Mastocytosis is characterized by an increase in mast cells in the skin, lymph nodes, liver, spleen, and bone marrow. There are four categories of mastocytosis: indolent mastocytosis, mastocytosis with an associated hematologic disorder, aggressive mastocytosis, and mast cell leukemia.1,2 Most patients with the disease have indolent mastocytosis and present with scattered small, reddish brown macules or papules (urticaria pigmentosa).
Clinical complaints include pruritus, cutaneous flushing, dyspepsia, and episodes of anaphylaxis and are usually the result of local and systemic mast cell mediator release.1 Management of mastocytosis is largely symptomatic, with treatment of hematologic disease recommended for mastocytosis patients with associated hematologic disorders. Genetic studies in women and first-degree relatives supported the association of mastocytosis with one or more activating somatic mutations in c-kit, the receptor for stem cell factor, which promotes the growth of mast cells.3,4 The possibility of genetic transmission of the disorder to fetuses remains a concern for male and female mastocytosis patients.
Despite our current understanding of mastocytosis, there is little information on how pregnancy might affect clinical features of, tolerance of medications by, and outcomes of gravid patients with mastocytosis. Mast cells have estrogen and progesterone receptors, so they are present in the myometrium and placenta, increase in number in the myometrium with pregnancy, and appear to affect the second stage of labor.5–8 Pregnancy could affect the health of pregnant women with mastocytosis, with potential secondary effects on fetuses.
To obtain information useful for counseling women with mastocytosis, we analyzed the clinical outcomes of women who conceived after developing mastocytosis and who were observed at the National Institutes of Health. We reviewed the experience of eight women with mastocytosis, who had a total of 11 pregnancies, to determine whether infants of mastocytosis patients are more likely to develop mastocytosis or other health or developmental problems.
Materials and Methods
We retrospectively reviewed medical records of 169 patients with mastocytosis, enrolled approximately between 1984 and 1998, after giving informed consent, in an Institutional Review Board–approved study at the National Institutes of Health (NIH) designed to evaluate the natural history of mastocytosis.
Nine women of childbearing age were identified among 87 women with mastocytosis. Eight of the nine had successful pregnancies, with 11 live births reported. Some women had conceived before 1984. We sent detailed questionnaires to those women, requesting additional prepartum, intrapartum, and postpartum medical history and asking specific questions regarding the health of their infants at delivery and afterward. The status of their partners' health and the presence or absence of mastocytosis also were addressed in the questionnaire. All nine women completed questionnaires, the results of which were analyzed in conjunction with medical records maintained at the NIH. Additional medical records were received when available from hospitals where women delivered. Mastocytosis was diagnosed and categorized using published criteria.3 An associated review of articles published between 1966 and 1999, inclusive, was conducted using MEDLINE, with “mastocytosis,” “mast cells,” and “pregnancy” as search terms. Three relevant case reports were identified.9–11
Clinical characteristics of individuals in this study are presented in Table 1. Indolent mastocytosis was diagnosed in all women, with approximately equal numbers of cases of category Ia mastocytosis, involving the skin only (n = 5), and category Ib mastocytosis, systemic mastocytosis with or without skin involvement (n = 4). Skin findings in every woman were urticaria pigmentosa. Women with systemic involvement had disease primarily limited to bone marrow. Most women had pruritus and/or flushing; abdominal symptoms were the next most common symptoms. One woman, who had a point mutation in the c-kit receptor in peripheral blood mononuclear cells,4 had more severe disease than the rest of the women. Reported difficulties included repeated upper gastrointestinal symptoms, malabsorption that required treatment with daily oral corticosteroids, and moderate to severe musculoskeletal pain. One woman had concomitant immune thrombocytopenic purpura (ITP). Nevertheless, the only treatment generally required for the group before pregnancy was H1 and H2 antihistamine therapy.
Evaluation of gynecologic history showed that in three of the nine women, infertility problems ranging from primary ovarian failure to endometriosis were diagnosed by obstetrician-gynecologists, similar to the rate in the general population. Two of those three women eventually were able to conceive and carry fetuses to term. In one case, clomiphene treatment was used to help achieve pregnancy. In the other, no pharmacologic intervention was attempted. Two women reported miscarriages during the first trimester.
The duration of mastocytosis at pregnancy in the eight individuals who carried fetuses to term ranged from several months to 19 years. Three women had two or more term pregnancies each. Mastocytosis was not diagnosed in their partners, nor did the partners have symptoms suggestive of early disease (eg, recurrent flushing, anaphylaxis, or urticaria pigmentosa). There appeared to be no consistent discernible negative impact of mastocytosis on the women's ability to conceive and carry fetuses to term.
