Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study
BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d5931 (Published 18 October 2011) Cite this as: BMJ 2011;343:d5931
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Li et al(1) reported that mothers who used ACE inhibitors in the
first trimester had a similar risk regarding foetal malformation as
those who used other antihypertensive drugs.
However, it is surprising that ACE inhibitors are still used, given the high rate of fetal malformations caused by them. Indeed ACE
inhibitors are responsible for malformations of the cardiovascular system
and the central nervous system, which is not the case for other
antihypertensive drugs such as calcium-channel blockers(3). Moreover ACE
inhibitors may cause stillbirths, neonatal deaths, foetal hypotension
oligohydramnios and intrauterine growth restriction (3)
The use of ACE inhibitors was not compared to another single class of
antihypertensive drug but to a heterogeneous group containing diuretics,
beta blockers, methyldopa and calcium-channel blockers, which made the
interpretation of results confused. In addition, the maternal use of
diuretics is not recommended during the first trimester of pregnancy as
they cause hypovolaemia and dehydration (3).
The safety of maternal use of calcium-channel blockers on the foetus
is demonstrated in many studies (3, 4, 5). Therefore they are recommended
to treat hypertension during the first trimester of pregnancy.
As ACE inhibitors have teratogenic and many foetal adverse effects
they should be avoided during the first trimester of pregnancy. They could
be replaced by calcium-channel blockers, which are not responsible for
foetal malformations.
References
1. Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure
to angiotensin converting enzyme inhibitors in the first
trimester and risk of malformations in offspring: a retrospective cohort
study. BMJ. 2011 Oct 18;343:d5931. doi: 10.1136/bmj.d5931.
2. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S,
Gideon PS, Hall K, Ray WA. Major congenital malformations after first-
trimester exposure to ACE inhibitors. N Engl J Med. 2006 ;354:2443-51.
3. Podymow T, August P. Antihypertensive drugs in pregnancy. Semin
Nephrol. 2011 ;31:70-85.
4. [No authors listed] Chronic hypertension in pregnancy. N Engl J
Med. 2011 ;365:1650.
5. Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine
administered in pregnancy: effect on the development of children at 18
months. BJOG. 2000 ;107:792-4.
Competing interests: No competing interests
This study has done well to lay emphasis on the fact that maternal
hypertension per se, can increase risk of birth defects. There are,
however, limiting factors to this study as it is based on electronic
health records which could fail to take into consideration compliance
issues, the use of other "over the counter", "on the internet"
medications, undisclosed addictions etc.
This study also seems to echo the observations in PG Pryde &
colleagues' paper (from 1993) which gave birth to the entity of "ACE-
inhibitor fetopathy".1 On the basis of their own observations of human
cases, & those reported by others and from the results of experiments
on animal models, they highlighted the emergence of a specific pattern of
fetal adversity they classed as "fetopathy" in patients who took ACE
inhibitors in the second and third trimester. Most of patients reported
had pre-existing disease such as essential hypertension, renovascular
disease, SLE, renal transplantation or developed PIH or pre-eclampsia,
suggesting that the underlying microvascular disease per se may have lead
to adverse fetal outcomes. Further fetal hypotension & renal
hypoperfusion associated with the use of an ACE inhibitor was postulated
as the pathophysiological mechanism in producing the classical picture.
Another issue that merits further thought is the practice of
accepting BP greater than or equal to 140/90 as hypertension.2-3 It would
seem unrealistic to adopt a similar target in all pregnant asymptomatic
women. BP in pregnancy is a dynamic variable on a continuous parabola;
dropping initially as a result of progestogenic vasodilatation until about
20 weeks & thereafter rising. Hence BP targets ought to be
individualized on the basis of serial measurements beginning from the
preconception stage or early pregnancy. Perhaps adopting the recent NICE
guidance on using ambulatory BP monitoring to establish a diagnosis of
hypertension 4 could well be used to rule out the "white coat element" and
establish a circadian pattern to the BP. In a small case- control study
pathological blood pressure in pregnant women was shown to have a less
pronounced circadian oscillation & the severity of hypertension seemed
to favour the loss of diurnal rhythm.5 If this is established as a routine
practise in antenatal clinics, then thresholds for normality may emerge
for individual pregnancies.
