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The Family Practice Newsletter
The Ohio University College of Osteopathic Medicine
The Ohio Northern University Raabe College of Pharmacy
Doctors Hospital Family Practice
Volume 5, Issue 11
June, 2006
Safety of ACE Inhibitors, Selective Serotonin Reuptake Inhibitors, and HMG-CoA Reductase
Inhibitors in Pregnancy
Laura Dickey, Ohio Northern University Doctor of Pharmacy Candidate
Use of a potentially teratogenic, class D or X, medication by a woman of childbearing age is documented
on 1 of every 13 visits made to US ambulatory practices.8 The use of medications during pregnancy poses a
potential risk not only to the mother, but also the developing fetus. Health care providers and patients alike agree
to have less knowledge then desired on safety of prescription drugs during pregnancy and breastfeeding. Most
women are not aware of pregnancy at first onset and some drug therapy during the months of pregnancy is
controversially related to fetal malformations. Angiotensin converting enzyme inhibitors (ACEIs), selective
serotonin receptor reuptake inhibitors (SSRIs), and HMG –CoA reductase inhibitors are three classes of
medications used daily for treatment of chronic diseases in females of childbearing age. Recent studies have
evaluated medication use in pregnancy, with a focus on the above mentioned medication classes.
In order to objectively measure teratogenicity, medications are classified into 5 pregnancy risk categories; A,
B, C, D, and X.3 The categories are described below. Understanding these categories and the medications which
fit into the categories is crucial to prevent the unnecessary and harmful side effects.
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Category A: medications that have been used in multiple well-controlled studies without any increased
risk of fetal abnormalities in the first trimester. This is the safest class of medications for pregnant
females.
Category B: animal reproduction studies have not demonstrated a risk to the fetus but there are no
controlled studies in pregnancy women. This category may also include medications in which a risk was
observed in animals, but not repeated in women during the first trimester of pregnancy.
Category C: medications that have shown through animal studies to have an increased risk of fetal
abnormalities and/or no animal/human studies have been done on the medications.
Categories D: medications that have human studies that show increased risk of fetal abnormalities with
use of drug. With category D medications, physicians and health care providers need to weigh out risk
versus benefit with use of medications.
Category X: medications have shown increased risk of fetal abnormalities on multiple occasions and are
contraindicated in all patients that are or can become pregnant.
ACEIs are used for control of hypertension. These medications work by preventing angiotensin I from being
converted to angiotensin II, a potent vasoconstrictor. ACEIs are considered to be drug of choice in patients with
high blood pressure.1 Upon first coming to market, all ACEIs were labeled pregnancy category C for use in the
first trimester use and category D for second and third trimester use. Until recently, pregnant females were
instructed to remove/discontinue ACEIs upon notification of pregnancy in order to prevent exposure to the fetus
during the second or third trimester. A recent study done by Cooper et al shows otherwise.2
This study, published in New England Journal of Medicine on June 8, 2006, identified infants born from
1985-2000. It counted the number of pregnant patients on ACEIs (or other antihypertensives) within the first
trimester and compared that number to the pregnant patients with no exposure to ACEIs or antihypertensives. The
results showed that infants exposed to ACEIs had an increased risk of major congenital malformations (risk ratio
of 2.71 with 95 percent confidence interval) compared to infants with no exposure The major congenital
malformations noted in the study included cardiac septal defects (accounted for 50%) and central nervous,
urologic or other systems (accounted for other 50%). The study also included ACEI exposure beyond the first
trimester in order to solidify previous results. If you recall from above, ACEIs are listed as category D in second
and third trimester. Second and third trimester ACEI exposure has been showed to cause damage to the fetus’
kidneys.4 Although there is no current movement towards switching categories for ACEI in first trimester of
pregnancy, there is information to support the avoidance of ACEIs in pregnancy in clinical situations where the
risk outweighs the benefit.
The SSRIs are used for treatment of psychiatric disorders. Their mechanism of action is to block the
serotonin reuptake in synapses in order to help with mood.1 Serotonin is a neurotransmitter involved in mood and
anxiety response; in deficient quantities in the brain, patients could experience anxiety and/or depression.3 With
minimal side effects, these are the treatment of choice in most panic, anxiety and depression conditions.1 Initially,
SSRIs were thought to be appropriate treatment for pregnancy without any risk of fetal abnormalities but recent
studies and information have contradicted these previous statements.
