Mitoxantrone exposure in pregnancy: a new case report in a multiple sclerosis patient

Introduction

Mitoxantrone (MIX) is a chemotherapeutic agent used for the treatment of prostate and breast cancer, non-lymphocytic leukemia and aggressive cases of multiple sclerosis (MS). As it intercalates with DNA, MIX is considered a potential human teratogen, and is classified by the US Food and Drug Administration in pregnancy category D. Thus, it is recommended to avoid pregnancy during treatment. Until now, the animal studies with MIX used at dosage >0.1 mg/kg/day did not show any teratogenic effects. However, there was an increased incidence of premature delivery in rabbits and decreased fetal weight in rats [1]. In humans, there have been only six reported cases of MIX exposure during pregnancy or during the preconception period. The first four were described in oncological patients, where MIX was administered in combination with other drugs in the second trimester of pregnancy [2], [3], [4]. The outcomes of these cases were: one fetal death [2], one growth-restricted baby [3], and two healthy newborns [3], [4]. The other two cases involved women with MS [5], [6]. In the first case [5], the patient received four infusions of MIX at a dosage of 20 mg, the last one at 30 weeks of pregnancy, because she was considered in menopausal status. During the pregnancy, ultrasound showed oligohydramnios and growth restriction. At birth, the infant was normal, but was kept in an incubator due to its low weight and sent home after 14 days. In the second case [6], there were only two infusions at a dosage of 12 mg/m². These were given during the preconception period. Ultrasound and amniocentesis were normal during the pregnancy, and the fetus did not show any growth restriction or abnormalities. At birth, however, the infant was affected by the Pierre Robin sequence (PRS), a severe disease characterized by various malformations. The authors conclude that the relationship between MIX and the syndrome is possible, but not certain. In fact, genetic and toxic factors could be implicated in the etiology of PRS. The patient in question smoked, and smoking could also be associated with an increased risk of this disease.

Case history

We describe the case of a 24-year-old female with MS. The onset of the disease was in the summer of 2011, and diagnosis in March 2013. The patient had had one previous pregnancy in 2009, with a good outcome. She had no other disease out of MS. Because of the aggressiveness of her clinical and neuroradiological course, she needed to begin an induction therapy very quickly. She therefore started MIX infusions in July 2013, 4 months from diagnosis. She received a cumulative dose of 60 mg/m² and a total of six infusions since discovering she was pregnant. The first five doses were administered monthly, with the last of these on March 24. Due to a relapse, she also received methylprednisolone 1 g for 5 days between February and March 2014. The conception day was between March 19 and 21. The patient smoked until April 17, and took oxybutynin daily for bladder dysfunction. The pregnancy was regular, and the ultrasound exams were always normal. However, a growth restriction was observed over the entire period. At week 29 (September), ultrasound also showed a low reduction of amniotic liquid. On December 3 (week 39), the patient delivered a healthy female baby by natural childbirth. The child’s weight was 2.314 kg (<5^th percentile), with a length of 45 cm (<5^th percentile) and a cranial circumference of 30 cm. After 3 days, the infant was sent home in good condition, and she is healthy at the time of writing.

Discussion

This is only the third such reported case of MIX exposition in pregnant women with MS. In the first of these, treatment was during pregnancy, and in the second, only during the preconception period. Our patient received treatment before the date of conception, and only one dose after that. A growth restriction was observed, but the baby was otherwise healthy. Similar results have been reported by De Santis et al. [5] in an MS woman, by Giacalone et al. [3] in an oncological patient, and in studies on rats [1].

Concerns about fertility and pregnancy, particularly in relation to disease-modifying treatment, are very important in MS and the topic of many studies. MS is more prevalent in women, and onset is often in early adulthood, a time when people are planning their professional and personal lives.

MIX is a treatment used only in very aggressive cases of MS due to its possible adverse events, and its negative effects on women’s fertility are well known [7]. Physicians recommend that women avoid pregnancy during MIX therapy, and the use of estroprogestinic drugs is also suggested to reduce the risk of chemotherapy-induced amenorrhea [7]. Moreover, the introduction in recent years of other second-line treatments such as Natalizumab and Fingolimod has reduced the use of MIX. For all of these reasons, pregnancies during MIX are very rare. As such, it is difficult to study the effects of the drug during pregnancy over a large sample of patients.

In conclusion, given the current knowledge, pregnancy should be avoided by women undergoing chemotherapeutic treatments such as MIX. Nevertheless, in only one of three cases involving MIX monotherapy for MS [6], and in one other reported case using MIX in polytherapy in an oncological patient [2], the outcomes were very serious (PRS syndrome and death, respectively). This suggests that if accidental pregnancy occurs, its interruption is not mandatory, and continuation could be discussed with the patient. To enhance existing knowledge about this important topic, and to have access to more safety data, it is important to collect all available information about accidental MIX exposition during pregnancy.