Are ACE Inhibitors Safe During the First Trimester?

Jane Conyers, Mercer University College of Pharmacy

Angiotensin converting enzyme inhibitors (ACEIs) cross the placenta during pregnancy and increase the risks of fetal malformations. Because of this, the Food and Drug Administration (FDA) has labeled ACEIs as contraindicated in the second and third trimesters since 1986.  [1]

The risks of congenital malformations due to first trimester ACEI exposure are stated to not yet be conclusive [2]; however, the FDA still recommends that ACEIs should be discontinued as soon as pregnancy is detected due to the risk of fetal malformations after first trimester use. [3]

The most documented manifestation of renin-angiotensin system (RAS)  fetopathy is impaired renal function and not direct kidney malformation. Fetopathic damage from RAS occurs in the latter half of pregnancy; this may be due to the effect of angiotensin II on renal developmental later in gestation. [4]  

Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations [5]
Design Retrospective, cohort study; N= 1,333,624
Objective To examine the association between first-trimester ACEI exposure and the risk of major congenital malformations
Study Groups Exposed to ACEI (n= 4,107); unexposed to ACEI (n= 1,329,517)
Methods Females who delivered liveborn neonates were identified using Medicaid Analytic eXtract claims from 46 states and the District of Columbia.  Pregnancies exposed to known teratogens were excluded.  First trimester use of an antihypertensive from any class was excluded in the non-exposure group.  Outcomes were restricted to claims from the infant record alone to prevent confounders from the maternal data.  Exposure was defined based on two dispensings of an ACEI during the first trimester, and included combination and monotherapy.  A propensity score was used to account for all measured confounders of the association between ACEIs and malformation.
Duration 2000-2010
Primary Outcome Measure 1) Overall major congenital malformations, 2) cardiac malformations,  3) central nervous system (CNS) malformations; and 4) propensity scores analysis
Baseline Characteristics
Exposed to ACEI Unexposed to ACEI
Maternal age, years, n (%)
≤19 86 (3.3) 1,755 (11.1)
20-24 290 (11) 4,958 (31.2)
25-29 667 (25.4) 4,554 (28.7)
30-34 789 (30) 2,762 (17.4)
35-39 569 (21.6) 1,421 (9.0)
≥40 230 (8.7) 434 (2.7)
Race, n (%)
Caucasian 827 (31.4) 5,462 (34.4)
African-American 1,331 (50.6) 7,211 (45.4)
Hispanic 274 (10.4) 1,726 (10.9)
Asian 68 (2.6) 352 (2.2)
Native American 25 (1) 245 (1.5)
Comorbidities, n (%)
Diabetes 829 (31.5) 1,565 (9.9)
Renal disease 134 (5.1) 309 (2)
Dyslipidemia 321 (12.2) 911 (5.7)
Congestive heart failure 94 (3.6) 129 (0.8)
Ischemic heart disease 57 (2.2) 153 (1)
Tobacco use 122 (4.6) 879 (5.5)
Drug use or dependence 43 (1.6) 326 (2.1)
Alcohol use or dependence 24 (0.9) 143 (0.9)
Multifetal gestation 186 (7.1) 877 (5.5)
Results
Congenital malformations Exposed to ACEI, n (%) Unexposed to ACEI, n (%) RR (95% CI) Propensity score analysis

RR (95% CI)

Overall 244 (5.94) 43,323 (3.26) 1.82 (1.61–2.06) 0.89 (0.75–1.06)
Cardiac 139 (3.38) 15,272 (1.15) 2.95 (2.50–3.47) 0.95 (0.75–1.21)
CNS 11 (0.27) 2,433 (0.18) 1.46 (0.81–2.64) 0.54 (0.26–1.11)

Subgroup analysis

Exposed to ACEI Chronic hypertension, RR (95% CI) Diabetes,

RR (95% CI)

Overall 1.35 (1.13–1.61) 0.97 (0.79–1.19)
Cardiac 1.79 (1.39–2.30) 1.08 (0.81–1.44)
CNS 1.07 (0.51–2.27) 0.68 (0.30–1.54)
Adverse Events Common Adverse Events: not disclosed
Serious Adverse Events: not disclosed
Percentage that Discontinued due to Adverse Events: not disclosed
Study Author Conclusions Exposure early in pregnancy during the period of organogenesis does not confer an increased risk of malformations.  This class of medication may be appropriate for use in women of reproductive age who become pregnant provided they are able to present for prenatal care before the end of the first trimester.

 

Strengths of this study include the large cohort from which the data was extracted, the requirement that the prescription for the ACEI had to be filled twice in order for inclusion in the exposure group, and the subgroup analysis of women with hypertension and diabetes.  The study that caused the FDA to strengthen its initial warning included just over five percent of the total number of women exposed to ACEIs in this study.  Additionally, receiving two prescriptions for an ACEI is stronger evidence of exposure compared to receiving only one.  Finally, the subgroup analysis on malformation risks in women with chronic hypertension or diabetes, two distinct but often related comorbidities, gives clinicians more information to evaluate their own patients.

 

References

  1. Podymow T, Joseph G. Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors. Clin Nephrol. 2015;83(2):73-9.
  2. Al-maawali A, Walfisch A, Koren G. Taking angiotensin-converting enzyme inhibitors during pregnancy: is it safe?. Can Fam Physician. 2012;58(1):49-51.
  3. Food and Drug Administration. MedWatch: Angiotensin-converting enzyme inhibitor (ACE inhibitors) drug class. Updated July 7, 2006. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150412.htm. Accessed February 2, 2017.
  4. Cragan JD, Young BA, Correa A. Renin-Angiotensin System Blocker Fetopathy. J Pediatr. 2015;167(4):792-4.
  5. Bateman BT, Patorno E, Desai RJ, et al. Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations. Obstet Gynecol. 2017;129(1):174-184.
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