Mastocytosis and Pregnancy
Almudena Matito, MD, PhD
Instituto de Estudios de Mastocitosis de Castilla La Mancha, Toledo, Spain
Spanish Network on Mastocytosis (REMA)
Almudena Matito, MD, PhD
Instituto de Estudios de Mastocitosis de Castilla La Mancha
Hospital Virgen del Valle, Carretera de Cobisa s/n, Toledo 45071, Spain
Mastocytosis is a heterogeneous group of disorders characterized by an abnormal expansion and accumulation of mast cells (MC) in one or multiple organs. While the skin, bone marrow (BM), and gastrointestinal tract are more frequently involved, other tissues can be affected. Patients with mastocytosis have symptoms due to the release of MC mediators, the infiltration of tissues by MC, or both. In non-aggressive categories of the disease, symptoms are mostly due to the effects of MC-mediators released by known and unknown triggers, after MC activation through immunologic and non-immunologic pathways. Triggers include some hormones like estrogens (1), indicating that changes in sexual hormone serum levels throughout pregnancy and after delivery might translate into changes in the profile of MC-mediator release-associated symptoms. Despite this, information on the influence of sexual hormones on MC is limited and mostly based on in vitro and animal models (2-5).
The discontinuation of antimediator therapy during pregnancy because of safety concerns, and the stress of labour along with the potential administration of anesthetic and analgesic drugs in its management, may also worsen MC-mediator related symptoms. Some case series of pregnant mastocytosis patients have been published (6-8), the largest of which was reported by the Spanish Network on Mastocytosis (REMA) in 2011 (9). Neither maternal nor infant severe complications secondary to mastocytosis were reported in this series, supporting the notion that mastocytosis is not a contraindication for pregnancy. However, these women must be adequately managed to prevent severe intrapartum (during labour) MC-related symptoms. In this report we present the recommendations for pregnancy and delivery in women with mastocytosis. These recommendations are based on the experience of 84 patients who presented 138 pregnancies and deliveries, which were followed by the REMA.
Overall, the 84 women who presented 138 single pregnancies (referred to as cases from now on) had non-aggressive categories of the disease (disease category numbers based on number of pregnancies): 7 cutaneous mastocytosis (CM), 23 mastocytosis in the skin (MIS; a category designating those who have not had the possibility of systemic disease ruled out), 87 indolent systemic mastocytosis (ISM) of which 5 did not have the typical skin lesions of mastocytosis, and 21 well-differentiated systemic mastocytosis (WDSM). Of note, 3 of the women developed the skin lesions during the second and third trimesters, and were diagnosed with CM (n=1) and ISM (n=2) after delivery, respectively.
Median age at pregnancy was 32 years (range: 18 to 44 years), while median time from the onset of mastocytosis to delivery was 11 years (range: 4 months to 39 years). Five pregnancies were achieved by in vitro fertilization, due to a history of infertility. Eleven patients (8%) had suffered a total of 15 miscarriages before their first full-term pregnancy, 3 of them occurring within a two-year interval in 1 patient. By contrast, 5 (4%) additional women suffered 10 miscarriages after previous successful pregnancies. The frequency of miscarriages was similar to that described for the general population (10).
Evolution of MC-Mediator Related Symptoms
MC-mediator release-associated symptoms such as pruritus, flushing, gastrointestinal symptoms, and anaphylaxis, were recorded during three periods: pregestation (before pregnancy) (baseline), pregnancy, and postpartum. All symptoms were graded according to the published REMA criteria on the basis of their frequency: (i) absent, (ii) daily, (iii) weekly (>1 but <7 days per week), (iv) monthly, and (v) occasionally (<once/month) (9). Any changes in the frequency of pre-gestational (pre-pregnancy) MC-related symptoms were recorded during pregnancy and puerperium (the six week period after birth). Worsening of symptoms was defined as the predominant increase in the frequency of symptoms and/or the development of new MC-related symptoms that were previously absent, in any of the trimesters of pregnancy. Symptom improvement was categorized as: (i) complete resolution (CR), if all MC-mediator release-associated symptoms disappeared, (ii) partial resolution (PR), if at least one MC-related symptom disappeared, (iii) major resolution (MR), if a decrease in the frequency of pre-gestational MC-related symptoms was observed, and (iv) minor resolution (mR), when at least one pre-gestational MC-related symptom disappeared or decreased in frequency, but worsening of this or other symptoms occurred in the following trimesters of pregnancy. Anaphylaxis was the most severe symptom recorded. Cases with changes in this and other symptoms were classified according to the evolution of symptoms following the criteria described above. Following these criteria, no changes in MC-related symptoms were observed during pregnancy in 83 cases (60%). Worsening of MC-related symptoms during pregnancy was observed in 20 cases (15%), including an increase in their frequency in 5 cases, the development of symptoms that were absent before pregnancy in 12 cases or both in 3 cases. Of these 3 cases, 2 of them had idiopathic anaphylaxis episodes, and the other had anaphylaxis triggered by hymenoptera sting. Additionally, 3 women developed skin lesions during the second and third trimesters of pregnancy, and were diagnosed with CM (n=1) and ISM (n=2) after delivery. The typical skin lesions of mastocytosis increased in number in 5 other cases.
