|Year : 2015 | Volume
| Issue : 1 | Page : 45-48
Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy
Maria Giuseppa Sullo1, Domenico Perri2, Michelina Sibilio2, Concetta Rafaniello1, Annamaria Fucile3, Francesco Rossi1, Annalisa Capuano1
1 Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Naples, Italy
2 Department of Pediatric, Moscati Hospital, Aversa, Italy
3 Azienda Sanitaria Locale Di Caserta, Caserta, Italy
|Date of Submission||04-Feb-2014|
|Date of Decision||15-Mar-2014|
|Date of Acceptance||28-Jun-2014|
|Date of Web Publication||12-Jan-2015|
Maria Giuseppa Sullo
Department of Experimental Medicine, Section of Pharmacology, Pharmacoepidemiology and Pharmacovigilance Centre of the Campania Region, Second University of Naples, Via Costantinopoli 16, Naples - 80138
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Nebivolol is a third-generation beta blocker that exerts selective antagonistic activity on β1 receptors. It has vasodilating properties that result from direct stimulation of endothelial nitric oxide synthase. Nebivolol is indicated for the treatment of hypertension and heart failure, and is generally well tolerated. In this article, we report a case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mg/dL). He was born by spontaneous delivery after a normal term pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Clinical and instrumental investigations carried out during hospitalization did not reveal any congenital or perinatal abnormalities. After treatment for metabolic and electrolyte imbalance, he was discharged on the 10 th day of hospitalization, in good clinical condition and with normalization of clinical and laboratory parameters. Currently, there are no specific studies on nebivolol tolerability during pregnancy. Our data suggest that the risk profile of nebivolol during pregnancy is the same as that of other β-blockers. Therefore, further studies are required to determine the safety of β-blockers during pregnancy and the risks to the unborn child.
Keywords: Adverse drug reactions, nebivolol, newborn, pregnancy
|How to cite this article:|
Sullo MG, Perri D, Sibilio M, Rafaniello C, Fucile A, Rossi F, Capuano A. Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy. J Pharmacol Pharmacother 2015;6:45-8
|How to cite this URL:|
Sullo MG, Perri D, Sibilio M, Rafaniello C, Fucile A, Rossi F, Capuano A. Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy. J Pharmacol Pharmacother [serial online] 2015 [cited 2019 Nov 22];6:45-8. Available from: http://www.jpharmacol.com/text.asp?2015/6/1/45/149148
| Introduction|| |
Nebivolol is a third-generation β1 - selectiveblocker that is indicated for the treatment of hypertension and heart failure.  It has vasodilatory properties mediated by direct stimulation of the endothelial nitric oxide synthase (eNOS).  Nebivolol is a racemic mixture of two enantiomers in a 1:1 ratio,  namely a d-and an l-isomer. The D-isomer selectively blocks the β1 receptor and has mild vasodilatory properties, while the L-isomer stimulates eNOS, thereby resulting in vasodilatation.  The hemodynamic changes induced by nebivolol may lead to a negative chronotropic effect, inhibition of sympathetic outflow from cerebral vasomotor centers, inhibition of peripheral β1 -adrenoceptors,  suppression of renin activity, and decreased peripheral vascular resistance. The very high selectivity of the nebivolol D-isomer for β1 - versus β2-adrenergic receptors involves the limited effects on airway reactivity, insulin sensitivity , and the lesser negative inotropic effect of nebivolol in patients with heart failure. , Although nebivolol has no intrinsic sympathomimetic activity, it exerts an agonistic effect on β3 -receptors, which may partially explain its effects on the endothelium. 
Nebivolol is well tolerated. The most frequently occurring adverse events (AEs) associated with nebivolol reported in clinical trials are fatigue (4-79%), headache (2-24%), paresthesia (7-13%), bradycardia (6-11%), rhinitis (1-7%), and dizziness (2-5%). Other commonly reported (>1%) nebivolol-associated AEs are diarrhea (2-3%) and nausea (1-3%), both of which are consistent with AEs reported for other β-blockers. Adverse events reported in <1% of patients are insomnia, asthenia, hypercholesterolemia, and hyperuricemia.  The following AEs were communicated to the manufacturer after nebivolol became commercially available: abnormal hepatic function, acute pulmonary edema, acute renal failure, atrioventricular block, bronchospasm, erectile dysfunction, hypersensitivity, myocardial infarction, pruritus, psoriasis, Raynaud's phenomenon, intermittent claudication, somnolence, syncope, and thrombocytopenia.  Nebivolol is contraindicated in patients with severe bradycardia, atroventricular nodal block greater than first degree, cardiogenic shock, decompensated heart failure, and severe liver disease. Like the use of other β-blockers, abrupt cessation of nebivolol therapy is not recommended because it may lead to a rebound effect and to the precipitation of severe angina, myocardial infarction, and ventricular arrhythmias. 
