Correspondence tion or retardation of eye formation and a n equal number show haematomas in the brain. At present it is not yet known whether y-IFN by itself or in association with class I1 induction, or even the combination of all of the above plus the pancytopenic syndrome obtained, is responsible for the problematic fetal development. As it is reported for the first time that y-IFN has a n unknown and harmful role during gestation, our results may be of value in clinical practice if y-IFN is to be administered to the mother for some anti-viral or other reason. Treatment of pregnant women with y-IFN may be catastrophic for both the mother and the child as appears to be the case in the murine model. ACKNOWLEDGMENT This work was supported by the Greek Secretarial for Research and Technology through Institutional (IMBB) Funding.
lnstitute of Molecular Biology and Biotechnology (lMBB), P.O. Box 1527, and Department of Biology, University of Crete, P.O. Box 1470, Heraklion, 711-1 0, Crete, Greece
78 3
SIMONVASSILIADIS IRENEATHANASSAKIS*
REFERENCES Athanassakis-Vassiliadis. I.. Galanopoulos. V.K.. Grigoriou. M. & Papamatheakis, 1. (1990) Induction of class I1 MHC antigen expression on murine placenta by 5-AzaC correlates with fetal abortion. Cellular Immunology. 128, 438-449. Athanassakis-Vassiliadis, I., Thanos, D. & Papamatheakis,J. (1 989) Induction of class I1 major histocompatibility antigens in the murine placenta by 5-azacytidine and interferon-gammainvolves different cell populations. European Journal of Immuriology, 19,
2341-2348. Balkwill. F.R. (1979) Interferonsas cell regulatory molecules. Cancer Immunology and Irnmunopathology. 7, 7-14. Epstein, L. (1981) Interferon-gamma. i. Is it really different? Interferon. 3 , 13-44.
PREGNANCY DURING MYELOSUPPRESSIVE TREATMENT FOR CHRONIC MYELOGENOUS LEUKAEMIA Baer et a1 (1992) recently reported o n the safe use of recombinant interferon-a (IFN-a) during pregnancy in four women with chronic leukaemia. Among these patients only one conceived while being treated with IFN-c(, whereas in the others IFN-E was begun at 10, 22 and 3 1 weeks gestation. Chronic myelogenous leukaemia (CML) may affect women of childbearing age and usually requires permanent myelosup-
pressive therapy with either cytostatic agents or recombinant IFN-E. For patients with a suitable donor, allogeneic bone marrow transplantation (BMT)performed early in the course of the disease remains the only treatment with curative intent. Nevertheless, the conditioning regimen induces a definitive infertility except in a very few cases (Giri et al. 1992); therefore young women often wish for pregnancy
Table 1.
Case
Date of diagnosis
Date of pregnancy
Age at pregnancy
1
june 1986
July 1989
34
Treatment during conception and pregnancy
Outcome of pregnancy
IFN 3 MU/d Normal vaginal ( 3 MU every other day delivery at
Patient's outcome Alive in continuous Ph-positive chronic phase
during third trimester) 40 weeks: male, weight 3.6 kg: normal phenotype 2
May 1985
May 1986
24
HU 1500 mg/d
Eclampsia at 26 weeks: stillborn male fetus: normal phenotype
3
January 1989
September 1989
23
HI7 1500 mg/d
Normal vaginal Allogeneic BMT in March 199 1 ; delivery at died of GVHD and CMV 40 weeks; pneumonia in June 1991 male, weight 3.2 kg: normal phenotype
Allogeneic BMT in February 1987: alive in complete remission: infertile: four unsuccessful attempts of pregnancy with oocyte donation
784
Correspondrnr~o
before HMT. LL'e report here additional experience in such a setting in three nulliparous patients with Philadelphia chromosome-positive CMI,. I:nlike the cases recently reported. all our patients conceived while receiving myelosuppressive therapy. IFN-r in one case and hydroxyurea ( H E )in the two others. The main characteristics of the patients and the outcome of pregnancies itre shown in Table I. Patient 1 had been receiving IFN-r for 32 months when she became pregnant. IFN-r therapy had been initiated at h million unitsld and subsequently decreased to 3 million units,'d because of poor haematological tolerance. The pregnancy was uncomplicated and resulted in a normal delivery of a fullterm healthy baby. The others patients were treated with HI: at an average dosage of 1 5 0 0 mg,'d for 12 and 8 months when they conceived. In addition. patient 3 had also received previously IFN-r for 2 months but it had been stopped because of severe side-effects. I n one of these cases. the pregnancy ended at the 26th week in eclampsia and death of a male fetus without gross abnormality. In the remaining. the