Medical Genetics Branch Medical Genetics Branch A Safety Concern? Human Teratogenicity of Lovastatin: Robin J. Edison, MD, MPH Maximilian Muenke, MD Medical Genetics Branch Division of Intramural Research National Human Genome Research Institute National Institutes of Health
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Medical Genetics Branch A Safety Concern? Human Teratogenicity of Lovastatin: Robin J. Edison, MD, MPH Maximilian Muenke, MD Medical Genetics Branch Division.
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Medical Genetics BranchMedical Genetics BranchMedical Genetics BranchMedical Genetics Branch
A Safety Concern?
Human Teratogenicity of Lovastatin:
Robin J. Edison, MD, MPHMaximilian Muenke, MD
Medical Genetics BranchDivision of Intramural Research
National Human Genome Research InstituteNational Institutes of Health
Method: Review of Case ReportsTeratologic Assessment
All available MedWatch case report forms, and literature reports
Hypothesis-generating strategy: assessment includes search for patterns of malformation, comparison with animal data, and plausibility of biological association
No existing epidemiologic data have sufficient exposures or follow-up to generate reliable risk estimates
HMG-CoA
Mevalonate
Isoprenoids
Protein PrenylationGrowth Factor ActivityCell Signaling, MigrationMitochondrial CoEnz Q10
All lipophilic statins were associated with reports of malformation following exposure
Pravastatin, hydrophilic and minimally detectable in the embryo, generated 20 evaluable reports of exposure but no reports of malformation or adverse pregnancy outcome
Insufficient exposure data were available to assess fluvastatin; no data available on rosuvastatin exposure
Lovastatin Pharmacodynamics:Distribution to Embryo
Lovastatin is lipophilic crosses placenta and blood-brain barrier
Concentration of lovastatin in embryonic tissues is approximately 25% of maternal plasma concentration (esp. liver, adrenal)
Neuroepithelium of early embryo shows highest expression of HMG-CoA reductase (CNS is first tissue to undergo expansion)
behavioral deficits (low-dose) Mouse: skeletal and visceral malformations without maternal toxicity Rabbit: visceral “variations”; delayed ossification (very low dose)
Other lipophilic statins (none reported for pravastatin): Simvastatin: neural tube defect; malformations of gut, heart, skeleton Atorvastatin: neuro-behavioral deficits; visceral variations; fetal loss Cerivastatin: skull defects; major vascular anomalies; clefting; death Fluvastatin: vertebral malformations; perinatal mortality
Other chemical inhibitors of cholesterol biosynthesis: Holoprosencephaly (many species); aqueductal stenosis;
hydrocephalus; malformations of vertebrae, limbs, palate, gut, heart In susceptible species, any of the above malformations may be
observed, depending on timing of exposure
Biological Plausibility: Biomechanisms Under Study
Lovastatin in vivo decreases cholesterol levels in the CNS and alters neuron membrane properties and synapse formation. Decreases caveolae, site of folate receptors.
Lovastatin induces neuronal cell death in vitro at sub-physiologic concentrations
VACTERL association is induced in mice by decreasing the activity of a cholesterol-regulated patterning molecule (sonic hedgehog).
Mevalonate pathway intermediates (dolichols, prenylation of proteins, Co-enzyme Q10) modulate many critical regulatory and metabolic functions used by dividing cells
Factors Supporting Potential Teratogenicity Of Lovastatin in Humans
Most malformations reported following lovastatin exposure are similar to those observed in animal studies of lovastatin and other lipophilic statins
Two rare malformations (holoprosencephaly and the VACTERL association) were reported following exposures to both lovastatin and another lipophilic statin (cerivastatin and simvastatin, respectively)
The recurrence of these particular malformations could be interpreted as unexpected given the apparently small population of exposed pregnant women (manufacturer reports, registries)
Clinical Points to Consider
Observed malformations are generally induced very early, shortly after implantation and before the likely recognition of pregnancy
11% of CUSTOM uptake was by women <45 years of age, 5% < 40 years of age. Unplanned pregnancy is common throughout the population
Discontinuation of a teratogenic medication upon recognition of pregnancy may be insufficient to prevent severe effects
Conclusions
According to standard criteria for assessing teratogenicity, the data shown suggest the hypothesis that lovastatin MAY be a human teratogen, particularly in the central nervous system.
Prospective studies following exposed pregnancies and offspring through the age of five years are essential to test the teratogenic hypothesis and to characterize any adverse neurodevelopmental or other impact of lovastatin (or any statin) on the developing fetus
Acknowledgments
This work was supported by the Division of Intramural Research at the National Human Genome Research Institute, National Institutes of Health.
The views expressed here are those of the authors alone and do not represent the official position of the NHGRI, the NIH, or the Department of Health and Human Services.
Additional Abnormalities Craniofacial
Cleft Lip (+ IUGR)Cleft Lip*Cleft Palate? Palate agenesisMicrotia, no canal
1. Pregnancy outcome unknown (Lost)2. Elective Termination unrelated to fetal status (TAb)3. Spontaneous Pregnancy Loss <= 12 wks. gestation (SAb)4. Severe Maternal Illness, acute or chronic, or other clear attributable cause of adverse event (Maternal)5. Functional adverse events at birth or later (Function)