Table 2.
Overview of 40 included studies.
| Source | Study Group | Number of Patients | Country | Study Design | Objective | Treatment Indication | Outcome |
|---|---|---|---|---|---|---|---|
| Bigelow CA, 2021 [29] | Nulliparous patients undergoing term induction of labor with a single, non-anomalous gestation received propranolol or placebo | n = 121 cases vs. n = 119 controls | United States | RCT | To determine whether the addition of a single dose of propranolol to induce labor in nulliparous women would decrease total time to vaginal delivery | Induction of labor | Hypoglycemia |
| Kayser A, 2020 [30] | Neonates of hypertensive women treated with metoprolol and/or bisoprolol after the first trimester, but not with methyldopa at any time during pregnancy | n = 294 cases vs. n = 225 controls (methyldopa) vs. n = 588 controls (nonhypertensive mothers) | Germany | Cohort study | To evaluate the effects of beta blockers during the second and third trimester on fetal growth, length of gestation and postnatal symptoms in exposed infants | Chronic or pregnancy-induced hypertension | Hypoglycemia and bradycardia |
| Kumar N, 2020 [31] | All the infants born ≥34 weeks with mothers using beta blockers prenatally compared to mothers with diabetes, both beta-blockers and diabetes or without pregnancy conditions | n = 228 cases (BB) and n = 60 both vs. n = 379 controls (diabetes), and n = 4.103 controls (no pregnancy condition) | United States | Cohort study | To evaluate whether pregnancy glycated hemoglobin (HbA1c) levels of ≤6% and maternal race impacts neonatal hypoglycemia and birthweight, and whether diabetes and beta blocker use during pregnancy additively impacts neonatal outcomes | Not described in article | Hypoglycemia |
| Mazkereth R, 2019 [32] | Infants born to mothers who were treated with beta-blockers during pregnancy and until delivery | n = 153 cases vs. n = 153 controls | Israel | Case–control | To evaluate infants exposed to intrauterine beta blockers in order to estimate the need of postnatal monitoring | Cardiac disease (arrhythmia, rheumatic heart disease and cardiomyopathy), chronic hypertension, migraine, PIH (pregnancy induced hypertension) and pre-eclampsia | Hypoglycemia and bradycardia |
| Easterling T, 2019 [33] | Pregnant woman older than 18 years and gestational age of at least 28 weeks received labetalol, nifedipine or methyldopa | n = 295 cases vs. n = 298 controls (nifedipine) vs. n = 301 controls (methyldopa) | India | RCT | To compare the efficacy and safety of oral labetalol, nifedipine retard and methyldopa for the management of severe hypertension in pregnancy | Hypertension in pregnancy | Hypoglycemia and bradycardia |
| Thewissen L, 2017 [34] | Preterm neonates prenatally exposed to labetalol because of maternal HDP | n = 22 cases vs. n = 22 controls with maternal HDP without labetalol and n = 22 controls without maternal HDP | Belgium | Case–control | To investigate labetalol-induced effects on neonatal hemodynamics and cerebral oxygenation in the first 24 h after birth | Hypertensive disorders in pregnancy (HDP) | Bradycardia |
| Bateman BT, 2016 [35] | Completed pregnancies linked to liveborn infants | n = 2,292,116 | United States | Cohort study | To define the risks of neonatal hypoglycemia and bradycardia associated with maternal exposure to beta blockers at the time of delivery |
Pre-existing or gestational hypertension, pre-eclampsia, migraine, cardiac arrhythmia, ischemic heart disease, anxiety and congestive heart failure | Hypoglycemia and bradycardia |
| Singh R, 2016 [36] | Women with severe hypertension in pregnancy who received labetalol or hydralazine | n = 50 cases vs. n = 50 controls | India | RCT | To evaluate the efficacy and safety of intravenous labetalol and intravenous hydralazine in managing hypertensive emergency in pregnancy | Hypertension in pregnancy | Hypoglycemia |
| Heida KY,2012 [37] | Infants from mothers suffering from severe preeclampsia and/or HELLP treated with labetalol | n = 55 cases and n = 54 controls | The Netherlands | Case–control | Analysis of possible association between intrauterine labetalol exposure and side effects | Preeclampsia and/or HELLP-syndrome | Hypoglycemia and bradycardia |
