Interferon alfa treatment for pregnant women affected by essential thrombocythemia: Case reports and a review

doi:10.1016/j.ajog.2004.05.001

American Journal of Obstetrics and Gynecology

Volume 191, Issue 6, December 2004, Pages 2016-2020

https://doi.org/10.1016/j.ajog.2004.05.001 Get rights and content

Objectives

In the past essential thrombocythemia was considered a disease of the elderly. At present, the number of young people suffering from this disease is growing, with a slightly higher frequency in females. We investigated the effects of interferon alfa therapy in these patients.

Study design

We describe 9 pregnancies in 4 women affected by essential thrombocythemia.

Results

Four pregnancies were carried out without interferon alfa therapy, and resulted in 2 intrauterine deaths, 1 spontaneous abortion, and 1 neonatal death. Interferon alfa was given during another 5 pregnancies; among them, 2 ended in preterm deliveries with normal infants, and 3 in full-term deliveries. The literature is reviewed.

Conclusion

Our cases and published series suggest that fetal outcome is improved by therapy, and that interferon alfa may be the best therapeutic option.

Section snippets

Case report

The clinical characteristics of our patients at diagnosis are described in Table I. Information about platelet count, type, dose, and length of therapy for all of our cases are summarized in Table II.

Patient 1

This patient had thrombocytosis (platelet count 814 × 10³/μL) since 1992. At her first pregnancy (October 1992 to May 1993), intrauterine death occurred while she was receiving only ASA. In August 1993, a diagnosis of ET was made at our institution, and α-IFN therapy at the dose of 3 international megaunits (MU), 5 days per week, was started. In November 1993, still under α-IFN therapy, she became pregnant again. After counselling, α-IFN was continued, and ASA (100 mg daily) was added, starting

Patient 2

This woman was diagnosed with ET in March 1997, and soon started α-IFN therapy (3 MU 5 days per week) because of her history of bleeding episodes. In June 1997, she became pregnant. After counselling, she agreed to continue α-IFN therapy, and the dose was reduced to 3 MU 3 days per week starting from 20 weeks of gestation. ASA was not prescribed because of patient's history of bleeding. She had an uneventful pregnancy and was delivered of a normal male newborn weighing 3070 g at 41 weeks of

Patient 3

This patient was 28 years old when ET was diagnosed; she had had her first pregnancy before ET appearance in 1996, at the age of 25 years. Being symptomatic with headache and erythromelalgia, she was treated with α-IFN (3 MU 3 times per week). As soon as the second pregnancy was documented (at 14 weeks of gestation), the dose was reduced and ASA (100 mg daily) was added. After counselling, this treatment was continued throughout the pregnancy. The pregnancy was uneventful, with normal growth of

Patient 4

This woman was diagnosed with ET in 1991 when she was 25, and was given α-IFN (3 MU 3 times per week) until 1995, when she decided to stop the therapy. In July 1996, intrauterine fetal death occurred at 27 weeks' of gestation. In August 2000, she became pregnant again, and after counselling, at 8 weeks of gestation, therapy with α-IFN was started again, combined with ASA, 100 mg daily. This treatment was continued throughout the pregnancy. The pregnancy was uneventful with normal fetal

Comment

The issue of when and how to treat patients with ET is of particular concern in young patients because they will be receiving therapy for many years, with increasing risk for treatment-related side effects. ET in pregnancy has been reported to be complicated by recurrent abortion, intrauterine death, stillbirth, premature delivery, preeclampsia, and fetal growth restriction caused by placental infarction resulting from thrombosis. Maternal complications, such as bleeding or thrombotic events,²

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Cited by (28)