pregnancy progressed normally with the delivery of a healthy baby, In this latter case. R51T lvas postponed for 1 year in order to allow the pregnancy to take place: however. this delay was deleterious and HMT was performed in accelerated phase of the disease. Although the adverse influence of pregnancy on the course of the disease has been repeatedly debated in numerous haematological malignancies. there is no clear data which supports this hypothesis. The use of cytostatic agents during pregnancy in animal experiments and in humans. is associated with an increased risk of spontaneous abortion. congenital malformations. premature deliveries and intrauterine growth retardation. However. this risk is dependent on the timing of the drug administration during the pregnancy. In humans, most of the reports published so far do not show an increased risk of malformations in comparison with the whole population when the drugs are administered after the organogenetic period. Teratogenicity o f HI- has been
shown in animals (Chaube & Murphy. 1966: Asano & Okaniwa. 1987)but very little information is available about its use in humans. during the period of conception and early pregnancy (Patel et trl. 199 1 ). HU could not be incriminated with certainty in the unfavourable outcome we observed. In the patient with either CML or essential thrombocythaemia wanting to bear a child there is no consensus on the best timing and management of pregnancy. Because it lacks mutagenicity iri vitro and teratogenicity in animals. IFN-c( may offer an interesting and safe option in such circumstances even in the early weeks ofpregnancy. as suggested by our own and Baer t't crl's experience. S(wic.ed'HPtticrtologir~. H6 tc,l-Dirir. 7 5 I X 7 I'm-is c~&r04. Frrtricc~
ALAINUELMEK BERNARD KIO FKEDEKICBAIIDIJER FLORENCE AJCHENBAUM JEAN-PIERRE MARIE ROBERTZITTOUW
KEFERENCES .\saiio. Y. K Okaniwa. A. ( 1 9 8 7 ) In utero morphological effects of hydroxyurea on the fetal development in Sprague-Dawley rats. \ikk?rt Z ) o f J l t l S l ! : Esperiniefital Animals. 36, 14 3-149. h e r . S1.K.. Ozer. H. K Foon. K.A. (1 992) Interferon-%therapyduring pregnancy in chronic myelogenous leukaemia and hairy cell 81, 167-1 69. leukaemia. British ]ourrial of Ha~rfiarolog~~. Chaube. S. K Murphy. M.I.. (1966) The effects of hydroxyurea and related coniponds o n the rat foetus. Curicer Research. 20, 1448l45i. Giri. N..\'on.els. M.R.. Barr. A.L. & Marneghan. H. ( I 992) Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia. B o w Marrow Tmnsplaritution. 10, 9 3-95. Patel. 51.. Dukes. I.A.F. & Hull. J.C. (1991) llse of hydroxyurea in chronic inyeloid during pregnancy: a case report. American \uurrml O / O b S t F t r i C S Urid G!/flPCO/Og!l. 1 6 5 , 565-566.
lnstitute of Molecular Biology and Biotechnology (lMBB), P.O. Box 1527, and Department of Biology, University of Crete, P.O. Box 1470, Heraklion, 711-1 0, Crete, Greece
78 3
SIMONVASSILIADIS IRENEATHANASSAKIS*
REFERENCES Athanassakis-Vassiliadis. I.. Galanopoulos. V.K.. Grigoriou. M. & Papamatheakis, 1. (1990) Induction of class I1 MHC antigen expression on murine placenta by 5-AzaC correlates with fetal abortion. Cellular Immunology. 128, 438-449. Athanassakis-Vassiliadis, I., Thanos, D. & Papamatheakis,J. (1 989) Induction of class I1 major histocompatibility antigens in the murine placenta by 5-azacytidine and interferon-gammainvolves different cell populations. European Journal of Immuriology, 19,
2341-2348. Balkwill. F.R. (1979) Interferonsas cell regulatory molecules. Cancer Immunology and Irnmunopathology. 7, 7-14. Epstein, L. (1981) Interferon-gamma. i. Is it really different? Interferon. 3 , 13-44.
PREGNANCY DURING MYELOSUPPRESSIVE TREATMENT FOR CHRONIC MYELOGENOUS LEUKAEMIA Baer et a1 (1992) recently reported o n the safe use of recombinant interferon-a (IFN-a) during pregnancy in four women with chronic leukaemia. Among these patients only one conceived while being treated with IFN-c(, whereas in the others IFN-E was begun at 10, 22 and 3 1 weeks gestation. Chronic myelogenous leukaemia (CML) may affect women of childbearing age and usually requires permanent myelosup-
pressive therapy with either cytostatic agents or recombinant IFN-E. For patients with a suitable donor, allogeneic bone marrow transplantation (BMT)performed early in the course of the disease remains the only treatment with curative intent. Nevertheless, the conditioning regimen induces a definitive infertility except in a very few cases (Giri et al. 1992); therefore young women often wish for pregnancy
Table 1.
