Normal Pregnancy and Healthy Child After

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APGAR scores for the baby at 1 and. 5 minutes were 8 and 10, respectively, and no .... macrosomie, et l'hypoglycémie néonatale. D'un autre côté, les inhibiteurs.
Normal Pregnancy and Healthy Child After Continued Exposure to Gliclazide and Ramipril During Pregnancy Oykun Kolagasi, Funda Sari, Munire Akar, and Ramazan Sari

aternal and fetal complications can be seen during pregnancy in womOBJECTIVE: To report a case of exposure to gliclazide and ramipril during pregnancy in a patient with diabetes mellitus and hypertension. en with hypertension and diabetes mellitus. High blood pressure and glucose CASE SUMMARY: A 42-year-old female with type 2 diabetes mellitus and hypertension who had been taking gliclazide 30 mg/day and ramipril 10 mg/day levels during pregnancy continue to be an for 2 years was admitted in the 16th week of gestation. The following week, important cause of maternal, fetal, and gliclazide and ramipril were discontinued and methyldopa 500 mg 4 times daily neonatal morbidity and mortality. Normal and intensive insulin therapy were instituted. Blood glucose concentrations and maternal blood glucose and blood presblood pressure remained within acceptable levels throughout the pregnancy. The sure levels are expected to decrease the patient gave birth to a healthy child (3200 g) by cesarean section after completing an uneventful gestation period. incidence of spontaneous abortions, congenital abnormalities, macrosomia, fetal DISCUSSION: Oral antidiabetic drug use in pregnancy is not recommended 1-3 secondary to known effects on the fetus such as congenital abnormalities, fetal death, and neonatal morbidities. hyperinsulinemia, macrosomia, and neonatal hypoglycemia. Although this infant Generally, sulfonylurea use in preghad no abnormalities after being exposed to gliclazide and ramipril during the first nancy is not recommended, secondary to 16 weeks of gestation, this case is not an unconditionally acceptable indication known effects on the fetus such as confor safety of these medications in pregnancy. Angiotensin-converting enzyme genital abnormalities, fetal hyperinsulineinhibitors increase fetal risks and therefore should not be used during pregnancy, according to data from animals and humans. There are few data available on use mia, macrosomia, and neonatal hypoof sulfonylureas; thus, their use should also be avoided during pregnancy. glycemia. Ideally, blood glucose levels in CONCLUSIONS: Although the normal pregnancy outcome in our patient does not women with type 2 diabetes should be indicate that use of gliclazide and ramipril is safe during gestation, these data regulated by diet intervention and insulin contribute to limited information regarding human exposure to these drugs. therapy during pregnancy and lactation KEY WORDS: gliclazide, pregnancy, ramipril. periods, starting 2–3 months before con4,5 Ann Pharmacother 2009;43:147-9. ception. Published Online, 23 Dec 2008, www.theannals.com, DOI 10.1345/aph.1L332 Antihypertensive medications like methyldopa, hydralazine, labetalol, and other β-adrenoceptor blockers are safe for use in hypertensive pregnant women.1,2,6 However, anCase Report giotensin-converting enzyme (ACE) inhibitors increase fetal A woman with hypertension and type 2 diabetes mellirisks and therefore should not be used during pregnancy, actus who had been taking gliclazide 30 mg/day and ramipril 7 cording to data shown in animals and humans. 10 mg/day for 2 years was admitted to the Division of EnWe describe a patient who used gliclazide and ramipril docrinology, Akdeniz University Hospital, during the 16th in the first 16 weeks of pregnancy and gave birth to a week of gestation. Her fasting blood glucose level was 88 healthy child. mg/dL and hemoglobin HbA1c (A1C) level was 5.1% one month before her last menstrual period; she had not reported for scheduled control examinations since that time. She Author information provided at the end of the text. had not taken any other medications during this period.