Like most antihypertensive agents used in pregnancy, nebivolol is designated a pregnancy category C medication (no human data supporting safety or toxicity during pregnancy). Category C includes drugs for which human studies are lacking but animal studies showing a fetal risk. Category C drugs should be administrated only if the potential benefits outweigh the potential risks to the fetus. This category is difficult to interpret because there is no evidence of risk and it is so broad to be preclude usefulness in practice. 
| Case report|| |
Here we report the case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mgl/dL). He was born at term by spontaneous delivery after a normal pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Because of jaundice and hypoglycemia, the infant immediately underwent phototherapy and intravenous administration of 10% glucose solution. The laboratory tests carried out at admission revealed polycythemia with hematocrit 63.7%, red blood cells count of 6,230,000/mm 3 , mild hyponatremia (132 mEq/L) and mild thrombocytopenia (platelets = 99,000/mm 3 ) with prolongation of prothrombin time and activated partial thromboplastin time. Tests during hospitalization showed blood glucose level within normal limits, despite treatment with intravenous glucose solution, and coagulation remained deranged without overt clinical manifestations, and hyponatremia became more pronounced.
Urinary electrolytes were below normal, hence it was decided to reduce fluid intake and increase the administration of sodium chloride. Abdominal ultrasonography, cardiology consultation, electrocardiography, echocardiography, and brain CT scan were unremarkable. Serial C-reactive protein, urinalysis, urine cultures and blood cultures were also unremarkable.
The clinical condition of the newborn gradually improved and coagulation test and the levels of blood glucose, bilirubin and serum sodium normalized. Consequently, the patient was discharged on the 10 th day, in a good clinical condition and with normalization of clinical and laboratory parameters.
| Discussion|| |
The detection of adverse drug events (ADEs) is crucial to improving the quality of health care system both in adults and, especially in pediatrics. To date, pharmacovigilance studies on vaccine and drug safety are still not enough in pediatric population. ,,, Moreover, pregnant women are often excluded from clinical studies, and this could induce an inadequate pharmacological treatment which could compromise both fetal and maternal well-being.
In this scenario, we report the first case, to our knowledge, of nebivolol induced a hypoglycemia, polycythemia and hyponatremia in a newborn after a spontaneous at-term delivery. During pregnancy, the mother received an off-label prescription of nebivolol for unspecified tachycardia. The consequences of β-blocker treatment during pregnancy are debated. Some studies found an association between β-blocker treatment and small for-gestational-age (SGA) newborns and preterm births, ,,,, but not others. , A study conducted in a cohort of all births in Denmark between 1995 and 2008 revealed an association between exposure to β-blockers and preterm birth and perinatal mortality. When the analysis was adjusted for maternal comorbidity, co-medication and smoking, only labetalol was found to be associated with perinatal mortality.  However, other studies show that labetalol is safer than other β-blockers during pregnancy, , thus this drug is becoming the first-line choice for hypertension and other chronic conditions during pregnancy. In any event, the risk of SGA, preterm birth and perinatal mortality following exposure to β-blockers could be a class effect. 
