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

Cholesterol Cell Membranes Steroid Synthesis

HMG-CoA Reductase

Statin Mechanism of Action

STATINS

Morphogenetic Signaling (CNS, skeleton, viscera)

1st Trimester Exposures (N=214)

Evaluable = 71

Structural Anomaly

= 22

Atorvastatin: 4Lovastatin: 7Simvastatin: 10 Cerivastatin: 1

“Normal”=40

Intra-UterineFetal Demise

= 5

Lovastatin: 2Simvastatin: 3

Simvastatin: 4

Adverse Outcomes = 31

IUGR

= 4

Lovastatin Malformation Reports (N = 7)3 of 7 reports include midline CNS defects

1. Incomplete separation of lateral cerebral ventricles (Holoprosencephaly); aortic hypoplasia, ASD, death dose: 40 mg/d, gestational weeks 0 - 7 birth prevalence: 1/16,000

Holoprosencephaly was also reported as 1 of 1 cerivastatin malformation (dose 0.25 mg/d, weeks 0-8)

2. Aqueductal stenosis with hydrocephalus dose: 40 mg/d, gestational weeks 0 – 4.5 birth prevalence: 1/10,000

3. Extensive neural tube defect, absent palate dose: 20 mg/d, gestational weeks 0 - 18 birth prevalence: < < 1/10,000

Lovastatin Malformation Reports (N = 7)non-CNS malformations

1 report of VACTERL association (vertebral, anal,

cardiac, tracheo-esophageal, renal, limb defects) dose: 10 mg/d, gestational weeks 6-11 birth prevalence: 1/500,000 (5 VACTERL features) VACTERL was also reported as 1 of 10 simvastatin

malformation cases dose: 10 mg/d simvastatin, gestational weeks 0 - 13 birth prevalence: 1/50,000 (4 VACTERL features)

4 additional malformations reported: microtia with absent auditory canal (40 mg/d); unspecified cardiovascular malformation; unspecified “severe deformity” (doses unknown)

Biological Plausibility: Statin Pharmacodynamics & Clinical Reports

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)

Biological Plausibility:Teratogenicity in Animals

Lovastatin: Rat: vertebral/skeletal defects; neural tube defect; gastroschisis; neuro-

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

VisceralEsophageal AtresiaDuodenal Atresia*Cardiac-NOSReversed laterality

aorta (VACTERL)

Genito-urinary Pyelo-ureteral stenosis* Hypospadias*

Limb Clubfoot Polydactyly (PAP-B)*

IUGR Length 41 wks = 34 wks IUGR 33 wks, wt = 27 wks IUGR 35 wks, wt = 31 wks IUGR 35 wks, wt = 30 wks

*Prospective report

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)

"Excluded" Cases

Lova Prava Simva Fluva Atorva Ceriva Total

Lost 1 14 0 1 4 5 25

TAb 3 2 41 0 1 1 48

SAb 1 3 29 2 7 4 46

Maternal 7 4 8 1 1 1 21

Function 1 0 2 0 0 0 3

Total 13 22 80 4 13 11 143

5 CNS Malformations

1. Cerivastatin……Holoprosencephaly

2. Lovastatin….......Holoprosencephaly

(+ aortic hypoplasia, ASD)

3. Lovastatin…..….Aqueductal Stenosis (+ atretic thumb)

4. Lovastatin…..….Large open NTD, duplicate spinal cord, hydrocephalus

( + absent palate?)

5. Atorvastatin………..Spina Bifida (Type 1 DM)

Mevalonate, Cholesterol & Hedgehogs

2. Cholesterol biosynthesis disorders: Skeletal hypoplasia, IUGR, CNS

3. Sonic Hedgehog down-regulation, KO: Holoprosencephaly Midline, craniofacial defects VACTERL association

1. Statin effects on tissues:

Oxidative; pro-apoptotic; anti-angiogenic

5 Limb Reduction Defects

Lower Limb Simvastatin, n = 2

Upper Limb Lovastatin, n = 2

Upper Limb Atorvastatin, n = 1

2 VACTERL cases

Epidemiologic ComparisonsSelected Reports

“Mixed” LRD (n = 3)

1 / 100,000 births

VACTERL (n = 2) 1 / 50K – 500K births

Holoprosencephaly (n = 2)

1 / 16,000 births

Exposure Estimates

through year 2000:

Ceriva: 150 births Simva: 5000 births Lova: 3500 births Atorva: 6000 births Fluva: 200 births Prava: 3200 births

Experimental Findings HMG-CoA expressed in blastocyst, gastrula,

neuroepithelium at high levels

Lovastatin alters gastrulation by depletion of dolichol for cell migration (echinoderm)

Lovastatin cholesterol in vivo brain: plasma membranes, caveolae, synaptic vesicles

Simvastatin target organ includes thyroid Range animals had complex limb defects and

HPE: exposure from conception on to inhibitor of Hedgehog signal transduction.

Estimated Statin Exposures in Pregnancyfor the year 2000, by Drug and Country

Prava Simva Fluva Atorva Total

USA 407 1030 45 2055 3537

UK 50 184 17 123 374

France 215 159 50 250 674

Total 672 1373 112 2428 4585

Numbers of exposed pregnancies are tiny relative to occurrence of rare outcomes

Pravastatin use is non-trivial: a meaningful negative control

Multiple Malformation Cases1. Semi-lobar HPE; ASD; aortic hypoplasia (died)2. Aqueductal Stenosis; banded, atretic thumb3. Large NTD; cerebellar herniation;palate absent4. VACTERL # 1 (Lovastatin): esophageal atresia;

radial ray aplasia; hypoplastic ulna; fused ribs, butterfly vertebrae, scoliosis; renal dysplasia; anal atresia. Plus: torticollis; hemi-hypertrophy; ptosis. 46,XX Fanconi negative.(1/ 500,000)

5. VACTERL # 2 (Simvastatin): lower limb reduction defects (femur, foot); aortic arch laterality reversed; disorganized lumbo-sacral vertebrae; renal dysplasia (1 / 50,000)