Antilipemic Agent
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Infants with malformations following in utero exposure to lovastatin have been described in published and unpublished reports. A causal relationship between the drug and some of the defects is possible, but some might have occurred by chance. Additional data are needed. Because there is apparently no maternal benefit for the use of lovastatin during gestation and because of the human cases and the teratogenicity observed in one animal species, the drug should be avoided during pregnancy.
FETAL RISK SUMMARY
Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (“statins”) that is lipophilic, is used to lower elevated levels of cholesterol. It has the same mechanism of action as other available drugs in this class, atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin (cerivastatin was withdrawn from the market in 2001).
The drug is teratogenic in mice and rats, producing decreased fetal weight and skeletal malformations in exposed fetuses, at doses of 800 mg/kg/day (40 and 80 times the maximum recommended human dose based on BSA [MRHD], respectively) (1,2). However, the skeletal malformations were thought to be due to maternal toxicity that involved gastric lesions and not due to the drug (3). No teratogenic effects were observed in rabbits administered doses ≤15 mg/kg/day (3 times the MRHD), the maximum tolerated dose (1,2).
A surveillance study of lovastatin and simvastatin exposures during pregnancy, conducted by the manufacturer, was reported in 1996 (2) and updated in 2005 (4). Of the 477 reports, all involving 1st trimester exposure, 386 were prospective (67 lovastatin, 319 simvastatin) and 91 were retrospective (38 lovastatin, 53 simvastatin). The pregnancy outcomes were known for 225 (58%) of the prospective reports. There were congenital defects in five liveborn and one stillborn, all involving simvastatin. (See Simvastatin.) Other outcomes were 18 spontaneous abortions (SABs), 49 elective abortions (EABs), 4 fetal deaths, and 148 live births without defects. All of the outcomes, with the exception of fetal deaths, were similar to the population background rate. Although the number of fetal deaths was increased, there was no specific pattern to suggest a common cause. One death involved a nuchal cord and another was a trisomy 18. No congenital defects were reported in the SABs or EABs (4).
There were 13 cases of congenital defects in retrospective reports; 7 involving lovastatin and 6 with simvastatin (4). The details of the congenital defects after exposure to lovastatin (daily dose and exposure in weeks from last menstrual period) were as follows:
(a)atrial and ventricular septal defect, aortic hypoplasia, infant died on day 32 (40 mg, 0–5 weeks)
(b)features of VATER association with other abnormalities, mother also took dextroamphetamine at the same time (10 mg, 6–11 weeks)
(c)spina bifida, EAB (20 mg, 1st trimester)
(d)rudimentary right thumb, skull defects (40 mg, 0–4 weeks)
(e)“severe deformity” (dose and exposure not reported)
(f)open neural tube defect, duplication of spinal cord, cleft palate, EAB (20 mg, 0–18 weeks)
(g)deformed right ear, no auditory canal (microtia) (dose not reported, 0–8 weeks)
The case involving the VATER association is also described below. There was no specific patterns observed in the above reports (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 3 newborns had been exposed to lovastatin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (33.3%) major birth defect was observed (none expected), a cardiovascular defect. Eight other exposures to lovastatin occurred after the 1st trimester without apparent fetal harm (5).
Three retrospective spontaneous reports of birth defects suspected of being associated with 1st trimester use of lovastatin have been received by the FDA (5). The anomalies described were aortic hypoplasia, ventricular septal defect with cerebral dysfunction, death (one case); anal atresia and renal dysplasia (one case); and short forearm, absent thumb, and thoracic scoliosis (one case).
A 1992 case report described the use of lovastatin in a human pregnancy (6). A woman was treated for 5 weeks with lovastatin and dextroamphetamine, starting approximately 6 weeks from her last menstrual period, for progressive weight gain and hypercholesterolemia. Therapy was discontinued when her pregnancy was diagnosed at 11 weeks’ gestation. A female infant was delivered by cesarean section at 39 weeks’ gestation. Gestational age was confirmed by an ultrasound examination at 21 weeks’ gestation and the Dubowitz score at birth. The infant had a constellation of malformations termed the VATER association (vertebral anomalies, anal atresia, tracheoesophageal fistula with esophageal atresia, renal and radial dysplasias). Specific anomalies included an asymmetric chest, thoracic scoliosis, absent left thumb, foreshortened left forearm, left elbow contracture, fusion of the ribs on the left, butterfly vertebrae in the thoracic and lumbar spine, left radial aplasia, and a lower esophageal stricture. Chromosomal analysis was normal, and the family history was noncontributory (6). This case is also described above (see reference 2).
The cause of the defects in the above infant is unknown, but drug-induced teratogenicity cannot be excluded as in utero exposure to both drugs occurred during organogenesis. Experiments with mice and rabbits indicated that amphetamines are teratogenic, but the anomalies primarily involve the heart and CNS (7). Moreover, the use of amphetamines during human pregnancy for medical indications has not been found to present a significant risk to the fetus in terms of fetotoxicity or teratogenicity (see Amphetamines).
A 1995 abstract reported an extensive NTD in a fetus exposed during the 1st trimester to lovastatin (8). A causal relationship could not be established.