Our patient was affected by hypoglycemia, polycythemia and hyponatremia after being exposed to nebivolol during the last 4 months of pregnancy. There are numerous reports of hypotension, bradycardia and hypoglycemia in infants after administration of β-blockers, particularly labetalol, during pregnancy.  In particular, a cohort study showed that exposure to β-blockers in the last trimester of pregnancy is associated with an increased risk of hypoglycemia in infants. In fact, β-blockers spread through the placenta, and can increase insulin levels and decrease glucagon levels in the fetus, thereby resulting in hypoglycemia in the newborn.  However, hypoglycemia is common in neonates and usually occurs in the first 48 hours after birth. The risk of hypoglycemia in newborns is increased by prematurity, perinatal stress or asphyxia, small size for gestational age and being born to diabetic mothers.  Hypoglycemia can be transient or persistent. The persistent form may be due to metabolic diseases, such as hyperinsulinism and hypopituitarism, or hereditary hepatic enzyme deficiencies.  Instead, the transient hypoglycemia could represent a metabolic mechanism of adaptation to extrauterine life  and is commonly observed in at-risk infants.  Moreover, transient low blood glucose concentrations are frequently observed in healthy newborns  and, unlike in our case, it is a transient phenomenon.  Therefore, it is conceivable that exposure to nebivolol has favored the onset and persistence of hypoglycemia in our patient.
There are no reports of hyponatremia or polycythemia consequent to exposure to nebivolol. In our case, polycythemia may have resulted from placental insufficiency induced by nebivolol. In fact, β-blockers reduce placental perfusion.  The effects on placental hemodynamics have been observed in both human and animal studies. It has been suggested that β-blockers without intrinsic sympathomimetic activity cause selective vasoconstriction of placental vessels.  Placental insufficiency can lead to chronic or acute fetal hypoxia with birth asphyxia and hypothermia, neonatal hypoglycemia, polycythemia and coagulopathy.  Hyponatremia could be the consequence of increased blood viscosity resulting from polycythemia and thus it would be a pseudohypontremia.
| Conclusion|| |
To our knowledge, this is the first case of hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during the last 4 months of pregnancy.
The safety profile of beta blockers (β-blockers) used in pregnancy is still unclear and controversial. There is a lack of studies on the tolerability and safety of nebivolol during pregnancy. However, it appears that the risk profile of nebivolol for pregnancies is the same as that of other β-blockers. Therefore, there is a need for studies designed to assess the tolerability profile of this class of drugs when used in pregnancy in order to minimize risks both for the unborn that for pregnant women. For this reason pharmacovigilance post-marketing studies are key elements to monitor the safety and effectiveness of approved drugs, ,,,, especially when used in special conditions such as pregnancy.
| Acknowledgement|| |
The authors thank Jean Ann Gilder (Scientific Communication srl., Naples, Italy) for text editing.
| References|| |
Cheng JW. Nebivolol: A third-generation beta-blocker for hypertension. Clin Ther 2009;31:447-62.
Münzel T, Gori T. Nebivolol: The somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol 2009;54:1491-9.
Mangrella M, Rossi F, Fici F, Rossi F. Pharmacology of nebivolol. Pharmacol Res 1998;38:419-31.
Van Nueten L, De Crée J. Nebivolol: Comparison of the effects of dl-nebivolol, d-nebivolol, l-nebivolol, atenolol, and placebo on exercise-induced increases in heart rate and systolic blood pressure. Cardiovasc Drugs Ther 1998;12:339-44.
Rozec B, Quang TT, Noireaud J, Gauthier C. Mixed beta3-adrenoceptor agonist and alpha1-adrenoceptor antagonist properties of nebivolol in rat thoracic aorta. Br J Pharmacol 2006;147:699-706.
Cazzola M, Matera MG, Ruggeri P, Sanduzzi A, Spicuzza L, Vatrella A, et al
. Comparative effects of a two-week treatment with nebivolol and nifedipine in hypertensive patients suffering from COPD. Respiration 2004;71:159-64.
D'Agostino B, Gallelli L, Falciani M, Fici F, Mangrella M, Rossi F, et al
. Nebivolol and airway responsiveness in the rabbit. Life Sci 2001;68:2159-68.
Brixius K, Bundkirchen A, Bölck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol 2001;133:1330-8.
Bundkirchen A, Brixius K, Bölck B, Mehlhorn U, Bloch W, Schwinger RH. Nebivolol, carvedilol and metoprolol do not influence cardiac Ca(2+) sensitivity. Eur J Pharmacol 2001;422:175-80.
Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51:960-9.
Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, et al
. Drug-induced hepatic injury in children: A case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010;70:721-8.
Bertuola F, Morando C, Menniti-Ippolito F, Da Cas R, Capuano A, Perilongo G, et al
. Association between drug and vaccine use and acute immune thrombocytopenia in childhood: A case-control study in Italy. Drug Saf 2010;33:65-72.