| Verma R, 2012 [38] | Pregnant patients newly diagnosed with systolic blood pressure of ≥140 mmHg and a diastolic blood pressure of ≥90 mmHg and gestational age between 20–40 weeks of pregnancy received labetalol or methyldopa | n = 45 cases vs. n = 45 controls | India | RCT | (1) To evaluate the effect of labetalol versus methyldopa on maternal outcomes in the treatment of new onset hypertension during pregnancy (2) To evaluate the effect of labetalol versus methyldopa on fetal and neonatal outcomes in the treatment of new onset hypertension during pregnancy |
Pregnancy induced hypertension | 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 |
|
Vigil-De Gracia P, 2006 [40] |
Women with severe hypertension in pregnancy treated with labetalol or hydralazine | n = 100 cases vs. n = 100 controls (and n = 103 case children vs. n = 102 control children) | Panama | RCT | To compare the safety and efficacy of intravenous labetalol and intravenous hydralazine for acutely lowering blood pressure in pregnancy | Severe preeclampsia, gestational hypertension, superimposed preeclampsia, chronic hypertension, eclampsia and severe preeclampsia with HELLP | Hypoglycemia and bradycardia |
| Darcie S, 2004 [41] | Newborns of mothers treated with atenolol, isradipine or a low sodium diet during pregnancy | n = 40 cases vs. n = 39 controls (isradipine) vs. n = 14 controls (low sodium diet) | Brazil | RCT | To evaluate the effect of isradipine on the evolution of glycemia levels in newborns of pregnant women who have arterial hypertension, comparing it to the use of atenolol and situations where the blood pressure control was done without using antihypertensive medications | Specific hypertensive disease of pregnancy (SHDP) or chronic arterial hypertension and superimposed SHDP | Hypoglycemia |
| Paran E, 1995 [42] | Woman with moderate pregnancy-induced hypertension | n = 17 cases propranolol/hydralazine vs. n = 19 cases pindolol/hydralazine vs. n = 13 controls with hydralazine | Turkey | RCT | To compare the effect of propranolol/hydralazine to pindolol/hydralazine combination therapy with hydralazine monotherapy and to evaluate the clinical effects on the mother and on the fetus | Moderate pregnancy-induced hypertension | Hypoglycemia |
| Munshi UK, 1992 [43] | Neonates born to mothers suffering from pregnancy-induced hypertension (PIH) and receiving labetalol compared to children of mothers treated with drugs other than labetalol for their PIH | n = 48 cases vs. n = 81 controls | India | Case–control | To assess the incidence of birth asphyxia, intrauterine growth retardation and hypoglycemia in the neonates of mothers suffering from pregnancy induced hypertension treated with labetalol | Pregnancy induced hypertension | Hypoglycemia and bradycardia |
| Bott-Kanner G, 1992 [44] | Women presenting with a diastolic blood pressure of 85–90 mmHg before the 35th week of pregnancy treated with pindolol or placebo | n = 30 cases vs. n = 30 controls | Israel | RCT | To investigate the benefits of early treatment of hypertension of pregnancy with pindolol and to compare the effects of initiating treatment at a DBP of 85–99 mmHg as opposed to starting treatment when DBP is ≥100 mmHg. The study examined the effects of treatment in incidence of maternal and fetal complications. | A diastolic blood pressure of 85–90 mmHg before the 35th week of pregnancy | Hypoglycemia and bradycardia |
| Pickles CJ, 1989 [45] | Patients with mild to moderate, non-proteinuric pregnancy-induced hypertension treated with labetalol or placebo | n = 70 cases vs. n = 74 controls | England | RCT | The fetal outcome of labetalol versus placebo in pregnancy-induced hypertension | Pregnancy induced hypertension: a blood pressure of 140–160 mmHg systolic and 90–105 mmHg diastolic after 15 min rest on two occasions separated by 24 h | Hypoglycemia and bradycardia |