Management of hemopoietic neoplasias during pregnancy
2016, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Women receiving TKI should avoid breastfeeding (Rousselot et al., 2007a; Burchert et al., 2010; Aut et al., 2006; Rousselot et al., 2007b; Conchon et al., 2009; Jiang et al., 2012). Interferon is a safe drug in pregnant patients requring treatment even in 1 st trimester (Ali et al., 2004; Regeirer et al., 2006; Al Bahar et al., 2004; Mubarek et al., 2002; Martinelli et al., 2004). If patient does not tolerate interferon, imatinib may be used in 2nd trimester (Brenner et al., 2012).
Hemopoietic neoplasias are unique cancers generally affecting bone marrow, and requires a special attention for disease control and also their complications. When these neoplastic disorders accompany to pregnancy there are many risks both for mother and foetus. Diagnostic difficulties due to the limited use of imaging modalities is essential in pregnant women. On the other hand suboptimal using of the anti-neoplastic drugs and their higher toxicity in mother and foetus must be considered in the management of these neoplastic disorders. Due to the lack of therapeutic guidelines in these cases, team approach is essential and therapy requires to the use the art of medicine.
A systematic review of the fetal safety of interferon alpha
2012, Reproductive Toxicology
Citation Excerpt :
It is also used in hemato-oncological conditions, including essential thrombocythemia (ET), chronic myelocytic leukemia (CML), hairy cell leukemia, Kaposi's sarcoma, multiple myeloma, Non Hodgkin lymphoma, cutaneous T cell lymphoma, malignant melanoma, basal cell carcinoma, and polycythemia vera. In addition, IFN-α is used in conditions such as benign hemangioma, chronic inflammatory demelinating polyneuropathies, and sub-retinal neovascular proliferative diseases [4–40] (Table 1). Although some of the conditions treated with IFN-α (e.g. CML and multiple myeloma) occur in older age groups, many of them may occur in young adults, including women of childbearing age.
Interferon alpha (IFN) is an effective treatment for a variety of conditions including essential thrombocythemia (ET), chronic myelocytic leukemia, Hepatitis B and C. Because these conditions also occur in women of childbearing age who may become pregnant, information regarding the safety of this medication in pregnancy is essential. This systematic review attempts to summarize all published data on outcome of pregnancies exposed to IFN alpha, trying to differentiate between disease effect and drug effect.
Reports on the use of IFN alpha in human pregnancy and reports on essential thrombocythemia (ET) without use of any medication in pregnancy were identified by a systematic search of the medical literature. We were able to locate only case reports of IFN alpha exposure in pregnancy, of whom 40 out of 63 were diagnosed with ET. We also collected randomly 71 cases (more cases were available in the literature) that were diagnosed with ET due to different etiologies, but who had not received any medication in pregnancy.
Among the 63 IFN alpha exposures in pregnancy, the mean maternal age was 30 ± 6 years and the mean full term babies’ weight was 3096 ± 463 g. Mean gestational age at delivery was 37 ± 3 weeks. There were 55 single and 4 twin pregnancies. No cases of major malformations or stillbirths were reported. There was one case of spontaneous abortion and 13 preterm deliveries (20% of all exposed cases).
Among the 71 cases with untreated ET in pregnancy of different etiologies, 46 (65%) had early (within the first 12 weeks of pregnancy) or late (13–20 weeks of gestation) pregnancy loss. There were also 3 cases (4%) of stillbirth and 4 cases (5.6%) of preterm delivery. Only 18 women (25%) delivered healthy term babies.
The results of our systematic review suggest that IFN-α does not significantly increase the risk of major malformation, miscarriage, stillbirth or preterm delivery above general population rates. It is also possible that IFN-α may have a protective effect against pregnancy loss in cases of ET.
Essential thrombocythemia and pregnancy
2011, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Of note, one publication reports intrauterine growth-restriction, thrombocytopenia, and neonatal drug-induced lupus in a newborn whose mother received IFNα for ET during pregnancy [47]. Favorable pregnancy outcomes with IFNα treatment are around 90% [18,46,48]. Thus, IFNα seems to be the agent of choice in pregnant women who need platelet count reduction and/or when complications occur despite therapy with aspirin and LMWH.
Essential thrombocythaemia (ET) is an acquired myeloproliferative neoplasm, characterised by persistent thrombocytosis and a tendency for either thrombosis or haemorrhage. Among myeloproliferative neoplasms, ET is the most prevalent in young women, which constitute a special group due to their childbearing potential. An increased risk of fetal and maternal complications has been demonstrated in patients with ET. The most common pregnancy-related complication is spontaneous abortion during the first trimester. Recurrent abortion, fetal growth restriction, stillbirth and placental abruption are less frequent. Maternal complications are relatively rare and essentially represented by thromboembolic and bleeding events. Here we summarize the literature describing pregnancy and its outcome in patients with ET and discuss some recommendations for the management of pregnancy.
CML in pregnancy and childhood
2009, Best Practice and Research: Clinical Haematology
Citation Excerpt :
For women requiring additional treatment during pregnancy, either due to intolerance of leucapheresis or poorly controlled counts, IFN-α may have a role in the 2nd and 3rd trimesters. There are numerous case reports of successful pregnancies in women receiving IFN-α at all stages of pregnancy and for a variety of conditions including CML[60–63]. Due to its large size (19,300 daltons) it would seem unlikely that IFN-α crosses the placental barrier to any great extent [64].
With the improved survivals offered by the tyrosine kinase inhibitors has come the necessity to address issues relating to quality of life and one such area is that of fertility and parenting. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult males or females but human data remain limited. Children born to men who are actively taking imatinib at the time of conception appear healthy and current advice is not to discontinue treatment. In contrast the data relating to children born to women exposed to imatinib during pregnancy are less encouraging. Although numbers are small there has been a disturbing cluster of rare congenital malformations such that imatinib cannot be safely recommended, particularly during the period of organogenesis.
The appropriate management of children with CML has also been radically changed by the advent of imatinib. The features of the disease at presentation, the natural history and the response to therapy seem to be identical in children to that seen in adults. Now that imatinib has been in clinical use for almost ten years without severe long-term side effects, most physicians are now comfortable advising a trial of imatinib prior to consideration of transplant. Data relating to the efficacy and safety of second generation tyrosine kinase inhibitors in childhood is entirely absent and transplant remains the first choice for patients failing imatinib and perhaps also for young patients with sub-optimal responses.
Management of Philadelphia negative chronic myeloproliferative disorders in pregnancy
2008, Blood Reviews
Citation Excerpt :
It is not mutagenic in vitro or teratogenic in animal studies. So far, over 30 patients with ET received interferon alpha during pregnancy.33,22,23 The majority of pregnancies were successfully carried to term.
The management of pregnancy in Philadelphia negative chronic myeloproliferative disorders (CMPDs) is an increasingly frequent problem. In the literature, most pregnancies are reported for women with essential thrombocythemia (ET) with about 400 pregnancies in about 200 women. In ET, first trimester abortion is the most frequent complication occurring in about one third of pregnancies. Interestingly, the incidence of maternal complications is relatively low with 3% for major thromboembolic and 2% for major bleeding events. The presence of the Jak2 mutation seems to be an independent predictor of pregnancy complications. Pregnancies in ET should be stratified according to underlying risk factors in low, high and highest risk pregnancies. Women with low risk pregnancies are treated with low-dose aspirin, whereas women with high and higher risk pregnancies may benefit from low-dose aspirin plus interferon alpha ± low molecular weight heparin throughout pregnancy and at least for six weeks post-partum. In polycythemia vera (PV) there is only very few information on pregnancy outcome with 36 pregnancies reported in the literature. According to these data pregnancy in PV is per se a high risk situation. Accordingly, all women with PV should be treated with low-dose aspirin. Some pregnant PV patients may benefit from a more intensive therapy including interferon alpha ± low molecular weight heparin throughout pregnancy and at least for six weeks post-partum.
Haematological cancers in pregnancy
2012, The Lancet
Citation Excerpt :
However, 12 infants exposed to imatinib during the first trimester had congenital abnormalities, especially of the kidneys, skeleton, heart, brain, and gut (eg, exomphalos).70 Thus, if treatment is indicated during this period, interferon alfa should be considered.33,71 Additionally, patients who become pregnant after a prolonged molecular remission might be considered for imatinib discontinuation or substitution with interferon,72 and women with an inferior response should postpone pregnancy until they have a better response, or at least be treated with interferon alfa at early gestational stages with an option to readminister tyrosine kinase inhibitors in the second or third trimester, although data for this situation are scarce.
Haematological cancer in pregnancy, although rare, poses a substantial risk to both mother and fetus. Hodgkin's lymphoma is the most common, followed by non-Hodgkin lymphoma and acute leukaemia. Diagnosis of haematological cancers is challenged by an overlap of the disease and gestation-related symptoms and limitations of imaging studies in pregnancy. Data for safety and effectiveness of therapy are scarce and mostly retrospective. This report provides updated guidance for management, focusing on chemotherapy and biological agents. The primary goal of treatment is to preserve the mother's health; hence, pregnancy termination is often advisable at early stages, allowing delivery of adequate therapy. However, at later gestational stages treatment is often feasible. Pregnancy-related hypercoagulability, augmented by cancer, often necessitates thromboprophylaxis. The consequences and complex management of haematological cancer during pregnancy emphasise the need for collaborative research, focusing on basic mechanisms of disease and prospective epidemiological studies.

