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Statins are considered to be a standard treatment for hyperlipidemia. Central nervous system, limb and midline defects have been reported in newborns exposed to statins in utero, although causality has been questioned. A 22-month-old boy with severe microcephaly, growth retardation, dysmorphic features, profound global developmental delay and peri-Sylvian polymicrogyria on brain imaging is presented. He was born to a mother exposed to telmisartan during the first seven months and rosuvastatin throughout the entire pregnancy. There were no features of fetopathy associated with sartans including telmisartan, such as a history of oligohydraminios and renal abnormalities. Given the increasing prevalence of obesity and its related complications (including dyslipidemias and hypertension) in young women of childbearing age, more safety data for prenatal exposure to statins and sartans are urgently needed.
Les statines sont considérées comme un traitement standard de l’hyperlipidémie. On a fait état d’anomalies du système nerveux central, des membres et des structures médianes chez des nouveau-nés exposés aux statines in utero, même si la causalité a été remise en question. On expose le cas d’un garçonnet de 22 mois présentant une microcéphalie importante, un retard de croissance, des traits dysmorphiques, un retard du développement global profond et une microgyrie périsylvienne à l’imagerie cérébrale. Il est né d’une mère exposée au telmisartan pendant les sept premiers mois de sa grossesse et à la rosuvastatine tout au long de sa grossesse. On ne constatait aucune caractéristique de fœtopathie associée aux sartans, y compris le telmisartan, tels que des antécédents d’oligohydramnios et d’anomalies rénales. Étant donné la prévalence croissante d’obésité et de ses complications connexes (y compris les dyslipidémies et l’hypertension) chez les jeunes femmes en âge de procréer, il est urgent de colliger plus de données d’innocuité sur l’exposition prénatale aux statines et aux sartans.
Available information regarding the outcome of human pregnancies during which the fetus was exposed to statins and sartans is limited and inconclusive.
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, which catalyzes the formation of mevalonic acid from 3-hydroxy-3-methylglutaryl coenzyme A – the ratelimiting step in cholesterol synthesis. Statins are considered to be the standard treatment for hyperlipidemia, but are contraindicated during pregnancy because of potential teratogenic effects (1).
Telmisartan is an antihypertensive medication, which acts as an angiotensin II receptor antagonist, and has an inhibitory effect on the renin-angiotensin system. Telmisartan is contraindicated in pregnancy; adverse effects have been reported in both animal and human pregnancies (2).
The propositus was a 15-month-old boy born to a nonconsanguineous 31-year-old mother with hypertension and hyperlipidemia, and a healthy 29-year-old father, both of northern European descent. Other siblings included a healthy five-year-old brother and a 13-year-old maternal half brother with a history of pyloric stenosis and attention-deficit hyperactivity disoder. Neither sibling was exposed to statins or sartans in the prenatal period.
The patient was conceived naturally, and the pregnancy was not detected until the third trimester due to irregular maternal menstrual periods. There was occasional spotting during the first half of the pregnancy but no frank vaginal bleeding. The fetus was exposed to telmisartan (80 mg/day) during the first seven months and to rosuvastatin (10 mg/day) during the entire gestational period. The mother also reported smoking one-half pack of cigarettes per day, but she denied any alcohol intake. Fetal movements were reportedly absent, but prenatal ultrasounds were normal. Spontaneous vaginal delivery occurred at 39 weeks; the infant’s birth weight was 3.6 kg and there were no complications at birth. There were no anomalies noted at birth, except for microcephaly. The initial presentation to medical care was for global developmental delay.
On initial examination at 15 months, the patient was very irritable, appeared much smaller than his chronological age and was extremely microcephalic. His length was 75 cm (10th percentile for age), weight was 6.95 kg (less than the fifth percentile for age; 50th percentile for four months) and head circumference was 41.5 cm (less than the third percentile for age; 50th percentile for three months). On follow-up examination at 22 months, his length was 75.5 cm, weight was 7.41 kg and head circumference was 43 cm (all less than the third percentile for age with minimal growth since initial evaluation).
The patient’s craniofacial examination revealed features reminiscent of those seen in patients with Smith-Lemli-Opitz syndrome. There was microcephaly, bilateral epicanthal folds, hypertelorism and bilateral malar hypoplasia. The nose was short and upturned with a bulbous tip. The philtrum was very smooth and long, and the lips were thin. Primary dentition was delayed. The ears were posteriorly rotated, and the palate was very highly arched (Figure 1). Musculoskeletal examination revealed clinodactyly of the fifth digits of the hands and feet, mildly dysplastic nails and 2-3-4 toe syndactyly bilaterally. His neurological examination revealed axial hypotonia, increased tone of the lower extremities, scissoring of the legs on vertical suspension and opisthotonic posturing when irritated. The patient’s cardiac, respiratory, abdominal and genitourinary examinations were normal.
From a developmental perspective, the patient exhibited global delay in all spheres. He first rolled at eight months, and at 22 months of age, he could not sit unsupported or crawl. He could not clearly transfer objects from one hand to the other, and did not have a pincer grasp. From a language perspective, he did not utter any single words. He was able to follow simple one-step commands, but could not follow complex directions.