| Ramanathan J, 1988 [28] | Woman with pre-eclampsia who were scheduled to undergo caesarean section under general anesthesia receiving labetalol pretreatmemt or no antihypertensive therapy before induction of anesthesia | n = 15 cases vs. n = 10 controls | United States | RCT | To study the effectiveness of labetalol in attenuating the hypertensive and tachycardiac responses associated with laryngoscopy and endotracheal intubation in pre-eclamptic women undergoing general anesthesia for caesarean section | Pre-eclampsia (diastolic blood pressure 96 to 120 mmHg and proteinuria) in combination with caesarean section | Hypoglycemia and bradycardia |
| Ashe RG, 1987 [46] | Primigravida’s with severe hypertension in pregnancy at 32 weeks’ gestation or more receiving labetalol or dihydrallazine | n = 10 cases vs. n = 10 controls | South Africa | RCT | To compare the efficacy of dihydralazine with labetalol when administered as intravenous infusions to primigravida’s with severe hypertension in pregnancy at 32 weeks’ gestation or more | Severe hypertension in pregnancy (a diastolic blood pressure of 110 mmHg or more (Korotkoff phase IV sound), which had not settled after 2 h bed rest and sedation with phenobarbitone (sodium gardenal 200 mg intramuscularly)) | Hypoglycemia |
| Mabie WC, 1987 [47] | Pregnant women with hypertension during pregnancy or in the puerperium receiving labetalol or hydralazine | n = 40 cases vs. n = 20 controls | United States | RCT | To compare the safety and efficacy of intravenous labetalol and intravenous hydralazine hydrochloride for acutely lowering blood pressure in the pregnant or recently postpartum patient | Pre-eclampsia and chronic hypertension with or without superimposed pre-eclampsia | Hypoglycemia and bradycardia |
| Boutroy MJ, 1986 [48] | Hypertensive mothers | n = 7 | France | Case series | To evaluate the possible risk of exposure to beta blockers of newborn infants breast-fed by mothers being treated with acebutolol | Hypertension in pregnancy | Bradycardia |
| Macpherson M, 1986 [49] | Infants born to women with hypertensive disease of pregnancy who had received labetalol for at least 7 days before delivery although some had begun treatment at 16 weeks gestation | n = 11 cases vs. n = 11 controls | England | Case–control | To examine a number of aspects of sympathetic function in infants born to labetalol-treated mothers compared with untreated controls to see if there were any clinically important effects of combined alfa and beta blockade | Hypertensive disease of pregnancy | Hypoglycemia and bradycardia |
| Högstedt S, 1985 [50] | Women with mild and moderate hypertension in pregnancy treated with metoprolol and hydralazine vs. control | n = 82 cases vs. n = 79 controls | Sweden | RCT | To assess whether treatment with metoprolol, a beta-1 selective adrenoceptor blocking agent, in combination with hydralazine is of benefit for the mother and/or the fetus as compared with non-pharmacological treatment, in mild to moderate hypertension of pregnancy | A diastolic blood pressure of at least 90 mmHg on two or more occasions during pregnancy | Hypoglycemia and bradycardia |
| Reynolds B, 1984 [51] | Women who developed hypertension in the last trimester of pregnancy received Atenolol or placebo | n = 60 cases vs. n = 60 controls | Scotland | RCT | To describe the findings of pediatric follow up to 1 year of age after the use of atenolol in pregnancy-associated hypertension | Pregnancy-associated hypertension | Bradycardia |
| Williams ER, 1983 [52] | Women with mild to moderate hypertension | n = 9 Acebutolol and n = 11 Methyldopa | England | Case–control | To compare acebutolol with methyldopa in hypertensive pregnancy | A blood pressure of 130/90 mmHg or above, a systolic pressure of 135 mmHg or above or a diastolic pressure of 85 mmHg or above | Hypoglycemia and bradycardia |
| Rubin PC, 1983 [53] | Women with mild to moderate pregnancy-associated hypertension who were also initially managed conventionally by bed rest received atenolol or placebo | n = 46 cases vs. n = 39 controls | Scotland | RCT | To examine the efficacy and safety of atenolol in the treatment of pregnancy-associated hypertension | Pregnancy-associated hypertension: a blood-pressure between 140 and 170 mmHg systolic or between 90 and 110 mmHg diastolic (after 10 mins’ rest supine or after 5 mins’ standing) on two occasions separated by 24 h | Hypoglycemia and bradycardia |
