Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits Mark Pucci, Nadia Sarween, Ellen Knox, Graham Lipkin & Una Martin To cite this article: Mark Pucci, Nadia Sarween, Ellen Knox, Graham Lipkin & Una Martin (2015) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits, Expert Review of Clinical Pharmacology, 8:2, 221-231, DOI: 10.1586/17512433.2015.1005074 To link to this article: https://doi.org/10.1586/17512433.2015.1005074
Published online: 22 Jan 2015.
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Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierj20 Download by: [University of New England]
Date: 08 January 2018, At: 14:01
Downloaded by [University of New England] at 14:01 08 January 2018
Review
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits Expert Rev. Clin. Pharmacol. 8(2), 221–231 (2015)
Mark Pucci1, Nadia Sarween1, Ellen Knox2, Graham Lipkin1 and Una Martin*3 1 University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2WB, UK 2 Birmingham Women’s NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK 3 School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2SP, UK *Author for correspondence [email protected]
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients. KEYWORDS: angiotensin receptor blockers . angiotensin-converting enzyme inhibitors . chronic kidney disease .
congenital malformations
.
first trimester . hypertension . pregnancy
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most widely used drugs for the treatment of hypertension, heart failure and chronic kidney disease (CKD). In 2012, there were approximately 23.8 million community prescriptions for ramipril dispensed in England alone [1]. In the UK, ACEIs or ARBs are recommended by the National Institute for Health and Care Excellence (NICE) and the British Hypertension Society as the first-line drugs for non-black patients with hypertension under the age of 55 years [2]. However, some clinicians have called for the use of ACEIs and ARBs to be avoided altogether in women of childbearing age because of their potential teratogenic risks. The first reports of possible toxic effects of ACEIs on the developing fetus appeared in 1981 [3,4] and numerous subsequent case reports led to a now well-characterized syndrome when the fetus is exposed during the second and third informahealthcare.com
10.1586/17512433.2015.1005074
.
teratogenicity
trimesters of pregnancy, variably termed ACEI fetopathy or fetal >renin–angiotensin–system (RAS) blockade syndrome (TABLE 1). The pathogenesis of this syndrome is still not fully understood, but is likely to be due to a combination of factors, including fetal hypotension and the loss of a functional RAS, resulting in reduced renal blood flow and glomerular filtration pressure [5]. What has been more difficult to establish, however, is whether these drugs are harmful to the fetus when taken by the mother during the first trimester of pregnancy. Conflicting study results and inconsistent guidelines have led to confusion in the medical community over whether or not these drugs are safe to be used in women of reproductive age. Hypertension in women of childbearing age & during pregnancy
Hypertension in women of childbearing age is not uncommon. According to the Health Survey for England 2012, 6.7% of women
2015 Informa UK Ltd
ISSN 1751-2433
221
Review
Pucci, Sarween, Knox, Lipkin & Martin
Table 1. Features of fetal RAS blockade syndrome [5]. Oligohydramnios
Fetal growth retardation
Neonatal renal failure
Hypotension
Fetal pulmonary hypoplasia
Joint contractures
Patent ductus arteriosus
Hypocalvaria
Downloaded by [University of New England] at 14:01 08 January 2018
RAS: Renin–angiotensin system.
aged 25–34 years had high blood pressure (BP), rising to 8.1% of women aged 35–44 years [6], although the majority is untreated because of low overall cardiovascular risk. In the USA, the estimated prevalence of hypertension in women aged 20–44 years was 7.7%, according to analysis of the National Health and Nutrition Examination Survey 1999–2008 [7]. Among antihypertensive users in this age group, 44% were taking ACEIs and 20.4% were taking ARBs. In a retrospective cohort study looking at new referrals to a tertiary hypertension clinic in the UK, 47% of women aged 16–45 years were taking an ACEI, an ARB or both at the time of referral [8]. In addition, the average maternal age at delivery is increasing. In England and Wales, approximately half (50.5%) of all live births in 2013 were to mothers of 30 years of age and over, and the average age of mothers increased to 30 years for the first time [9]. Coupled with increasing rates of obesity and diabetes, the trend for increased maternal age is leading to an increased prevalence of hypertension in pregnancy. Hypertension is the most common medical complication affecting pregnancy, affecting 5–15% of all pregnancies [10]. The estimated incidences of pre-eclampsia and eclampsia are 4.6 and 1.4%, respectively, but there are wide regional variations [11]. Definitions of hypertensive disorders during pregnancy have changed over time, but are now classified internationally into four clinical categories (BOX 1). Women with chronic hypertension have worse pregnancy outcomes compared with the general population. A recent systematic review and meta-analysis demonstrated that women with chronic hypertension had high pooled average incidences of all adverse pregnancy outcomes, including superimposed pre-eclampsia (estimated incidence 25.9%), Caesarean section (41.4%), preterm delivery Box 1. Categorisation of hypertensive disorders of pregnancy [13]. .
.
.
.
Gestational hypertension is pregnancy-induced hypertension after 20 weeks gestation. Chronic hypertension is pre-existing hypertension of any cause. Pre-eclampsia is traditionally defined as hypertension with proteinuria, (but can occur in the absence of proteinuria); and eclampsia (associated with convulsions). Chronic hypertension with super-imposed pre-eclampsia.
222
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits Mark Pucci, Nadia Sarween, Ellen Knox, Graham Lipkin & Una Martin To cite this article: Mark Pucci, Nadia Sarween, Ellen Knox, Graham Lipkin & Una Martin (2015) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits, Expert Review of Clinical Pharmacology, 8:2, 221-231, DOI: 10.1586/17512433.2015.1005074 To link to this article: https://doi.org/10.1586/17512433.2015.1005074
Published online: 22 Jan 2015.