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Gliclazide and ramipril were discontinued in the 17th week of pregnancy. Amniocentesis performed at that time and radiologic fetal abnormality screening results were uneventful. Intensive insulin therapy (4 units of regular insulin 3 times a day and 6 units of NPH insulin once a day) was started for blood glucose regulation at an outpatient clinic. After 2 weeks of insulin therapy, her insulin requirement decreased and treatment was continued with NPH insulin twice daily (8 units in the morning, 4 units in the evening). On a follow-up examination, capillary blood fasting glucose (75–96 mg/dL), 1-hour postprandial glucose (132– 175 mg/dL), 2-hour postprandial glucose (104–122 mg/dL), fructosamine (32–36 mg/dL), and A1C (5.1–6.8%) levels were all within acceptable target levels. Methyldopa 500 mg 4 times daily (2000 mg/day) was started for control of high blood pressure. The woman’s mean arterial blood pressure was 130/80 mm Hg during methyldopa therapy. The patient was hospitalized in the 36th week for the control of preterm labor and gave birth to a female infant (3200 g) by caesarean section. APGAR scores for the baby at 1 and 5 minutes were 8 and 10, respectively, and no abnormality was observed. The infant’s blood glucose, C-peptide, and insulin levels were within normal limits. Results of abdominal ultrasonography and echocardiography were also normal. At time of writing, the child was 1.5 years old and considered to be healthy (physical examination; blood glucose, C-peptide, and insulin levels; abdominal ultrasonography; and echocardiography were normal). Discussion Maternal and perinatal morbidity in patients with diabetes mellitus are correlated with glycemic control in the mothers.8 Malformation and perinatal mortality rates decrease with good control of blood glucose levels.3,4,9,10 According to American Diabetes Association recommendations, the best approach to blood glucose regulation in diabetic women during preconception and pregnancy is insulin therapy. Most sulfonylureas are not recommended for use during pregnancy, as they can cross the placenta and may cause adverse effects such as fetal hyperinsulinemia, macrosomia, protracted neonatal hypoglycemia, and fetal malformation.3,4 Glyburide has shown minimal passage through the placenta, in contrast with other sulfonylureas.11,12 It has not demonstrated increased neonatal hypoglycemia and congenital abnormalities and has been shown to be effective in pregnant women13,14; thus, it is increasingly used in pregnant women. Data on gliclazide (a second-generation sulfonylurea) use in pregnancy are scarce. Yaris et al.15 followed a patient taking rosiglitasone, gliclazide, and atorvastatin during the first 7 weeks of pregnancy and did not observe any abnormalities in the infant after birth. We also did not detect any deformities in the child. 148

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In addition to oral antidiabetic drug use, our patient was also taking ramipril, an ACE inhibitor, for treatment of hypertension. Use of antihypertensive agents such as methyldopa, hydralazine, labetalol, and other β-adrenoceptor blockers is safe in pregnant women.1,2,16 ACE inhibitors, on the other hand, increase fetal risks and therefore should not be used during pregnancy.1,2,6,7 Experimental data suggest a role for angiotensin II in the regulation of uterine–placental blood flow, fetal growth, and development of fetal kidneys.16 An epidemiologic study has shown that angiotensin II receptor blockers and ACE inhibitors are not safe when used in the early phases of pregnancy.17 In that study, 209 patients who had used ACE inhibitors during the first 3 months of pregnancy were compared with 202 patients who used other antihypertensive agents during the same period. A significant excess in cases of major congenital malformations was observed in infants exposed to ACE inhibitors in comparison with those who were exposed to other antihypertensive drugs. The most frequently observed malformations were in the cardiovascular (risk ratio 3.72) and central nervous (risk ratio 4.39) systems. In addition, the investigators reported 305 of 850 infants with cardiovascular malformations (including 141 with atrial septal defect, 124 with patent ductus arteriosus, 76 with ventricular septal defect, 29 with pulmonic stenosis) and 83 of 850 infants with central nervous system malformations (including 24 with hydrocephalus, 17 with microcephaly, 9 with spina bifida, 2 with encephalocele).17 In another study, use of ACE inhibitors in the second and third trimesters of pregnancy resulted most commonly in abnormalities of the kidney, oligohydramnios, intrauterine death, neonatal anuria, and renal failure.18 Fetal risk of congenital malformations significantly increases with ACE inhibitor use in every phase of pregnancy.1,2,6,7,16-19 In conclusion, the presence of normal gestational findings after maternal use of gliclazide and ramipril during the first 16 weeks of gestation is not a sufficient indication of the safety of these medications in pregnancy. The data from our patient contribute to the limited knowledge available regarding human exposure to gliclazide and ramipril during pregnancy. Caution should be exercised in the use of these drugs in hypertensive women and in those with type 2 diabetes mellitus during their reproductive years, and the patients should be warned about these drugs’ effects on the fetus. When gliclazide and/or ramipril are used, they should be stopped as soon as pregnancy is detected and safer medications should be started. Oykun Kolagasi MD, Clinical Specialist, Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University, Turkey