A brain magnetic resonance imaging revealed bilateral peri-Sylvian polymicrogyria and decreased white matter volume (Figure 2). An abdominal ultrasound, including renal evaluation, and cardiac investigations, including electrocardiograms and echocardiograms, revealed no abnormalities. His karyotype and levels of cholesterol, 7-dehydrocholesterol, plasma amino acids, urine organic acids, urine oligosaccharides and mucopolysaccharides were all normal. Array comparative genome hybridization using the EmArray oligonucleotide array platform ([EmArray Cyto6000] Emory Genetics Laboratory, USA; 44,000 oligonucleotides with a median backbone coverage of 225 kb and 50 kb in regions of known clinical significance) was also normal.
Pharmacological suppression of the fetal renin-angiotensin system by sartans appears to disrupt fetal vascular perfusion and renal function. In humans, oligohydramnios, renal failure, pulmonary hypoplasia, limb contractures, and fetal or neonatal death have been associated with sartan exposure late in pregnancy, because expression of angiotensin type 1 receptors is low during the early stages of renal development and increases later in pregnancy (3,4). These complications were not observed in our patient, likely due to discontinuation of the medication before the third trimester.
Cholesterol biosynthesis is essential for normal fetal development. Cholesterol constitutes an important component of cell membranes and is a precursor of steroid hormone synthesis. Inhibition of biosynthesis of cholesterol in rapidly proliferating cells leads to suboptimal growth and affects important signalling processes (5). Decreased activity of the terminal enzyme of cholesterol biosynthesis, 7-dehydrocholesterol reductase, causes Smith-Lemli-Opitz syndrome, characterized by malformations such as microcephaly, holoprosencephaly and agenesis of the corpus callosum, typical facial dysmorphisms, cardiac and renal disorders, as well as abnormal development of male genitalia (5). Cholesterol is known to have a role in the post-translational modification of the Sonic hedgehog protein. Hedgehog pathways are important in the morphogenesis of the central nervous system, face, skeleton, musculature and viscera of the developing embryo (6).
In addition to developmental delay and dysmorphic features suggestive of the Smith-Lemli-Opitz syndrome, our patient also had decreased white matter bulk on brain magnetic resonance imaging, which could be related to abnormal myelin production. Cholesterol is a crucial component of normal central nervous system (CNS) myelination, which begins during the third trimester. Cholesterol is an essential component of myelin membranes, and its availability in oligodendrocytes has been shown to be a rate-limiting factor for brain maturation. Synaptogenesis occurs during the third trimester and the first years after birth; decreased fetal cholesterol levels are associated with inadequate synapse formation (7). In humans, it has been reported that very little maternal cholesterol reaches the fetal brain, and that disorders of fetal cholesterol biosynthesis are associated with CNS hypomyelination (8). Rosuvastatin is known to cross the placenta and can potentially inhibit fetal cholesterol biosynthesis necessary for myelination of the developing CNS (9).
In 2004, Edison and Muenke (10) presented a case series of all Food and Drug Administration (USA) reports, literature and manufacturer data on adverse birth outcomes following statin gestational exposure; of 214 ascertained pregnancy exposures (of which 70 had evaluable outcomes), there were 22 cases of newborns with structural defects. Gibb and Scialli (11) challenged the conclusions drawn by Edison and Muenke, stating that the prevalence of anomalies reported to be caused by the teratogenic effects of statins in the Edison and Muenke paper may not actually be greater than the prevalence in the general population. A recent study by Ofori et al (12) suggests that the anomalies reported to be associated with statins are phenomena occurring solely by chance. One of the major limitations of the study, however, is that only outcomes after the first trimester exposure to statins were measured. While well-designed, prospective studies would need to be performed to fully resolve this issue, statins are currently contraindicated during pregnancy because of concerns regarding their potential effects on the fetus, and for ethical reasons, it is unlikely that any prospective controlled studies will ever be performed.
Overall, controversy still exists regarding whether the potential benefit of treating maternal hyperlipidemia during pregnancy outweighs the risks to the fetus. Current recommendations suggest discontinuing statins once pregnancy is diagnosed due to the lack of conclusive data regarding safety of these drugs in pregnancy. We believe that our patient, who was exposed to rosuvastatin from conception until birth and presents with features consistent with Smith-Lemli-Opitz syndrome in the absence of other etiological risk factors, could represent a case of prenatal statin toxicity.
To our knowledge, this is the first reported case of a human fetus exposed to a statin from conception until term. The observed abnormalities may be associated with disruption of normal fetal cholesterol biosynthesis, particularly the developmental, facial and skeletal features, which are consistent with those seen in patients with Smith-Lemli-Opitz syndrome. However, teratogenicity of this class of drugs cannot be established based on a single case. More data are required to guide the use of lipid-lowering drugs in pregnancy.
CONFLICT OF INTEREST: The authors have no financial relationships to disclose.