A 2004 report evaluated 20 cases of adverse pregnancy outcomes reported to the FDA after exposures to statins (9). The cases were among 178 cases of 1st trimester pregnancy exposure to cholesterol-lowering statin drugs reported to the FDA. There were 52 cases suitable for evaluation after exclusion for spontaneous abortions, elective abortions, pregnancy loss due to maternal diseases, fetal genetic disorders, transient neonatal disorders, or loss to follow-up. In the 52 cases, there were 20 reports of malformation as follows (drug, dose, and exposure time in weeks after last menstrual period shown in parentheses):
CNS
(a)Holoprosencephaly (cerivastatin, 0.25 mg/day, 0–8 weeks)
(b)Holoprosencephaly (see reference 10) (defective septum separating lateral cerebral ventricles), atrial septal defect, aortic hypoplasia, death at 1 month of age (lovastatin, 40 mg/day, 0–7 weeks)
(c)Aqueductal stenosis with hydrocephalus, limb deficiency (right banded, atretic thumb) (lovastatin, 40 mg/day, 0–4.5 weeks)
(d)NTD, myelocele, duplication of spinal cord, cerebellar herniation with hydrocephalus, apparent agenesis of palate (lovastatin, 20 mg/day, 1st trimester)
(e)spina bifida, right arm abnormality (mother also type 1 diabetic) (atorvastatin, unknown dose, until pregnancy recognized)
Limb deficiency
(a)same as c above
(b)right leg fibula and tibia 9% shorter than left side, agenesis of one tarsal bone, right foot 16% shorter than left (reported at 4 years of age) (simvastatin, 20 mg/day, 0–6 weeks)
(c)left leg femur 16% shorter than right, foot with aplasia of metatarsals and phalanges 3, 4, and 5, additional VACTERL defects—left renal dysplasia, reversed laterality of aorta, disorganized lumbosacral vertebrae, single umbilical artery, additional findings—clitoral hypertrophy, vaginal and uterine agenesis (mother also took drug similar to progesterone 10 days/month, 0–13 weeks) (simvastatin, 10 mg/day, 0–13 weeks)
(d)left arm aplasia of radius and thumb, shortened ulna, additional VACTERL defects—left arthrogryposis, thoracic scoliosis, fusion of ribs on left, butterfly vertebrae in thoracic and lumbar region, esophageal stricture, anal atresia, renal dysplasia, additional findings—hemihypertrophy of entire left side, craniofacial anomalies (including asymmetric ears, ptosis of eyelids, high arched palate), torticollis (mother also took dextroamphetamine, 6–11 weeks) (lovastatin, 10 mg/day, 6–11 weeks)
(e)limb reduction deficiency, transverse deficiency of otherwise normal radius and ulna superior to wrist structures, with aplasia of all distal structures (atorvastatin, 10 mg/day, 0–9 weeks) (9)
The other 11 cases of malformations were simvastatin: cleft lip with intrauterine growth restriction; cleft lip; polydactyly; duodenal atresia; hypospadias; clubfoot; and unspecified major abnormalities; atorvastatin: cleft palate; esophageal atresia; lovastatin: microtia with absent auditory canal and severe unspecified deformity (9). All of the 20 defects involved a lipophilic statin (i.e., atorvastatin, cerivastatin, lovastatin, and simvastatin). There were no malformations in the 14 cases of exposure to pravastatin, a hydrophilic agent with low tissue penetration that is not related to reproductive toxicity in animals (see Pravastatin). Because of the voluntary nature of the reports to the FDA, the authors thought that the reports were likely to be biased toward severe outcomes. However, the nature of some of the CNS and limb deficiency malformations (i.e., primarily the cases of holoprosencephaly and VACTERL association) might be consistent with the inhibition of cholesterol biosynthesis (9,10).
In 2005, the authors of the above study reexamined the clinical report of the case listed as holoprosencephaly (CNS, case b) and discovered a coding error (11). The infant had a “ventricular septal defect,” not a “defective septum separating lateral cerebral ventricles,” thus reducing the number of lovastatin fetuses with midline CNS anomalies from three to two (11).
BREASTFEEDING SUMMARY
No human studies describing the use of lovastatin during lactation have been located. Because there is potential for adverse effects in the infant, the drug should not be used by women who are nursing.
References
1.Product information. Mevacor. Merck, 2000.
2.Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1996;10:439–46.
3.Wise LD, Cukierski MA, Lankas GR, Skiles GL. The predominant role of maternal toxicity in lovastatin-induced developmental toxicity (abstract). Teratology 2000;61:444.
4.Pollack PS, Shields KE, Burnett DM, Osborne MJ, Cunningham ML, Stepanavage ME. Pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res A Clin Mol Teratol 2005;73:888–96.
5.Rosa F. Anti-cholesterol Agent Pregnancy Exposure Outcomes. Presented at the 7th International Organization for Teratology Information Services, Woods Hole, MA, April 1994.
6.Ghidini A, Sicherer S, Willner J. Congenital abnormalities (VATER) in baby born to mother using lovastatin. Lancet 1992;339:1416–7.
7.Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:197–8.
8.Hayes A, Gilbert A, Lopez G, Miller WA. Mevacor—a new teratogen? Am J Hum Genet 1995;57(4 Suppl):A92.
9.Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 2004;350:1579–82.
10.Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genetics 2004;131A:287–98.
11.Edison RJ, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. N Engl J Med 2005;352:2759.