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Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia: A systematic review

  • Zsolt Szakács ,

    Contributed equally to this work with: Zsolt Szakács, Péter Jenő Hegyi

    Roles Conceptualization, Data curation, Methodology, Writing – original draft

    Affiliations Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary, Szentágothai Research Centre, University of Pécs, Pécs, Hungary

  • Péter Jenő Hegyi ,

    Contributed equally to this work with: Zsolt Szakács, Péter Jenő Hegyi

    Roles Conceptualization, Data curation

    Affiliation Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

  • Nelli Farkas,

    Roles Formal analysis, Visualization

    Affiliation Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary

  • Péter Hegyi,

    Roles Funding acquisition, Supervision, Validation, Writing – original draft

    Affiliation Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

  • Márta Balaskó,

    Roles Data curation, Writing – original draft

    Affiliation Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

  • Adrienn Erős,

    Roles Data curation

    Affiliations Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary, Szentágothai Research Centre, University of Pécs, Pécs, Hungary

  • Szabina Szujó,

    Roles Data curation

    Affiliation Division of Hematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

  • Judit Pammer,

    Roles Data curation, Investigation, Methodology

    Affiliation Division of Hematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

  • Bernadett Mosdósi,

    Roles Data curation, Methodology, Supervision

    Affiliation Department of Paediatrics, Medical School, University of Pécs, Pécs, Hungary

  • Mária Simon,

    Roles Data curation, Investigation, Writing – original draft

    Affiliation Department of Psychiatry and Psychotherapy, Medical School, University of Pécs, Pécs, Hungary

  • Arnold Nagy,

    Roles Investigation, Methodology

    Affiliation Department of Paediatrics, Medical School, University of Pécs, Pécs, Hungary

  • Gabriella Für,

    Roles Data curation

    Affiliation Institute of Pathophysiology, University of Szeged, Pécs, Hungary

  • Alizadeh Hussain

    Roles Conceptualization, Investigation, Supervision, Writing – original draft

    Affiliation Division of Hematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary

Pregnancy outcomes of women whom spouse fathered children after tyrosine kinase inhibitor therapy for chronic myeloid leukemia: A systematic review

  • Zsolt Szakács, 
  • Péter Jenő Hegyi, 
  • Nelli Farkas, 
  • Péter Hegyi, 
  • Márta Balaskó, 
  • Adrienn Erős, 
  • Szabina Szujó, 
  • Judit Pammer, 
  • Bernadett Mosdósi, 
  • Mária Simon



The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML). Although the efficacy of TKIs is beyond dispute, conception-related safety issues are still waiting to be explored, particularly in males. This systematic review aimed to summarize all available evidence on pregnancy outcomes of female spouses of male CML patients who fathered children after TKI treatment for CML.


We performed a systematic search in seven electronic databases for studies that reported on male CML patients who did or did not discontinue TKI treatment before conceiving, and the pregnancy outcomes of their female spouse are available. The search centered on the TKI era (from 2001 onward) without any other language or study design restrictions.


Out of a total of 38 potentially eligible papers, 27 non-overlapping study cohorts were analyzed. All were descriptive studies (case or case series studies). Altogether, 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. A total of ten offspring with a malformation (2.5%) were reported: six with imatinib (of 313 live births, 1.9%), two with nilotinib (of 26 live births, 7.7%), one with dasatinib (of 43 live births, 2.3%), and none with bosutinib (of 12 live births). Data on CML status were scarcely reported. Only nine pregnancies (from nine males) and no malformation were reported in males who discontinued TKI treatment before conception.


Malformations affected, on average 2.5% of live births from fathers who did not discontinue TKI treatment before conception, which is comparable with the rate of malformations in the general population. Large-scale studies with representative samples are awaited to confirm our results.


Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the presence of the BCR-ABL1 fusion product generated as a result of the t(9;22) Philadelphia chromosome (Ph). The annual incidence ranges between 0.4 and 1.75 per 100 000 inhabitants. Although CML can strike at any age and its incidence prominently increases with aging [1], peak incidence falls at around 60 years in Europe [2] but at a lower age in Asia [3].

The introduction of imatinib (IMA), a tyrosine kinase inhibitor (TKI), has revolutionized the treatment of CML, dramatically improving life-expectancies and resulting in a great 10-year survival rate exceeding 80% [47]. The success of IMA led to the development of second- and third-generation TKIs, such as nilotinib (NIL), dasatinib (DAS), bosutinib (BOS), and ponatinib (PON). Network meta-analyses confirmed the efficacy and safety of new-generation TKIs in IMA-resistant or IMA-failure cases and even as first-line alternatives of IMA [8, 9].