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General Obstetrics and Gynecology: ObstetricsInterferon alfa treatment for pregnant women affected by essential thrombocythemia: Case reports and a review

Objectives

Study design

Results

Conclusion

Section snippets

Case report

Patient 1

Patient 2

Patient 3

Patient 4

Comment

Obstet Gynecol

Am J Obstet Gynecol

Blood

Blood

Pregnancy in essential thrombocythaemia: treatment and outcome of 17 pregnancies

Eur J Haematol

Management of essential thrombocythemia during pregnancy with aspirin, interferon alpha-2a and no treatment

Acta Haematol

No treatment for low-risk thrombocythaemia: results from a prospective study

Br J Haematol

Successful treatment of essential thrombocythaemia and recurrent abortion with alpha interferon

Br J Haematol

Normal pregnancy in a patient with essential thrombocythemia treated with interferon-alpha 2b [letter]

Am J Hematol

Alpha 2b-interferon therapy and pregnancy-report of a case of essential thrombocythemia [letter]

Am J Hematol

Trophoblast interferon and pregnancy

Reproduction

A single institutional experience with 43 pregnancies in essential thrombocythemia

Eur J Haematol

Primary thrombocythaemia in pregnancy

Br J Haematol

Outcome analysis of 34 pregnancies in women with essential thrombocythemia

Arch Intern Med

Essential thrombocythemia in pregnancy: platelet count and pregnancy outcome

Am J Hematol

General Obstetrics and Gynecology: Obstetrics
Interferon alfa treatment for pregnant women affected by essential thrombocythemia: Case reports and a review