55,56,57,58,59,60,62,64,67,68,69,70,71,72,73,74,75,76,77,78,79]. Table 8 presents 28 of the articles [27,28,30,32,33,34,35,37,38,40,43,44,45,47,48,49,50,51,52,53,55,56,57,58,59,60,62,64] that reported on the heart rate of neonates exposed to beta-blockers in utero. The other thirteen articles are case reports [67,68,69,70,71,72,73,74,75,76,77,78,79], which are described in Section 3.6. One case in the study of Boutroy et al. [48] had hypotension. However, the extent of the hypotension and the need for treatment was not described [48].
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].
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].
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 long-lasting neonatal hemodynamic effect. However, another study comparing acebutolol to methyldopa found no signs of bradycardia in both groups [52].
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 growth-retarded [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.
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].
Funnel plot evaluation and Egger’s tests of the included RCTs in the meta-analyses for the outcome bradycardia indicated no publication bias (Figure 2a). The regression test however indicated publication bias for the proportion-based meta-analysis for bradycardia (Figure 2b). Beta-blockers possibly resulted in a higher risk of bradycardia when compared to other drugs or placebo or no therapy as assessed by the meta-analysis of RCTs (Relative risk (RR), 95% Confidence Interval (CI): 2.36, 1.33–4.18), with the CoE being low (Figure 3, Table 9). A sub-group analysis of RCTs revealed that the risk of bradycardia was possibly higher with beta-blockers when compared to placebo or no therapy (RR, 95% CI: 2.22, 1.07–4.64) and hydralazine (RR, 95% CI: 6.66, 1.61–27.57), but possibly similar when compared to methyldopa (RR, 95% CI: 11.0, 0.02–7032.32) and calcium channel blockers (RR not calculable due to zero events) (Figure 3). Clinical benefit or harm could not be excluded for the comparison beta-blockers versus placebo, no therapy or other drugs, as assessed from results of meta-analyses of cohort studies and case–control studies, because the estimates were statistically non-significant and the CoE was very low to low (Figure 4, Table 9). However, sub-group analyses of cohort studies (RR, 95% CI: 3.03, 2.60–3.53) and case–control studies (RR, 95% CI: 4.01, 1.50–10.75) showed that beta-blockers were possibly associated with higher risk of bradycardia when compared to placebo or no therapy, and a possibly similar risk when compared to methyldopa (Figure 4). The proportion-based meta-analysis showed that the overall incidence of bradycardia with beta-blockers was 6% (95% CI: 2%–13%) with statistically significant difference in the incidence between the various types of beta-blockers (p = 0.002) (Figure 5). While propranolol (2% (95% CI: 0%–16%)), metoprolol combined with hydralazine (3% (95% CI: 1–6%)) and labetalol (4% (95% CI: 0%–11%)) had the lowest risk, sotalol had the highest risk of possibly being associated with bradycardia (50% (95% CI: 22%–78%)).
Forty-seven out of the 55 included articles investigated the occurrence of hypoglycemia in neonates exposed to beta-blockers either in utero or during lactation [26,28,29,30,31,32,33,35,36,37,38,39,40,41,42,43,44,45,46,47,49,50,52,53,54,55,57,58,60,61,62,63,64,65,66,67,68,70,72,73,74,75,76,77,78,79,80]. Table 10 shows 34 of the articles reporting hypoglycemia and the definitions used by the authors [26,28,29,30,31,32,33,35,36,37,38,39,40,41,42,43,44,45,46,47,49,50,52,53,54,55,57,58,60,61,62,63,64,65]. The other 13 articles investigating hypoglycemia are case reports and are described in Section 3.6.
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].
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.
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.
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.
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.
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).
Quite like the results from the cohort studies, the meta-analysis of case–control studies indicated that beta-blockers were possibly associated with a higher risk of hypoglycemia when compared to placebo, no therapy or other drugs (RR, 95% CI: 1.72, 1.133–2.22), with the CoE being very low (Figure 6, Table 9). The sub-group analysis indicated a possibly higher risk of hypoglycemia with beta-blockers when compared to placebo or no therapy (RR, 95% CI: 1.68, 1.03–2.73), but not when compared with methyldopa (RR, 95% CI: 6.00, 0.87–41.21) (Figure 6). While the funnel plot of the included RCTs and the Egger’s test indicated no publication bias, we did detect publication bias for the proportion-based meta-analysis based on the regression test (Figure 7a,b). Clinical benefit or harm could not be excluded for the outcome of hypoglycemia from the results of the meta-analysis of RCTs, due to the result being statistically non-significant and the CoE being low (Figure 8, Table 9). The proportion-based meta-analysis suggested that the incidence of hypoglycemia with the use of any beta-blocker might be 12% (95% CI: 7–19%), with it being lowest with metoprolol (3% (95% CI: 2–4%)) and labetalol (8% (95% CI: 2–16%)) (Figure 9). Atenolol had the highest association with hypoglycemia (35% (95% CI: 3–77%)).
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 5.4 (sotalol) and 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.
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.
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 beta-blockers 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 beta-blockers 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 beta-blockers 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 meta-analyses 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.
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.