References
1. Pryde PG, Sedman AB, Nugent CE, Barr M Jr. Angiotensin-converting
enzyme inhibitor fetopathy. J. Am. Soc. Nephrol. 1993;3:1575-1582.
2. National Institute for Health and Clinical Excellence 2010
Hypertension in pregnancy. CG107. London: National Institute for Health
and Clinical Excellence.
3. Magee LA, Helewa M, Moutquin J-M et al. Diagnosis, Evaluation, and
Management of the Hypertensive Disorders of Pregnancy. Journal of
Obstetrics and Gynaecology Canada 2008;30:S1-S48.
4. National Institute for Health and Clinical Excellence 2011
Hypertension. CG127. London: National Institute for Health and Clinical
Excellence.
5. Benedetto C, Zonca M, Marozio L, Dolci C, et al. Blood pressure
patterns in normal pregnancy and in pregnancy-induced hypertension,
preeclampsia, and chronic hypertension. Obstet Gynecol. 1996;88(4 Pt
1):503-10.
Competing interests: No competing interests
Li et al's study of the association between maternal hypertension and
the risk of congenital anomalies has both aetiological and clinical
implications.[1] However, the study has one obvious limitation that raises
some important interpretational issues; it only includes live born cases
of congenital anomaly.
By far the most clinically-relevant aspect of Li et al's study is the
conclusion that 'the apparent increased risk of malformations association
with use of ACE inhibitors and other antihypertensive... is likely due to
the underlying hypertension rather than the medications'.[1] Although
alarming on a population-level, this would provide some relief for a
pregnant women's healthcare team, as it eliminates a potentially
challenging discord between the interests of the mother and her
offspring.[2] The validity of this result, however, hinges on the
robustness of the 'hypertension control' group, in which Li et al
identified an increased risk of congenital anomaly compared to those with
'neither a diagnosis of hypertension, nor use of any antihypertensive
drug'. We propose that, at least some of, this could be an artefact due to
the lack of data on terminations of pregnancy.
There are many benefits to capturing all cases of congenital anomaly,
not just those among live born infants, but the most important for any
aetiological study is for reducing the risk of sampling bias. By only
examining live born cases, any variable that is correlated with access or
uptake of prenatal screening or termination of pregnancy for fetal anomaly
will automatically appear to predict cases of congenital anomaly.
Furthermore, such studies have disproportionately low numbers of the more
severe subtypes, because these cases are selected-out by higher rates of
termination of pregnancy. This has implications if the exposure of
interest is more or less likely to affect these subtypes and, as with Li
et al, the analysis is only performed by anomaly group.
Both 'untreated hypertension' and termination of pregnancy for fetal
anomaly are socio-economically patterned.[3,4] As Li et al did not adjust
for socio-economic status and there was very limited adjustment for weight
(these data were missing for a large minority and the remainder were
simply dichotomised), it seems plausible that some of the live born excess
may be due to lower rates of terminations and fetal deaths.
While a few studies have now examined the association between risk of
congenital anomaly and use of anti-hypertensive medication,[5-7] Caton et
al is the only previous study previous to Li et al to have examined women
with 'untreated hypertension'.[5] Both studies are consistent in reporting
a greater risk of cardiovascular anomaly in women who used anti-
hypertensive medication during pregnancy (irrespective of the specific
drug), however the two studies disagreed on the effect of hypertension
alone. [1,5] Could this be because Caton et al included spontaneous fetal
deaths and terminations of pregnancy for fetal anomaly, while Li et al
did not?
There is now a reasonable consensus that congenital anomaly
surveillance programs should include more than just live born cases if
they are to present accurate and unbiased data,[8,9] we strongly advice
that all epidemiological studies of congenital anomalies aim to do the
same.
REFERENCES:
[1] Li D, Yang C, Andrade S, Tavares V, Ferber JR. Maternal
exposure to angiotensin converting enzyme inhibitors in the first
trimester and risk of malformations in offspring: a retrospective cohort
study. BMJ 2011;343:d5934. doi:10.1136/bmj.d5931
[2] Tomson T, Hiilesmaa V. Epilepsy in pregnancy. BMJ 2007;335:769-
73.