Bianciotto M, Chiappini E, Raffaldi I, Gabiano C, Tovo PA, Sollai S, et al
.; Italian Multicenter Study Group for Drugand Vaccine Safety in Children.Drug use and upper gastrointestinal complications in children: A case-control study. Arch Dis Child 2013;98:218-21.
GalloM, ClavennaA, BonatiM, SianiP, IrpinoA, Rossi F, et al
. Active surveillance of adverse drug reactions in children in five Italian paediatric wards. Open J Pediatr 2012;2:111-7.
Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2003;CD002863.
Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol 1987;70:323-7.
Magee LA, Elran E, Bull SB, Logan A, Koren G. Risks and benefits of beta-receptor blockers for pregnancy hypertension: Overview of the randomized trials. Eur J Obstet Gynecol Reprod Biol 2000;88:15-26.
Nakhai-Pour HR, Rey E, Bérard A. Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns. Birth Defects Res B Dev Reprod Toxicol 2010;89:147-54.
Lydakis C, Lip GY, Beevers M, Beevers DG. Atenolol and fetal growth in pregnancies complicated by hypertension. Am J Hypertens 1999;12:541-7.
Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: Management of hypertension in pregnancy. BMJ 1999;318:1332-6.
Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2007;CD002252.
Meidahl Petersen K, Jimenez-Solem E, Andersen JT, Petersen M, Brødbæk K, Køber L, et al
. β-Blocker treatment during pregnancy and adversepregnancy outcomes: A nationwide population-based cohort study. BMJ Open 2012;2.pii: e001185.
Karthikeyan VJ, Lip GY. Hypertension in pregnancy: Pathophysiology and management strategies. Curr Pharm Des 2007;13:2567-79.
Heida KY, Zeeman GG, Van Veen TR, Hulzebos CV. Neonatal side effects of maternal labetalol treatment in severe preeclampsia. Early Hum Dev 2012;88:503-7.
Davis RL, Eastman D, McPhillips H, Raebel MA, Andrade SE, Smith D, et al
. Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiol Drug Saf 2011;20:138-45.
Sweet CB, Grayson S, Polak M. Management strategies for neonatal hypoglycemia. J Pediatr Pharmacol Ther 2013;18:199-208.
LaFranchi S. Hypoglycemia of infancy and childhood. Pediatr Clin North Am 1987;34:961-82.
Hussain K. Investigations for neonatal hypoglycaemia. Clin Biochem 2011;44:465-6.
Arya VB, Senniappan S, Guemes M, Hussain K. Neonatal hypoglycemia. Indian J Pediatr 2014;81:58-65.
Tin W. Defining neonatal hypoglycaemia: A continuing debate. Semin Fetal Neonatal Med 2014;19:27-32.
Lennestål R, OtterbladOlaussonP, Källén B. Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. Eur J Clin Pharmacol 2009;65:615-25.
Halliday HL. Neonatal management and long-term sequelae. Best Pract Res Clin Obstet Gynaecol 2009;23:871-80.
Mazzitello C, Esposito S, De Francesco AE, Capuano A, Russo E, De Sarro G. Pharmacovigilance in Italy: An overview. J Pharmacol Pharmacother 2013;4(Suppl 1):S20-8.
Ruggiero S, Rafaniello C, Bravaccio C, Grimaldi G, Granato R, Pascotto A, et al
. Safety of attention-deficit/hyperactivity disorder medications in children: An intensive pharmacosurveillance monitoring study. J Child Adolesc Psychopharmacol 2012;22:415-22.
Rafaniello C, Ianniello B, De Vizia M, Mercogliano A, Lettieri B, Rinaldi B, et al
. Cardiorespiratory effects of change in posture after spinal anesthesia with hyperbaric bupivacaine. Minerva Med 2011;102:501-4.
Capuano A, Irpino A, Gallo M, Ferrante L, Illiano M L, Rinaldi B, et al
. Regional surveillance of emergency-department visits for outpatient adverse drug events. Eur J Clin Pharmacol 2009;65:721-8.
Capuano A, Motola G, Russo F, Avolio A, Filippelli A, Rossi F, et al
. Adverse drug events in two emergency departments in Naples, Italy: An observational study. Pharmacol Res 2004;50:631-6.