Clinical improvement during pregnancy occurred in 35 cases (25%), including complete resolution in 16, partial resolution in 10, major resolution in 3, and minor resolution in 6 cases. Complete resolution (CR) was achieved in 5 cases with anaphylaxis; 2 of them presented with idiopathic anaphylaxis, while in the other 3, anaphylactic episodes were triggered by hymenoptera (e.g., bee, wasp) sting or kiwifruit ingestion, hymenoptera sting, and codeine respectively. Thus, the absence of anaphylaxis cannot be attributed to pregnancy itself. Furthermore, of these 16 cases that achieved CR, 8 improved and 8 worsened in the aspect and number of the skin lesions of mastocytosis. Interestingly, 95 cases (69%) took antimediator therapy neither before nor during pregnancy. Among these cases, 67 maintained stable MC-mediator release related symptoms during pregnancy, 17 improved, while in the remaining 11 symptoms worsened during this period. Only 16 (12%) cases required specific scheduled antimediator therapy during pregnancy using different combinations H1 and H2 antihistamines, as well as isolated doses of corticosteroids in 3 pregnancies, to control severe MC-mediator release related symptoms (Figure 1).
MC-mediator release-associated symptoms after delivery compared to the pre-gestational profile did not change in 94 (68%) cases. Of these cases, 75 remained stable, 11 improved, and 8 worsened during pregnancy. These symptoms remained worse after delivery in 6 of the 16 cases that had worsened during pregnancy. Symptoms also worsened in 4 additional cases that did not experience any clinical changes during pregnancy, and in 6 cases that had improved during pregnancy (4 complete resolution, 1 major resolution, and 1 minor resolution). In addition, MC-mediator release-associated symptoms after delivery compared to the pre-gestational profile improved in 28 (20%) cases. Complete resolution (CR) was observed after delivery in 8 (6%); 2 of them had worsened, whereas 5 achieved CR, and 1 achieved partial resolution (PR) during pregnancy. PR was observed in 5 cases. Of these 5 cases, 3 had previously achieved PR and 1 had CR during pregnancy, while the remaining 1 case had worsened during pregnancy. Major resolution (MR) was observed in 5 other cases; 3 of them had presented during a CR, PR, and MR during pregnancy, respectively, and the other 2 cases had remained stable during pregnancy. Finally, minor resolution (mR) was achieved in 10 cases. In these 10 cases, symptoms had not changed during pregnancy in 2, symptoms worsened during pregnancy in 3, while symptom improvement during pregnancy was seen in the remainder, with mR in 3, MR in 1 and PR in 1.
Overall, 11 (8%) cases presented in anaphylaxis during this period, and some of them had one or more elicitors for the episodes. Anaphylaxis was idiopathic in 7 cases, triggered by drugs such as different non-steroidal anti-inflammatory drugs (n=1), diclofenac (n=1), aspirin (n=1), codeine (n=1), moxifloxacin (n=1), and ciprofloxacin (n=1). Anaphylaxis was elicited by hymenoptera sting and seafood ingestion in 1 case. It is noteworthy that the aspect and number of typical skin lesions of mastocytosis improved after delivery in 3 cases; the skin lesions had already improved in 1 case and remained stable during pregnancy in 2 cases. Furthermore, typical skin lesions worsened after delivery in 25 cases. Among these 25 cases, the lesions had worsened and improved in 4, and had not changed in 17, during pregnancy.
A total of 15 (11%) cases began specific scheduled therapy after delivery, including oral disodium cromolyn (n=8), hydroxyurea (n=1), as well as different combinations of H1 and H2 antihistamines. Furthermore, 12 (9%) cases required antimediator therapy on demand using H1 antihistamines (n=9), H2 antihistamines (n=2), montelukast (n=1), and corticosteroids (n=4). Figure 2 shows the evolution of MC-mediator related symptoms during this period and the administration of antimediator therapy.