A summary of the eight women's experiences prepartum, during labor, and postpartum is provided in Table 2. During pregnancy, five women had worsening of clinical symptoms, primarily pruritus and flushing. A more detailed analysis (data not shown) indicated that symptoms tended to be more severe during the first and second trimesters and severity lessened during the third. Three had increased numbers of urticaria pigmentosa lesions during pregnancy. In two of those and in two additional patients who did not experience an increase in the number of lesions during pregnancy, urticaria pigmentosa worsened postpartum. In one case, symptoms of dyspepsia essentially abated during breast-feeding and returned when breast-feeding was discontinued. Of non–mastocytosis-related conditions reported during pregnancy, preeclampsia occurred in one woman. There were no life-threatening manifestations of mastocytosis in the 11 pregnancies. However, in four pregnancies, women had increased cutaneous involvement during and after pregnancy.
Clinically significant events during labor immediately after delivery were reported by two women: transient acceleration of fetal heart rate during labor and excessive bleeding after cesarean delivery that necessitated a blood transfusion. The two women who needed prednisone to control malabsorption due to mastocytosis and ITP, respectively, had cesarean deliveries. Both had delayed healing at the incision site postpartum, attributed to corticosteroid use.
Medications used during pregnancy, during labor and delivery, and postpartum are listed in Table 3. Approximately half of the women continued to need medications—including H1 antihistamines and, less commonly, oral prednisone—to control mastocytosis symptoms. Doses were often decreased during pregnancy because of fetal health concerns. There was no higher incidence of adverse events during that period, and medications appeared to be well tolerated.
Medications given for inducing labor and anesthesia included oxytocin and, in one woman, intravenous (IV) morphine sulfate. An epidural anesthetic was used in most cases. Those data were consistent with reports that anesthetics and narcotic analgesics appear to be tolerated at standard doses during general anesthetic procedures in women with mastocytosis.12,13 One woman had natural childbirth with no anesthetics and an unremarkable delivery. Two women had corticosteroids during delivery because of prior maintenance to prevent addisonian crises. Prophylactic antihistamine therapy was not used.
A review of infant outcomes in our survey showed that all infants had normal Apgar scores at birth. Three of eight women had low birth weight infants (weight in the 10th percentile). Both infants born to patient 7 had fetal growth restriction and low birth weights, with associated health problems including low platelet count and jaundice, attributed to the mother's underlying ITP.
No significant feeding, gastrointestinal, or malabsorption problems were noted in any of the infants of those women. None of the children developed urticaria pigmentosa or systemic mastocytosis. There was one adverse outcome: hydrocephalus at birth and later a developmental delay. The infants of women with mastocytosis were healthy overall and without significant disease, and the several offspring who were observed into their late 20s through 50s were not found to have developed mastocytosis.
Review of infant outcomes showed that children were healthy overall. No infants were born with urticaria pigmentosa or systemic mastocytosis, and no new cases were found during follow-up, even follow-up in adulthood. These findings are consistent with published findings that mastocytosis is not generally heritable but is a sporadic genetic condition that might be the resultant phenotype of different underlying molecular etiologies.
We reviewed our mastocytosis patient database to gain a greater understanding of patient outcomes during pregnancy because little information is available on this topic. Mastocytosis is perceived as a medical management dilemma because of its potential for unpredictably heightened mast cell activity in response to various physiologic states, including pregnancy. Clarification is particularly relevant for many health care professionals and women.
Our data were based on findings of a survey of eight of 87 women with mastocytosis who were observed over 14 years at the NIH. These eight women had become pregnant after developing the disease. The data indicate that in some cases, pregnancy is associated with worsening of mastocytosis. However, underlying mastocytosis did not appear to cause significant medical complications or adverse fetal outcomes. Our findings were consistent with those presented in three case reports,9–11 in which exclusively cutaneous manifestations were reported. Two women had worsening of mastocytosis symptoms during pregnancy (worsening urticaria pigmentosa and anaphylactic symptoms, respectively).
Because of heterogeneity of symptoms in mastocytosis, shown in our series and reported by other investigators, it is difficult to attribute changes in any given manifestation to specific hormonal changes of pregnancy. With proper medical management, symptoms were controlled, with few or no apparent adverse effects on newborns. Conservative intrapartum management might consist of prophylactic H1 and H2 antihistamine therapy for women with severe disease, with treatment with IV epinephrine (1:10,000 dilution) if needed.14 Our findings show that standard epidural analgesics should be well tolerated and general anesthetics ought to be administered if needed, with close attention being paid to discern signs of anaphylaxis.
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