Funda Sari MD, Clinical Specialist, Antalya Education and Research Hospital, Ministry of Health, Division of Nephrology, Antalya

Munire Akar MD, Associate Professor, Department of Gynecology, School of Medicine, Akdeniz University

Ramazan Sari MD, Associate Professor, Division of Endocrinology and Metabolism, School of Medicine, Akdeniz University

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Normal Pregnancy and Healthy Child After Exposure to Gliclazide and Ramipril

Reprints: Dr. Sari, Akdeniz University, School of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, TR-07070, Antalya,Turkey, fax 90 242 2274490, rsari@ akdeniz.edu.tr, [email protected]

References 1. Ghanem FA, Movahed A. Use of antihypertensive drugs during pregnancy and lactation. Cardiovasc Ther 2008;26:38- 49. 2. Podymow T, August P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008;51:960-9. 3. Guideline Development Group. Management of diabetes from preconception to the postnatal period: summary of NICE guidance. BMJ 2008; 336:714-7. 4. Gestational diabetes mellitus. Position statements. Diabetes Care 2003; 26(suppl):S103-5. 5. Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabetes Care 2007;30(suppl 2):S206-8. 6. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med 1996;335:257-65. 7. Shotan A, Widerhorn J, Hurst A, et al. Risks of angiotensin-converting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med 1994;96:451-6. 8. Reece EA, Homko CJ. Diabetes mellitus in pregnancy: what are the best treatment options? Drug Saf 1998;18:209-20. 9. Steel JM, Johnstone FD, Hepburn DA, et al. Can prepregnancy care of diabetic women reduce the risk of abnormal babies? BMJ 1990;301: 1070-4. 10. Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception care of diabetes: glycemic control prevents congenital anomalies. JAMA 1991;265:731-6. 11. Elliott BD, Schenker S, Langer O, et al. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol 1994;171:653-60. 12. Moore TR. Glyburide for the treatment of gestational diabetes. A critical appraisal. Diabetes Care 2007;30(suppl 2):S209-13. 13. Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134-8. 14. Rochon M, Rand L, Roth L, et al. Glyburide for the management of gestational diabetes: risk factors predictive of failure and associated pregnancy outcomes. Am J Obstet Gynecol 2006;195:1090- 4. 15. Yaris F, Yaris E, Kadioglu M, et al. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod Toxicol 2004;18:619-21. 16. Ferris TF, Weir EK. Effects of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest 1983;71:809-15. 17. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51. 18. Hanssens M, Keirse MJ, Vankelecom F, et al. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991;78:128-35. 19. Tabacova S, Little R, Tsong Y, et al. Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol Drug Saf 2003;12:633- 46.

