Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case–control study

Abstract

Objective To study previously identified associations between specific maternal hypertensive disorders and/or prenatal exposure to antihypertensive medication and birth defects.Design Case-control study.Setting Slone Birth Defects Study, 1998-2010.Population A total of 5568 cases with birth defects and 7253 liveborn infants without malformations as controls.Methods Adjusted odds ratios (aORs) for birth defects associated with prenatal exposure to maternal hypertensive disorders and/or antihypertensive medication were calculated using multivariable logistic regression analyses.Main outcome measures Specific birth defects previously linked to maternal hypertension or antihypertensive medication use during pregnancy.Results Non-pharmacologically managed chronic hypertension was associated with a three-fold risk of oesophageal atresia (95% CI 1.2-8.3), and pre-eclampsia superimposed on nonpharmacologically managed chronic hypertension was associated with ventricular septal defects (aOR 3.9, 95% CI 1.3-11.7) and atrial septal defects (aOR 6.5, 95% CI 1.8-23.7). For chronic hypertension that was pharmacologically treated early in pregnancy, increased risks were observed for first-degree hypospadias (aOR 2.9, 95% CI 1.1-7.4). Non-pharmacologically managed pre-eclampsia was related to second-/third-degree hypospadias and ventricular septal defects. Pharmacological treatment for gestational hypertension was associated with a number of congenital heart defects.Conclusions Our results confirm some, but not all, previously identified associations between pharmacologically treated and non-pharmacologically managed hypertensive disorders and specific birth defects. They support the hypothesis that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias.

Pregnancy Outcome After First Trimester Use of Methyldopa

“…[26][27][28][29][30] The small number of major birth defects in our study does not allow further analysis with regard to other organ systems like urogenital malformations that were previously reported to be associated with antihypertensive treatment. 31 However, there is no distinct pattern of congenital anomalies among exposed neonates, neither in our prospective cohort nor among our retrospective reports. The low number of only 5 major birth defects reported to our adverse drug reaction in pregnancy database during the 15 years study period confirms the low risk of methyldopa during first trimester.…”

“…26,31 However, comorbidities associated with or predisposing to chronic hypertension, like a high BMI and diabetes mellitus, are known to be associated with adverse pregnancy outcome, including a higher malformation risk. 32,33 Of note, among our 9 methyldopa-exposed major birth defects, 2 mothers had preexisting diabetes mellitus type 2.…”

Farmacocinética E Mecanismos De Teratogenicidade Dos Medicamentos Na Gestação: Uma Revisão Da Literatura.

“…As principais enzimas associadas a esse efeito são: 1) perturbação do sistema renina-angiotensina fetal, produzindo hipotensão fetal, rompimento vascular e diminuição do tônus vascular renal fetal, quando da administração de inibidores da enzima conversora de angiotensina (ECA) e antagonistas dos receptores de angiotensina II (ARA); 2) as estatinas inibem a hidroximetilglutaril-coenzima A (HMG--CoA) redutase, a enzima limitante da velocidade na via que converte HMG-CoA em ácido mevalônico -a inibição desta via promovida por estatinas pode conduzir a uma ampla gama de defeitos que vão desde o crescimento embrionário até formação de estruturas; 3) a desacetilação das histonas por inibição da enzima histona desacetilase (HDACs) compromete uma grande quantidade de funções celulares, incluindo a regularidade da expressão gênica por remodelação da cromatina, a transcrição para o DNA, resultando em interrupção da proliferação celular, diferenciação e apoptose; 4) a inibição da ciclooxigenase I (COX--I) que catalisa a conversão do ácido araquidônico a prostaglandinas, interferindo no sistema renina-angiotensina, nesse grupo se encaixam todos os antiinflamatórios não esteroidais. 5) o bloqueio do receptor N-metil-D-aspartato (NMDA), causando erros na migração de elementos neuronais e gliais no cérebro em desenvolvimento; 6) o aumento ou a supressão da estimulação de receptores da 5-hidroxitriptamina ou a inibição do transporte pode causar anomalias congê-nitas e os fármacos envolvidos neste mecanismo são a buspirona e risperidona; 7) a inibição da anidrase carbônica, causando redução no pH intracelular embrionário sendo os fármacos envolvidos a acetazolamida e o topiramato (18,25,26,28,29,33,(37)(38)(39).…”

Preeclampsia y defecto cardiaco fetal: ¿existe una asociación? Revisión de la evidencia

“…Maternal hypertensive disorders, antihypertensive medication usea, and the risk of birth defects: a case-control study (4) Association between preeclampsia and congenital heart defects (10) …”

“…Así mismo la PE se asocia a diversas complicaciones fetales que incluyen la restricción del crecimiento intrauterino, prematuridad, defectos congénitos del sistema nervioso, digestivo, alteraciones hematológicas y recientemente se han descrito diversos tipos de defectos cardiacos (4).…”