Submit your article to this journal
Article views: 263
View related articles
View Crossmark data
Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierj20 Download by: [University of New England]
Date: 08 January 2018, At: 14:01
Downloaded by [University of New England] at 14:01 08 January 2018
Review
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits Expert Rev. Clin. Pharmacol. 8(2), 221–231 (2015)
Mark Pucci1, Nadia Sarween1, Ellen Knox2, Graham Lipkin1 and Una Martin*3 1 University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2WB, UK 2 Birmingham Women’s NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK 3 School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2SP, UK *Author for correspondence [email protected]
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are effective and widely used antihypertensive drugs. Exposure to these agents is known to be harmful to the fetus in the second and third trimesters of pregnancy. Concerns have also been raised about the risk of congenital malformations if ACEIs or ARBs are taken during the first trimester of pregnancy. The evidence to date, however, is conflicting and observed malformations may be due to confounders such as undiagnosed diabetes or maternal obesity, other antihypertensive medications or the hypertension itself. Nonetheless, in women who become pregnant while taking an ACEI or ARB, the drug should be stopped as soon as possible. In women with chronic kidney disease and proteinuria, it may be appropriate to continue taking an ACEI or ARB until the pregnancy is confirmed because of the significant benefit to their kidney function and the lower fertility rate in these patients. KEYWORDS: angiotensin receptor blockers . angiotensin-converting enzyme inhibitors . chronic kidney disease .
congenital malformations
.
first trimester . hypertension . pregnancy
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most widely used drugs for the treatment of hypertension, heart failure and chronic kidney disease (CKD). In 2012, there were approximately 23.8 million community prescriptions for ramipril dispensed in England alone [1]. In the UK, ACEIs or ARBs are recommended by the National Institute for Health and Care Excellence (NICE) and the British Hypertension Society as the first-line drugs for non-black patients with hypertension under the age of 55 years [2]. However, some clinicians have called for the use of ACEIs and ARBs to be avoided altogether in women of childbearing age because of their potential teratogenic risks. The first reports of possible toxic effects of ACEIs on the developing fetus appeared in 1981 [3,4] and numerous subsequent case reports led to a now well-characterized syndrome when the fetus is exposed during the second and third informahealthcare.com
10.1586/17512433.2015.1005074
.
teratogenicity
trimesters of pregnancy, variably termed ACEI fetopathy or fetal >renin–angiotensin–system (RAS) blockade syndrome (TABLE 1). The pathogenesis of this syndrome is still not fully understood, but is likely to be due to a combination of factors, including fetal hypotension and the loss of a functional RAS, resulting in reduced renal blood flow and glomerular filtration pressure [5]. What has been more difficult to establish, however, is whether these drugs are harmful to the fetus when taken by the mother during the first trimester of pregnancy. Conflicting study results and inconsistent guidelines have led to confusion in the medical community over whether or not these drugs are safe to be used in women of reproductive age. Hypertension in women of childbearing age & during pregnancy
Hypertension in women of childbearing age is not uncommon. According to the Health Survey for England 2012, 6.7% of women
2015 Informa UK Ltd
ISSN 1751-2433
221
Review
Pucci, Sarween, Knox, Lipkin & Martin
Table 1. Features of fetal RAS blockade syndrome [5]. Oligohydramnios
Fetal growth retardation
Neonatal renal failure
Hypotension
Fetal pulmonary hypoplasia
Joint contractures
Patent ductus arteriosus
Hypocalvaria
Downloaded by [University of New England] at 14:01 08 January 2018
RAS: Renin–angiotensin system.
aged 25–34 years had high blood pressure (BP), rising to 8.1% of women aged 35–44 years [6], although the majority is untreated because of low overall cardiovascular risk. In the USA, the estimated prevalence of hypertension in women aged 20–44 years was 7.7%, according to analysis of the National Health and Nutrition Examination Survey 1999–2008 [7]. Among antihypertensive users in this age group, 44% were taking ACEIs and 20.4% were taking ARBs. In a retrospective cohort study looking at new referrals to a tertiary hypertension clinic in the UK, 47% of women aged 16–45 years were taking an ACEI, an ARB or both at the time of referral [8]. In addition, the average maternal age at delivery is increasing. In England and Wales, approximately half (50.5%) of all live births in 2013 were to mothers of 30 years of age and over, and the average age of mothers increased to 30 years for the first time [9]. Coupled with increasing rates of obesity and diabetes, the trend for increased maternal age is leading to an increased prevalence of hypertension in pregnancy. Hypertension is the most common medical complication affecting pregnancy, affecting 5–15% of all pregnancies [10]. The estimated incidences of pre-eclampsia and eclampsia are 4.6 and 1.4%, respectively, but there are wide regional variations [11]. Definitions of hypertensive disorders during pregnancy have changed over time, but are now classified internationally into four clinical categories (BOX 1). Women with chronic hypertension have worse pregnancy outcomes compared with the general population. A recent systematic review and meta-analysis demonstrated that women with chronic hypertension had high pooled average incidences of all adverse pregnancy outcomes, including superimposed pre-eclampsia (estimated incidence 25.9%), Caesarean section (41.4%), preterm delivery Box 1. Categorisation of hypertensive disorders of pregnancy [13]. .
.
.
.
Gestational hypertension is pregnancy-induced hypertension after 20 weeks gestation. Chronic hypertension is pre-existing hypertension of any cause. Pre-eclampsia is traditionally defined as hypertension with proteinuria, (but can occur in the absence of proteinuria); and eclampsia (associated with convulsions). Chronic hypertension with super-imposed pre-eclampsia.
222