Embarazo Normal y Neonato Sano tras Exposición Continua a Glicazida y Ramipril Durante el Embarazo-Presentación del Caso

RESUMEN DEL CASO: Una mujer de 42 años con diabetes mellitus tipo 2 e hipertensión, bajo tratamiento con glicazida 30 mg/día y ramipril 10 mg/ día durante 2 años, fue ingresada en la semana 16 de gestación. En la semana 17 de embarazo, se retiró el tratamiento con glicazida y ramipril y se inició la terapia con metildopa e insulina. La paciente dio a luz un bebé sano mediante cesárea tras completar un periodo de gestación sin incidentes de interés. El nacimiento de un bebé sano después del tratamiento con glicazida y ramipril durante las primeras 16 semanas de gestación no constituye un criterio aceptable incondicional para mostrar la seguridad de estos medicamentos en el embarazo. DISCUSIÓN: No se recomiendan los fármacos antidiabéticos orales durante el embarazo debido a efectos secundarios conocidos sobre el feto como anomalías congénitas, hiperinsulinemia fetal, macrosomia, e hipoglucemia neonatal. Por otra parte, los inhibidores de la enzima convertidora de la angiotensina aumentan los riesgos fetales y, por lo tanto, no deben utilizarse durante el embarazo, de acuerdo con los datos obtenidos en animales y humanos. En estas páginas se presenta el caso de una paciente que tomó glicazida y ramipril en las primeras 16 semanas de embarazo y posteriormente completó un periodo normal de gestación y dio a luz a un bebé sano. CONCLUSIONES: Aunque el término normal del embarazo no asegura la seguridad de glicazida y ramipril durante el embarazo, estos datos contribuyen a un conocimiento limitado sobre la exposición humana a glicazida y ramipril.

Traducido por Enrique Muñoz Soler

Une Grossesse Normale et en Enfant en Santé Après une Exposition Soutenue au Gliclazide et au Ramipril Durant la Grossesse O Kolagasi, F Sari, M Akar, et R Sari Ann Pharmacother 2009;43:147-9. RÉSUMÉ OBJECTIF: Signaler le cas d’une patiente diabétique et hypertendue exposée au gliclazide et au ramipril durant sa grossesse. PRÉSENTATION SOMMAIRE DU CAS: Une dame de 42 ans diabétique et hypertendue et prenant depuis 2 ans du gliclazide à raison de 30 mg une fois par jour et du ramipril à raison de 10 mg une fois par jour est admise à l’hôpital lors de sa seizième semaine de grossesse. Durant la 16 semaine de grossesse, l’administration de gliclazide et de ramipril est discontinuée et un traitement à base de méthyldopa et une thérapie intensive à l’insuline sont instaurés. La dame a donné naissance par césarienne à un enfant en santé après une période de gestation complète et sans incident. La naissance d’un enfant en santé après l’utilisation de gliclazide et de ramipril durant les 16 premières semaines de grossesse n’est pas un critère qu’on peut accepter inconditionnellement pour démontrer la sécurité de ces médications durant la grossesse. DISCUSSION: L’utilisation des agents antidiabétiques oraux durant la grossesse n’est pas recommandée dû aux conséquences connues sur le fœtus telles les anormalités congénitales, l’hyperinsulinémie fœtale, la macrosomie, et l’hypoglycémie néonatale. D’un autre côté, les inhibiteurs de l’enzyme de conversion de l’angiotensine augmentent les risques au niveau fœtal et ne devraient donc pas être utilisés durant la grossesse selon des données chez des animaux et chez des humains. On présente ici le cas d’une patiente qui a utilisé le gliclazide et le ramipril durant les 16 premières semaines de sa grossesse et qui a par la suite complété une période normale de gestation et donné naissance à une enfant en santé. CONCLUSIONS: Bien que la survenue d’une grossesse normale ne rétablisse pas la sécurité de l’utilisation du gliclazide et du ramipril durant la grossesse, ces données s’ajoutent aux connaissances limitées concernant une exposition humaine au gliclazide et au ramipril durant la grossesse.

Traduit par Marie Larouche

O Kolagasi, F Sari, M Akar, y R Sari Ann Pharmacother 2009;43:147-9. EXTRACTO OBJETIVO: Notificar un caso de exposición a glicazida y ramipril durante el embarazo en una paciente con diabetes mellitas e hipertensión.

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