Labour Characteristics and MC-Mediator Related Symptoms Intrapartum
Overall, 118 (86%) infants were born by vaginal delivery and 20 (14%) had a caesarean birth. Labour induction was carried out for 41 vaginal deliveries using oxytocin (n=32) or dinoprostone (n=9). Prophylactic antimediator therapy for labour was given in 36 (26%) cases using different combinations of antihistamines and corticosteroids (n=13). Anesthetic procedures for labour and delivery were carried out in 91 cases (66%), including epidural (n=81), local (n=4), and general (n=6) anesthesia. Amide-derivative anesthetic drugs were used in the local and epidural techniques, in association with fentanyl in 16 cases. Only 1 case had excessive bleeding during delivery and needed a transfusion.
Mild MC-mediator release-associated symptoms intrapartum were observed in 5 cases (4%): pruritus (n=2), generalized erythema (n=2), and flushing (n=1) occurred without any fatal outcome. In addition, one patient who received dinoprostone experienced vomiting, diarrhoea, and hypotension, described as secondary effects of this drug. Of note, prophylactic antimediator therapy was used in only 1 of the intrapartum symptomatic cases, while 2 cases presented symptoms despite anesthesia not being used. In the 3 symptomatic cases that underwent epidural anesthesia, all of them tolerated this anesthetic technique after being given prophylactic antimediator therapy.
Perinatal Outcomes and Infants’ Health
Stillbirths were not observed in this case series. There were 11 (8%) preterm and 10 (7%) low birthweight births. The frequency of both is similar in the general Spanish population (11). Respiratory distress was observed in 3 newborns, of which 1 had fetal growth restriction during pregnancy and was diagnosed with Down syndrome at birth. Additionally, among newborns there were 3 cases of non-reassuring fetal heart rate tracing and 3 cases of transient neonatal physiological jaundice. These cases all achieved successful recovery with conservative management. Only 3 infants with low birthweight corresponded to mothers who had suffered from anaphylaxis during pregnancy. The median time of newborn follow-up at the end the study was 10 years (12 months – 41 years). During this follow-up, skin lesions of mastocytosis were detected in 18 of 138 (13%) infants (10 girls and 8 boys), at a median age of 3 years (range: newborn to 6 years). Interestingly, 12 of 84 (14%) mothers had children who developed the skin lesions of mastocytosis, and 8 of these mothers had a well-differentiated systemic mastocytosis (WDSM).
RECOMMENDATIONS FOR PREGNANCY AND DELIVERY
Based on these data, the Spanish Network on Mastocytosis (REMA) recommends using drugs with a well-established safety profile during pregnancy. In keeping with this recommendation, oral disodium cromolyn must be discontinued. H1 antihistamines such as dexchlorpheniramine, cetirizine, loratadine, and H2 antihistamines such as ranitidine, can be used. In addition, corticosteroids and/or epinephrine can be used only when strictly required, after careful evaluation of the risk-benefit ratio.
Multivitamins, folic acid, and ferrous sulfate supplements can be administered throughout pregnancy and puerperium.
Furthermore, we recommend administering prophylactic antimediator therapy with H1 and H2 antihistamines at the beginning of labour and/or one hour before anesthesia. If required, oxytocin can be used as a delivery inductor (9). Anesthetic techniques can be safely used, although each case must be evaluated in order to avoid drugs that previously elicited MC-mediator related symptoms and to use drugs with known tolerance by individual patients. If this information is not available or any of these drugs are indispensable, we recommend the use of drugs with a lower risk of eliciting MC degranulation (IgE mediated or not) in every pharmacological group, such as rigid neuromuscular blockers, synthetic opioids with short-acting and rapid offset modes of action, and amide derivatives as local anesthetics (12).
Mastocytosis has a heterogeneous clinical behaviour during pregnancy. In the case series presented, the profile of MC-related symptoms remained unchanged in more than half of the cases, while the remainder experienced either an improvement or an exacerbation of symptoms. To prevent potential life-threatening MC-related symptoms, adequate intrapartum prophylactic antimediator therapy should be systematically administered. The absence of both severe maternal and severe infant complications, suggest that patients with non-aggressive categories of mastocytosis should not be advised against pregnancy.
Denyse Nanan, MD
Valerie M. Slee, RN, BSN
Susan Jennings, PhD
The Mastocytosis Society, Inc.
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