A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis

doi:10.1016/j.jns.2011.05.003

Journal of the Neurological Sciences

Volume 307, Issues 1–2, 15 August 2011, Pages 164-165

https://doi.org/10.1016/j.jns.2011.05.003 Get rights and content

Abstract

Multiple sclerosis is a common disease of young adults in which accidental and unplanned pregnancies under disease modifying or immunosuppressive therapies may occur. The experience with mitoxantrone (MIX) especially in the first trimenon is very limited, until now only one case of a pregnant woman with MS who was exposed to MIX in early pregnancy and delivered a growth restricted but healthy child was published. We report a case of a secondary progressive MS patient who was exposed periconceptionally to MIX and delivered a child with Pierre Robin Sequence (PRS), a syndrome with the main features of glossoptosis, micrognathia, and palate clefts. PRS is a very rare defect and therefore a causal relation with MIX seems possible.

Introduction

Mitoxantron (MIX) is a chemotherapeutic agent which was first approved in the treatment of prostate and breast cancer as well as in the treatment of non-lymphocytic leukemia [1]. MIX is also used in the treatment of therapy refractory rapid progressive relapsing remitting (RRMS) or secondary progressive multiple sclerosis (SPMS). MS is a common neurological disease of young adults in childbearing age. Because of its genotoxic potential and very long half life time (Food and Drug administration pregnancy Category D: adequate, well controlled or observational studies in pregnant women have demonstrated risk on the fetus) MIX treated patients should assure effective contraception for 6 months [2]. Experience with MIX in early pregnancy is limited, only one case describes a pregnancy of a patient with MS resulted in birth of a healthy but growth and weight restricted baby [3]. In four other case reports oncological patients were exposed to MIX in combination with other chemotherapeutics during later pregnancy. In addition to a fetal death, two healthy babies and a growth restricted newborn were reported [4], [5], [6].

We describe a case of preconceptional MIX exposure in a 37 year-old female with SPMS, diagnosed in 1993, out of our pregnancy database with 180 pregnancies of women with MS. This is the only pregnancy exposed to MIX in our database. Due to SPMS the patient was treated for the first time in August with MIX (12 mg/m² body surface) in combination with ondansetron as anti-emetic. The next and last dose (12 mg/m²) she received on November 20th. When she presented at the beginning of March for the third cycle of MIX treatment, she was detected to be pregnant by routine testing before MIX application. Because of assumed infertility with long lasting unrealized desire for own children and irregularities of the menstrual cycle, she had not performed any contraceptive method. The patient had smoked 10 cigarettes/day for the last 10 years. She did neither drink alcohol on a regular basis not take any other drug than an anti-emetic regimen with ondansetron (before MIX application). MIX treatment was stopped. Ultrasound at this time revealed pregnancy at 10 weeks. Amniocentesis and repeated ultrasound inter alia in a hospital acknowledged by the German society of medical ultrasound diagnostic, did not reveal chromosomal or fetal abnormalities or significant growth restriction.

In October (40th weeks of gestation) the patient delivered by caesarian section a son of 2940 g and 50 cm. The infant suffers from Pierre Robin sequence (PRS) characterized by mandibular micrognathia, glossoptosis, retrogenia, and orofacial clefts, clinically emerging with intermittent upper airway obstruction [7]. PRS has not been observed in the family.

Section snippets

Discussion

We report a case of preconceptional MIX exposure in a woman with MS, which resulted in a child with PRS. The etiology of PRS is not resolved albeit genetic factors, drugs and/or toxins (alcohol) are discussed as possible causes of this very rare syndrome. Our patient was treated with MIX about 8–9 weeks before presumed conception and delivered an infant with PRS. Because of long half life it is possible that the fetus was exposed to the drug [1]. Because of incomplete closure of jaw, lips and/or

Acknowledgment

This pregnancy database was partly supported by Biotest, Biogen-Idec Germany, Serono and Teva Aventis Pharmaceuticals. We thank all patients and physicians attributing datasets to this database.

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Mitoxantrone is considered as a potential human teratogen because of its mechanism of action and developmental effects demonstrated by related agents. Only two cases of pregnant women with MS, who were exposed to mitoxantrone in early pregnancy, have been published: with a newborn with the Pierre Robin sequence and one newborn growth restricted but healthy [84,85]. According to European and USA labeling recommendations mitoxantrone is contraindicated during pregnancy.
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Data found both in the DRUGDEX database and in the literature drew the same conclusions [25]. One isolated case of Pierre Robin malformation was however recently reported in a patient exposed to mitoxantrone at the time of conception [26]. As stated on the mitoxantrone SPC, “due to the toxicity of mitoxantrone on DNA related to its mechanism of action, women of childbearing age should use an effective means of contraception in the month prior to the start of treatment, throughout the entire length of treatment and for 3 months after treatment withdrawal.”
The question of pregnancy in patients with multiple sclerosis is regularly raised due to the prevalence of the disease in middle age women. The multiple sclerosis think tank (Groupe de Réflexion sur la Sclérose en Plaques [GRESEP]) decided to develop recommendations on this issue, with consideration to both the impact of multiple sclerosis on pregnancy, and that of pregnancy on the disease. As with topics of previous works, the formal expert consensus method was used. The working group was composed of hospital-based and private practice neurologists. The reading group was composed of neurologists, anaesthetists and obstetricians. Each recommendation is presented with the relevant level of consensus.
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Short communicationA newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis

Abstract

Introduction

Section snippets

Discussion

Acknowledgment

Neurotoxicology

Anon Mitoxantron product information

Pregnancy and immunomodulatory therapy in multiple sclerosis patients

Nervenarzt

Mitoxantron and etoposid in breastmilk

Am J Hematol

Chemotherapy for breast carcinoma during pregnancy

Cancer

Short communication
A newborn with Pierre Robin sequence after preconceptional mitoxantrone exposure of a female with multiple sclerosis