Antilipemic Agent
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The interruption of cholesterol-lowering therapy during pregnancy should have no effect on long-term treatment of hyperlipidemia. Moreover, because cholesterol and products synthesized by cholesterol are important during fetal development, the use of atorvastatin is contraindicated during pregnancy. However, the absolute embryo risk from inadvertent exposure in the 1st trimester appears to be low.
FETAL RISK SUMMARY
Atorvastatin, a lipophilic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as an adjunct to diet to reduce total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride levels in patients with primary hypercholesterolemia and mixed dyslipidemia. It has the same mechanism of action as other available drugs in this class, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin (cerivastatin was withdrawn from the market in 2001). Atorvastatin is extensively metabolized and some of the metabolites are as pharmacologically active as the parent compound. Atorvastatin is highly bound (≥98%) to plasma proteins and it has a mean plasma elimination of about 14 hours. However, because of the active metabolites, the half-life of inhibitory activity for HMG-CoA reductase is 20–30 hours (1,2).
In reproduction studies with pregnant rats and rabbits, doses that were about 30 and 20 times, respectively, the human exposure (HE) based on BSA, were not teratogenic. With maternal dosing in rats from gestation day 7 through lactation day 21 (weaning), at a dose 22 times the HE based on AUC, there was decreased pup survival at birth, during the neonatal period, at weaning, and at maturity, and decreased pup weight at birth, during nursing, and at maturity. In addition, pup development was inhibited at this dose (1–3). A 1994 report described developmental toxicity of atorvastatin at maternally toxic doses in pregnant rats and rabbits (4). There was no evidence, however, of teratogenicity in either species (4).
It is not known if atorvastatin or its active metabolites cross the human placenta. The relatively high molecular weight (about 1161 for the nonhydrated form) and extensive protein binding suggest that transfer across the placenta will be inhibited. In pregnant rats, however, fetal liver levels of atorvastatin were equivalent to maternal concentrations (1–3).
A 2002 report described the use of atorvastatin in early pregnancy (5). A 35-year-old woman with several diseases (hypertension, diabetes mellitus, hypercholesterolemia, anxiety disorder, epilepsia, and morbid obesity) conceived while being treated with multiple drugs: atorvastatin (40 mg/day), rosiglitazone, gliclazide (a sulfonylurea), acarbose, spironolactone, hydrochlorothiazide, carbamazepine, thioridazine, amitriptyline, chlordiazepoxide, and pipenzolate bromide (an antispasmodic). Her pregnancy was diagnosed in the 8th week of gestation and all medications were stopped. She was treated with methyldopa and insulin for the remainder of her pregnancy. At 36 weeks’ gestation, a healthy, 3.5-kg female infant was delivered by cesarean section. Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. The infant was developing normally after 4 months (5).
A 2004 report described the outcomes of pregnancy that had been exposed to statins and reported to the FDA (see Lovastatin).
A 2005 abstract reported 19 pregnancies exposed to a statin in the 1st trimester, 7 of which involved atorvastatin (6). The pregnancy outcomes included one healthy newborn, two spontaneous abortions (one with trisomy 18), one elective abortion, one newborn with jaundice, and two infants with congenital defects (VACTERL association, also exposed to trandolapril and insulin) and unilateral dilated renal pelvis (also exposed to enalapril) (6).
A 2008 prospective, observational cohort study compared the pregnancy outcomes of 64 women who had taken a statin in the 1st trimester with 64 matched controls without exposure to known teratogens (7). The statin exposures were atorvastatin (N = 46), simvastatin (N = 9), pravastatin (N = 6), and rosuvastatin (N = 3). Sixty-one women discontinued the drug in the 1st trimester, but three continued taking a statin into the 2nd trimester. Twenty-one (33%) women in the exposed group had other medical conditions, in addition to hyperlipidemia, and seven had more than one chronic condition. The rates of major malformations in the two groups were 2.2% (1/46 live births) and 1.9% (1/52 live births) (p = 0.93), respectively. There were also no statistical differences in the other outcomes: live births (71.9% vs. 81.2%), spontaneous abortions (21.9% vs. 17.2%), elective abortions (4.7% vs. 0%), and stillbirths (1.5% vs. 1.6%). Gestational age at birth (38.4 vs. 39.3 weeks) and birth weight (3.14 vs. 3.45 kg) were significantly lower in the exposed group (7).
BREASTFEEDING SUMMARY
No reports describing the use of atorvastatin in human lactation have been located. The relatively high molecular weight (about 1161 for the nonhydrated form) suggests that excretion into milk would be inhibited, but some excretion should be expected. Because of the potential for adverse effects in a nursing infant, women who are taking atorvastatin should not breastfeed.
References
1.Product information. Lipitor. Parke-Davis, 2004.
2.Product information. Lipitor. Pfizer, 2004.
3.Henck JW, Craft WR, Black A, Colgin J, Anderson JA. Pre- and postnatal toxicity of the HMG-CoA reductase inhibitor atorvastatin in rats. Toxicol Sci 1998;41:88–99.
4.Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 1994;50:387–94.
5.Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod Toxicol 2004;18:619–21.
6.McElhatton P. Preliminary data on exposure to statins during pregnancy (abstract). Reprod Toxicol 2005;20:471–2.
7.Taguchi N, Rubin ET, Hosokawa A, Choi J, Ying AY, Moretti M, Koren G, Ito S. Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol 2008;26:175–7.