血管紧张素转换酶抑制剂对灵长类动物妊娠的胚胎毒性：一项在狒狒（阿拉伯狒狒）中进行的前瞻性、安慰剂对照研究。

Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas).

作者信息

Harewood W J, Phippard A F, Duggin G G, Horvath J S, Tiller D J

机构信息

Department of Renal Medicine, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales, Australia.

出版信息

Am J Obstet Gynecol. 1994 Sep;171(3):633-42. doi: 10.1016/0002-9378(94)90075-2.

DOI:10.1016/0002-9378(94)90075-2

PMID:8092208

Abstract

OBJECTIVES

Serious concerns have been raised about angiotensin-converting enzyme inhibition in pregnancy. The central question remains: does toxicity of angiotensin-converting enzyme inhibition pertain to pregnant humans?

STUDY DESIGN

A prospective, placebo-controlled study was performed to investigate the effect of angiotensin-converting enzyme inhibition on pregnancy outcome in the baboon. Subjects (N = 12) received active and placebo treatments sequentially in a crossover protocol. Data were analyzed with two-sample t tests, analysis of variance, Fisher's exact test, or Kaplan-Meier survival analysis, where appropriate.

RESULTS

Chronic administration of enalapril (7.5 mg per day) from before conception achieved moderate but sustained angiotensin-converting enzyme inhibition as determined by repeated measures of renin-angiotensin system parameters (serum angiotensin-converting enzyme activity, plasma renin activity and plasma angiotensin I, angiotensin II, and aldosterone concentrations). Serum angiotensin-converting enzyme activity was significantly reduced throughout (< 10 nmol.ml-1.min-1, p < 0.01), with significant increases in plasma renin activity and angiotensin I (p < 0.01). Angiotensin II and aldosterone were maintained unchanged compared with placebo. There was a significant incidence of fetal death or intrauterine growth retardation in fetuses exposed to enalapril (eight of 13, zero on placebo, p < 0.01). When the definition of adverse pregnancy outcome was restricted to fetal death alone (four of 13) the difference remained significant (p < 0.05). Maternal arterial pressure was unchanged before conception, but a small and significant fall (10 to 15 mm Hg, p < 0.01) was detected throughout pregnancy. There was no fetal malformations.

CONCLUSION

The study provides definitive evidence for serious consequences of angiotensin-converting enzyme inhibition in pregnancy of high-order primates.

摘要

目的

人们对孕期使用血管紧张素转换酶抑制剂提出了严重关切。核心问题依然存在：血管紧张素转换酶抑制剂对孕妇是否有毒性？

研究设计

进行了一项前瞻性、安慰剂对照研究，以调查血管紧张素转换酶抑制剂对狒狒妊娠结局的影响。受试者（N = 12）按照交叉方案依次接受活性药物和安慰剂治疗。在适当情况下，使用双样本t检验、方差分析、Fisher精确检验或Kaplan-Meier生存分析对数据进行分析。

结果

从受孕前开始长期给予依那普利（每天7.5毫克），通过对肾素-血管紧张素系统参数（血清血管紧张素转换酶活性、血浆肾素活性以及血浆血管紧张素I、血管紧张素II和醛固酮浓度）的重复测量确定，实现了中度但持续的血管紧张素转换酶抑制。整个孕期血清血管紧张素转换酶活性显著降低（<10纳摩尔·毫升⁻¹·分钟⁻¹，p<0.01），血浆肾素活性和血管紧张素I显著升高（p<0.01）。与安慰剂相比，血管紧张素II和醛固酮保持不变。暴露于依那普利的胎儿出现胎儿死亡或宫内生长受限的发生率显著（13例中有8例，安慰剂组为0例，p<0.01）。当不良妊娠结局的定义仅限于胎儿死亡时（13例中有4例），差异仍然显著（p<0.05）。受孕前母体动脉压未改变，但整个孕期检测到有小幅但显著的下降（10至15毫米汞柱，p<0.01）。未发现胎儿畸形。