In January 2006, the FDA reported on two unpublished studies on the use of paroxetine in pregnancy. The
first study illustrated that pregnant women who received paroxetine in early pregnancy (1st trimester) have
approximately 2-fold increased risk for having an infant with a cardiac defect compared to the rest of the
database.5 The second study demonstrated that infants of women who received paroxetine in the first trimester
had 1.5-fold increased risk for cardiac malformations and 1.8-fold increased risk for congenital malformations
overall compared to infants who received other antidepressant classes in the first trimester. The cardiac
malformations included atrial or ventricular septal defects.6 Both of these studies evaluated paroxetine. Other
studies evaluating SSRI use during pregnancy showed a correlation with maternal SSRI use and persistent
pulmonary hypertension. In this study, 4 SSRIs were evaluated (fluoxetine, paroxetine, citalopram and sertraline).
The results concluded that infant exposure to SSRIs after 20th week of pregnancy produced an increased risk of
persistent pulmonary hypertension.7 Because of this and other studies with paroxetine, the Food and Drug
Administration (FDA) requested paroxetine change to a category D medication. Alternatives to SSRIs include
buproprion(Wellbutrin) and venlaflaxine(Effexor).
The third medication class to be discussed is the HMG-CoA reductase inhibitors (statins), used for the
management of hyperlipidemia. These medications are considered category X in pregnancy.
A review article discussed side effects of statin use in the 1st trimester.9The effects on the fetus include
multiple accounts of fetal defects of the central nervous system and limb malformations. Another study
determined risk versus benefit with treatment of hyperlipidemia in pregnancy.10 Effects reported were extreme
fetal abnormalities and death. Due to these teratogenic reports, statins are not recommended to be used in
pregnant females and females attempting to become pregnant in order to prevent these devastating conditions.
Alternatives to statin therapy include the bile acid sequestrants, colesevelam and colestipol (category B), and
cholestyramine (category C). Other category C medications used for the management of hyperlipidemia include
fenofibrate (Tricor), gemfibrozil (Lopid) and ezetimibe (Zetia).
Three very popular medication classes, ACEIs, SSRIs, and statins, potentially increase the risk of birth
defects when used in pregnant women. Alternatives to these medications should be used when a woman is
contemplating pregnancy, or already pregnant. Due to lack of human studies with many medications during
pregnancy, use should be limited to those cases in which the benefit outweighs the risk of harm. Remind patients
that they should be making overall healthy lifestyle decisions during pregnancy to increase their chances of
delivering a healthy infant.
Reference:
1. Lexi-Comp (Lexi Comp Drugs) [computer program]. Lexi-Comp; Ver 1.5.060608/July 14, 2006.
2. Tabacova S. Mode of Action: Angiotensin-Converting Enzyme Inhibition—Developmental Effects Associated With Exposure to ACE Inhibitors.
Clinical Rules in Toxicology.2005: 35;8/9: 747-755.
3. Wells BG, Dipiro JT, Schwinghammer TL, Hamilton CW. Pharmacotherapy Handbook. 6th ed. New York: McGraw Hill; 2006.
4. Cooper W, Hernandez-Diaz S, Arbogast P, et al. Major congenital malformations after first trimester exposure to ACE inhibitors. New
England Journal of Medicine. 2006; 354: 23:2443-2451.
5.Glaxo Smith Kline. Dear Healthcare Professional letter. 2005. Available at http:www.fda.giv/medwatch/safety/2005/Paxil_dearhcp_letter.pdf. Accessed
July 16, 2006.
6. Food and Drug Adminstraion. Public Health Advisory. Paroxetine. 2005. Available at http:www.fda.gov/cder/drug/advisory/paroxetine200512.htm.
Accessed July 16, 2006.
7. Malm H, Klaukka T, Neuvonen PJ. Risks Associated with selective serotonin reuptake inhibitors in pregnancy.
8. Schwarz EB, Maselli J, Norton M, Gonzales R. Prescription of teratogenic medications in United States ambulatory practices. American Journal of
Medicine. 2005; 118: 11: 1240-1249.
9. Statins contraindicated in pregnancy. Australian Adverse Drug Reaction Bulletin. 2005; 24: 1:4.
10. Zaiken K, Raval KD. Treatment of Hypercholesterolemia in Pregnancy: Risks Versus Benefits. Journal of Pharmacy Technology. 2005.
September/October: 21: 258-261.
Edited by Stephanie Gibson, PharmD. Director of Clinical Pharmacy, Doctors Hospital Family Practice. Clinical Assistant Professor, ONU Raabe College
of Pharmacy. Questions and comments welcome at [email protected].