[3] Bella AC, Adaira LS, Popkina BM. Understanding the role of
mediating risk factors and proxy effects in the association between socio-
economic status and untreated hypertension. Social Science & Medicine
2004;59: 275-83.
[4] Smith LK, Budd JL, Field DJ, Draper ES. Socioeconomic
inequalities in outcome of pregnancy and neonatal mortality associated
with congenital anomalies: population based study. BMJ 2011;343:d4306.
doi: 10.1136/bmj.d4306.
[5] Caton AR, Bell EM, Druschel CM, Werler MM, Lin AE, Browne ML, et
al. Antihypertensive medication use during pregnancy and the risk of
cardiovascular malformations. Hypertension 2009;54:63-70.
[6] Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S,
Gideon PS, et al. Major congenital malformations after first-trimester
exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.
[7] Lennestal R, Otterblad OP, Kallen 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.
[8] Cragan JD, Gilboa SM. Including Prenatal Diagnoses in Birth
Defects Monitoring: Experience of the Metropolitan Atlanta Congenital
Defects Program. Birth Defects Res A Clin Mol Teratol 2009;85:20-29.
[9] Peller AJ, Westgate M, Holmes LB. Trends in Congenital
Malformations, 1974-1999: Effect of Prenatal Diagnosis and Elective
Termination. Obstet Gynecol 2004;104:957-64.
Competing interests: No competing interests
Re: Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study
Fetal risk from ACE-inhibitors in the first trimester
A report by Cooper et al1 described an alarming high malformation rate of 7.12% in fetuses exposed to ACE inhibitors. We agree that the ACE-inhibitors should not be prescribed to women who are pregnant or have child-bearing potential, but these results stand out from the bulk of data now available. The recent paper by Li et al2, and its’ accompanying editorial3, together with two other reports4-5, including our own5 of outcomes in 71 exposed pregnancies from a single maternity unit, where we found no major developmental anomalies, are reassuring for women inadvertently exposed to ACE-inhibitors during pregnancy.2-5
A more important question is why any of these women were treated with antihypertensive drugs in the first place. In mildly hypertensive patients under age 40 years, with no other risk factors, the 10-year cardiovascular risk is well below 20% and will be even lower in females. The short-term cardiovascular risk must therefore be negligible. In our series, where we stopped all ACE-inhibitors at the first antenatal visit, in 28 women we did not consider it necessary to substitute another antihypertensive agent, although in a further 11 women we did continue with the other drugs they were already receiving.5 If we had performed 24 hour ambulatory monitoring maybe more antihypertensive drugs could have been discontinued.
The treatment of mild chronic essential hypertension in pregnancy reduces the chances of hospital admission and the progression to more severe grades of hypertension. Antihypertensive drugs might also reduce the small risk of stroke in mildly hypertensive women in pregnancy, although there is no evidence for this. There is, though, no evidence that it reduces peri-natal mortality, prematurity, small-for-gestational age babies, low Apgar score or maternal proteinuria.6
REFERENCES
1. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006; 354: 2443-51.
2. Li D-K, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011; 343: d5931.
3. Mitchell AA. Fetal risk from ACE inhibitors in the first trimester. BMJ 2011; 343: d6667.
4. Caton AR, Bell EM, Druschel CM, Werler MM, Line AE, Browne ML, McNutt LA, Romitti PA, Mitchell AA, Olney RS, Correa A; National Birth Defects Prevention Study. Antihypertensive medication use in pregnancy and the risk of cardiovascular malformations. Hypertension 2009; 54: 63-70
5. Karthikeyan VJ, Ferner RE, Baghdadi S, Lane DA, Lip GYH, Beevers DG. Are angiotensin converting enzyme inhibitors and angiotensin receptpr blockers safe in pregnancy? A report of ninety-two pregnancies. J Hypertens 2011; 29: 396-9.
6. Magee LA, Ormstein MP, Von Dadelszen P. Management of hypertension in pregnancy. BMJ 1999; 318: 1332-6.
Competing interests: No competing interests