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ossible association of clomiphene with holoprosencephaly

eorgios Eleftheriou ∗, Raffaella Butera, Maria Luisa Farina

Poison Control Centre and Teratology Information Service, Ospedaliiuniti, Bergamo, Italy

Introduction: Clomiphene is widely used for inducing ovulation.vidence for congenital abnormalities, in particularly neural tubeefects (NTD), in babies born from clomiphene-induced pregnan-ies is conflicting. We report a case of holoprosencephalia (HPE) infetus delivered from a mother receiving clomiphene.

Case report: A 29-years-old woman was treated withlomiphene, used for inducing ovulation, for two consecutiveycles starting on day 2 of her menstrual cycle (50 mg for fiveays). After the 2nd cycle of clomiphene she became pregnant.he pregnancy course was normal and no illness or drug con-umption was reported. An ultrasound at 20 weeks of gestationas not conclusive; the echographic examination repeated after 6eeks showed cerebral malformations. At 32 weeks of gestation

he patient terminated voluntary the course of pregnancy: sheelivered a 1690 g fetus affected by holoprosencephaly and cleft

ip. Genetic consultation revealed a normal fetal karyotype.Discussion: Holoprosencephaly is a rare disorder characterized

y extreme clinical variability, from mild to lethal cases. In about0% of cases the etiology of HPE remains unknown: the existencef several candidate genes and/or predisposing environmental fac-ors has been postulated, sometimes combined in a “multiple-hitypothesis”. The environmental risk factors include maternal dia-etes, maternal alcoholism, and prenatal exposure to drugs, e.g.etinoic acid or cholesterol biosynthesis inhibitors. Epidemiolog-cal studies suggest that clomiphene used for inducing ovulationoes not appear to substantially contribute to the occurrence of iso-

ated NTD [1]. Moreover, Geier et al. demonstrated the absence oflomiphene and/or active metabolites during organogenesis in thelood of patients previously treated with clomiphene [2]. However,ome case reports point out a possible cause–effect relationship3,4] and Speroff et al. reported that significant plasma concentra-ions can be detected up to one month after single dose of 50 mg,uggesting that the presence of clomiphene after the “all or noth-ng” time could have unwanted effects in some patients [5].

Conclusion: Although there are no elements to provide evidencehat clomiphene therapy may be a risk factor for holoprosen-ephaly, our experience adds a further possible case to thoselready published. Case–control studies are needed to better under-tand if clomiphene has some teratogenic potential.

eferences

1] Werler MM, Louik C, Shapiro S, Mitchell AA. Ovulation induction and risk ofneural tube defects. Lancet 1994;344(8920):445–6.

2] Geier A, Blankstein J, Kokia E, Pariente C, Lunenfeld B. Absence of clomipheneand/or active metabolites in blood of clomiphene citrate-treated patients dur-ing organogenesis: determination by radioreceptor assay. Am J Obstet Gynecol1987;157(4 Pt 1):1009.

3] Dyson JL, Kohler HG. Anencephaly and ovulation stimulation. Lancet1973;1(7814):1256–7.

4] Vollset SE. Ovulation induction and neural tube defects. Lancet1990;335(8682):178.

5] Speroff L, Robert HG, Nathan GK. Induction of ovulation. Clinical gynecologicendocrinology and infertility. 6th ed. Philadelphia: Williams & Wilkins; 1999. p.1099–00.

oi:10.1016/j.reprotox.2010.12.027

ctive Toxicology 31 (2011) 255–268 257

Neonatal paroxetine toxicity

Georgios Eleftheriou a,∗, Raffaella Butera a,b, Sonia Radice c, LuigiManzo b, MariaLuisa Farina a

a Poison Control Centre and Teratology Information Service, OspedaliRiuniti, Bergamo, Italyb Poison Control Centre, IRCCS Fondazione Maugeri and University ofPavia, Italyc Unit Clinical Pharmacology, University Hospital Luigi Sacco, Milano,Italy

Introduction: Neonatal withdrawal syndrome following in uteroexposure to paroxetine is a well known consequence but some-times may be confounded with serotonin toxicity, as both hyper-and hyposerotoninergic states can result in similar symptoms innewborns. We report a case of paroxetine toxicity in a newbornafter in utero exposure to paroxetine and olanzapine.

Case report: A 3060-g boy was delivered at 38 weeks of gesta-tion to a 32-year-old mother who was affected by major depressivesyndrome and treated with paroxetine 20 mg and olanzapine 5 mgonce daily. Apgar scores were 4 at 1 min and 8 at 5 min. At birth theinfant was cyanotic, failed to show respiratory effort and was ven-tilated for 30 s. After 1 h, he was bradycardic, hypotonic and withopisthotonus posturing; at 6 h, convulsions ensued and lorazepambolus was administered. The patient was discharged 5 days afterdelivery with no symptoms and normal laboratory values. Cordblood levels of paroxetine and olanzapine at the time of deliv-ery were 17.2 ng/ml and 4.6 ng/ml, respectively; neonatal serumconcentrations at 24 h of age were 10.2 ng/ml and 4.5 ng/ml, respec-tively. Paroxetine and olanzapine maternal serum levels one dayafter delivery were 30.6 ng/ml and 6.7 ng/ml, respectively. Aftertherapeutic dosing of paroxetine and olanzapine, expected serumlevels are 10–100 ng/ml and 10–50 ng/ml, respectively.

Discussion: There is an ongoing debate about whether theadverse effects seen in some neonates are due to a paroxe-tine withdrawal syndrome, or are due to toxicity [1]. In adults,serotonin syndrome could occur with two or more medicationsthat elevate brain serotonin levels are used or after an overdoseof these drugs, although mild serotoninergic symptoms may beencountered among patients receiving therapeutic doses of a singleselective serotonin reuptake inhibitor (SSRI). As opposed to sero-tonin syndrome, cases of withdrawal would be expected whenserum concentrations of SSRIs are low or undetectable. Parox-etine is a highly potent inhibitor of 5-HT reuptake and couldrender neonates, when in utero exposed to paroxetine, susceptibleto both syndromes: (i) serotonin withdrawal through cholinergicoverdrive that occurs with declining levels of paroxetine and (ii)serotonin syndrome with immediate onset of symptoms at birth.In our case, other causes explaining the observed clinical picturewere excluded. Neonatal serum concentrations of paroxetine inthe typical adult therapeutic range and the onset of the symptomsimmediately after birth render difficult the diagnosis of withdrawalsyndrome. Therefore, the hypothesis of serotoninergic syndromeseems more plausible: this is supported by both drug levels andtime-course of symptoms.

Conclusion: Normal or low plasma concentrations of paroxetinemay be associated with serotoninergic perinatal complications insusceptible infants when exposed to paroxetine during late preg-

nancy, as observed in our case. A definitive differential diagnosisbetween paroxetine toxicity and withdrawal syndrome is possibleonly if neonatal paroxetine blood levels are available.

doi:10.1016/j.reprotox.2010.12.028