Case
Date of diagnosis
Date of pregnancy
Age at pregnancy
1
june 1986
July 1989
34
Treatment during conception and pregnancy
Outcome of pregnancy
IFN 3 MU/d Normal vaginal ( 3 MU every other day delivery at
Patient's outcome Alive in continuous Ph-positive chronic phase
during third trimester) 40 weeks: male, weight 3.6 kg: normal phenotype 2
May 1985
May 1986
24
HU 1500 mg/d
Eclampsia at 26 weeks: stillborn male fetus: normal phenotype
3
January 1989
September 1989
23
HI7 1500 mg/d
Normal vaginal Allogeneic BMT in March 199 1 ; delivery at died of GVHD and CMV 40 weeks; pneumonia in June 1991 male, weight 3.2 kg: normal phenotype
Allogeneic BMT in February 1987: alive in complete remission: infertile: four unsuccessful attempts of pregnancy with oocyte donation
784
Correspondrnr~o
before HMT. LL'e report here additional experience in such a setting in three nulliparous patients with Philadelphia chromosome-positive CMI,. I:nlike the cases recently reported. all our patients conceived while receiving myelosuppressive therapy. IFN-r in one case and hydroxyurea ( H E )in the two others. The main characteristics of the patients and the outcome of pregnancies itre shown in Table I. Patient 1 had been receiving IFN-r for 32 months when she became pregnant. IFN-r therapy had been initiated at h million unitsld and subsequently decreased to 3 million units,'d because of poor haematological tolerance. The pregnancy was uncomplicated and resulted in a normal delivery of a fullterm healthy baby. The others patients were treated with HI: at an average dosage of 1 5 0 0 mg,'d for 12 and 8 months when they conceived. In addition. patient 3 had also received previously IFN-r for 2 months but it had been stopped because of severe side-effects. I n one of these cases. the pregnancy ended at the 26th week in eclampsia and death of a male fetus without gross abnormality. In the remaining. the pregnancy progressed normally with the delivery of a healthy baby, In this latter case. R51T lvas postponed for 1 year in order to allow the pregnancy to take place: however. this delay was deleterious and HMT was performed in accelerated phase of the disease. Although the adverse influence of pregnancy on the course of the disease has been repeatedly debated in numerous haematological malignancies. there is no clear data which supports this hypothesis. The use of cytostatic agents during pregnancy in animal experiments and in humans. is associated with an increased risk of spontaneous abortion. congenital malformations. premature deliveries and intrauterine growth retardation. However. this risk is dependent on the timing of the drug administration during the pregnancy. In humans, most of the reports published so far do not show an increased risk of malformations in comparison with the whole population when the drugs are administered after the organogenetic period. Teratogenicity o f HI- has been
shown in animals (Chaube & Murphy. 1966: Asano & Okaniwa. 1987)but very little information is available about its use in humans. during the period of conception and early pregnancy (Patel et trl. 199 1 ). HU could not be incriminated with certainty in the unfavourable outcome we observed. In the patient with either CML or essential thrombocythaemia wanting to bear a child there is no consensus on the best timing and management of pregnancy. Because it lacks mutagenicity iri vitro and teratogenicity in animals. IFN-c( may offer an interesting and safe option in such circumstances even in the early weeks ofpregnancy. as suggested by our own and Baer t't crl's experience. S(wic.ed'HPtticrtologir~. H6 tc,l-Dirir. 7 5 I X 7 I'm-is c~&r04. Frrtricc~
ALAINUELMEK BERNARD KIO FKEDEKICBAIIDIJER FLORENCE AJCHENBAUM JEAN-PIERRE MARIE ROBERTZITTOUW
KEFERENCES .\saiio. Y. K Okaniwa. A. ( 1 9 8 7 ) In utero morphological effects of hydroxyurea on the fetal development in Sprague-Dawley rats. \ikk?rt Z ) o f J l t l S l ! : Esperiniefital Animals. 36, 14 3-149. h e r . S1.K.. Ozer. H. K Foon. K.A. (1 992) Interferon-%therapyduring pregnancy in chronic myelogenous leukaemia and hairy cell 81, 167-1 69. leukaemia. British ]ourrial of Ha~rfiarolog~~. Chaube. S. K Murphy. M.I.. (1966) The effects of hydroxyurea and related coniponds o n the rat foetus. Curicer Research. 20, 1448l45i. Giri. N..\'on.els. M.R.. Barr. A.L. & Marneghan. H. ( I 992) Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia. B o w Marrow Tmnsplaritution. 10, 9 3-95. Patel. 51.. Dukes. I.A.F. & Hull. J.C. (1991) llse of hydroxyurea in chronic inyeloid during pregnancy: a case report. American \uurrml O / O b S t F t r i C S Urid G!/flPCO/Og!l. 1 6 5 , 565-566.