| Liedholm H, 1983 [54] | Hypertensive pregnancies | n = 88 cases vs. n = 22 controls | Sweden | Cohort study | To determine the effects of atenolol and metoprolol on maternal blood pressure and on the fetus and new-born | Chronic or pregnancy-related hypertension | Hypoglycemia |
| Liedholm H, 1983 [27] | Pregnant women under treatment with atenolol for hypertension (during pregnancy or in the peripartum) | n = 7 | Sweden | Case series | 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 |
| Rubin PC, 1982 [57] | Infants of women using atenolol for management of essential hypertension in pregnancy | n = 9 | Scotland | Case series | To report the experience of using atenolol for several weeks during pregnancy in the management of essential hypertension | Systolic blood pressure exceeding 140 mmHg or diastolic pressure exceeding 90 mmHg on two separate occasions at least one day apart | Hypoglycemia and bradycardia |
| Sandström B, 1982 [58] | Pregnant women with hypertension treated with metoprolol combined with thiazide or hydralazine compared with women treated with hydralazine and a thiazide | n = 184 cases (n = 101 with thiazide and n = 83 with hydralazine and n = 97 controls | Sweden | Case–control | To report further experiences of using metoprolol in hypertension of pregnancy. (In addition to a previous study) | Pregnancy-induced hypertension, pre-existing hypertension, eclampsia and hypertension with moderate/marked proteinuria | Hypoglycemia and bradycardia |
| Garden A, 1982 [59] | Women with severe hypertension in pregnancy treated with labetalol or dihydralazine | n = 3 cases vs. n = 3 controls | South Africa | RCT | To compare the effect of labetalol and dihydralazine in increasing doses in woman with severe hypertension in pregnancy | Severe hypertension and imminent eclampsia or eclampsia | Bradycardia |
| Dumez Y, 1981 [60] | Infants born to mothers who received acebutolol or methyldopa during pregnancy | n = 10 cases vs. n = 10 controls | France | Case–control | To evaluate any deleterious effect of the beta-adrenergic-blocking agent in newborn infants. | If the diastolic blood pressure exceeded 90 mm Hg on two occasions at least 24 h apart during pregnancy | Hypoglycemia and bradycardia |
| Bott-Kanner G, 1980 [61] | Infants of mothers treated with propranolol and hydralazine because of longstanding hypertension during pregnancy | n = 14 | Israel | Case series | To assess the efficiency of a combination of hydralazine and propranolol in the management of pregnant patients with essential hypertension | Essential hypertension | Hypoglycemia |
| O’Hare MF, 1980 [62] | Hypertensive pregnant women receiving sotalol | n = 12 | Northern Ireland | Case series | To study the effects and distribution of sotalol by administering it as sole therapy to a group of chronically hypertensive pregnant women. | Chronic or pregnancy-induced hypertension | Hypoglycemia and bradycardia |
| Gallery ED, 1979 [63] | Pregnant women with moderately severe hypertension treated with oxprenolol or methyldopa | n = 26 cases vs. n = 27 controls | Australia | RCT | To examine the effects of antihypertensive treatment more closely and to evaluate alternative forms of treatment |
Moderately severe hypertension in pregnancy | Hypoglycemia |
| Pruyn SC, 1979 [64] | Infants from mothers who used propranolol chronically during pregnancy | n = 12 | United States | Case series | To examine maternal, fetal and neonatal complications of propranolol therapy in pregnancy | Thyrotoxicosis, hypertension, Barlow syndrome with arrhythmia, Lown-Ganong-Levine syndrome and supraventricular/paroxysmal atrial tachycardia | Hypoglycemia and bradycardia |
| Eliahou HE, 1978 [65] | Infants from mothers treated with propranolol during pregnancy | n = 22 | Israel | Case series | To report the experience of 25 women who received propranolol orally for the treatment of hypertension during 26 pregnancies with 22 liveborn infants | Essential hypertension, recurrent hypertension of pregnancy, pre-eclampsia and unilateral chronic pyelonephritis | Hypoglycemia |
Abbreviations: HDP: Hypertensive Disorders in Pregnancy, HELLP: Hemolysis, Elevated Liver enzymes and Low Platelets, RCT: Randomized Controlled Trial.