As a result of the widespread use of TKIs and the subsequent improvement in life quality, hematologists faced new challenges of procreation. Around one-fourth of CML patients, both males and females, are diagnosed at a reproductive age. While women are often in the spotlight, research on male fertility issues is less popular [1012].

Fertility issues may derive from the molecular mechanism of the agents. TKIs are competitive inhibitors of ABL kinase, inhibiting the autophosphorylation of BCR-ABL, which results in the induction of apoptosis in the corresponding cells. However, TKIs are not purely selective to ABL kinase: targets include c-kit, PDGFR-alpha, c-FMS, and other kinases [13]. This non-selective enzymatic inhibition may interfere with the steps of spermato- and spermiogenesis: sporadic reports indicated that IMA affects the human reproductive system [14, 15]. The most comprehensive report included the semen samples of 48 IMA-treated CML males and proved that IMA is secreted to the semen, reduces sperm survival and activity, but does not significantly affect the levels of gonadotrophic hormones and sexual steroids [16].

Turning to the conception outcomes, the first report that discussed males being exposed to IMA at the time of conception was released in 2003 by Hensley and Ford [17]. Several relevant cases have been reported since then, and expert reviews summarized the available evidence on fertility-related safety issues [1012, 16, 1822]. These were all high-quality but non-systematic summaries except in a 2016 review of about 200 cases with a restricted search to one database and other non-electronic data sources [11]. The niche of analyzing disease status at conception has remained unoccupied.

In this study, we aimed to perform a strict systematic review with a transparent, reproducible methodology to summarize conception-related outcomes of TKI-treated males, with a special focus on CML status at conception.


This work is reported following the Preferred Reporting Items for Systematic Review (PRISMA) Statement [23]. The pre-protocol of the systematic review was registered a priori in PROSPERO under registration number CRD42018087127.


We performed a comprehensive search of the medical literature. The search strategy covered the following sources:

  1. Electronic databases including MEDLINE (via PubMed), EMBASE, Web of Science, Scopus, WHO Global Health Library, Cochrane Controlled Register of Trials (CENTRAL), and were searched for relevant reports from 2001 (date of approval of IMA in the US) up to Nov 2020 without other restrictions. We used Medical Subject Heading (MeSH) in combination with free-text terms to capture all relevant papers. The query was designed to include the Chemical Abstract Service (CAS)-numbers of agents: (chronic AND (myeloid OR myelogenous) AND (leukemia OR leukaemia)) AND (“tyrosine kinase inhibitor*” OR imatinib OR “152459-95-5” OR nilotinib OR “641571-10-0” OR dasatinib OR “302962-49-8” OR bosutinib OR “380843-75-4” OR ponatinib OR “943319-70-8”) AND (pregnant* OR gestation OR conception OR fertile* OR inseminate* OR childbearing OR embryotoxic* OR genotoxic* OR teratogenic*).
  2. Reference lists of relevant included and excluded reports, including previous non-systematic reviews, were hand searched.
  3. Citing papers of relevant articles were identified by using Google Scholar.
  4. Abstract books of The European Hematology Association (EHA) and The American Society of Hematology (ASH) were hand-searched from 2001 on.

Selection, eligibility, and data collection

We included records reporting on male patients suffering from CML and receiving TKIs (IMA, NIL, DAS, BOS, or PON) before or at the time of conception if pregnancy-related or neonatological outcomes are available. We excluded cases with cryopreservation of sperm donated before the initiation of TKI treatment. Since unfavorable pregnancy outcomes are rare events, any record containing original data (full-text articles and conference papers) of at least one patient was eligible for inclusion.

All records were combined in a reference manager software (EndNote X7.4, Clarivate Analytics, Philadelphia, PA, US) to remove database overlaps and duplicate references. Then, records were tested against our eligibility criteria by title, abstract, and full-text. Eligible records were subjected to data collection. Two review authors selected the records and collected data in duplicates; discrepancies were resolved by third-party arbitration after each step of selection and data collection. We collected data on patients’ baseline characteristics, therapy regimens (agent, dose, timing), pregnancy course; obstetric, neonatal, and pediatric complications; and disease activity of males at conception. We had no contact with the authors of the included papers.

Finishing data collection, we reviewed all records carefully to identify overlaps across study populations. Overlapping records (and data) were linked together, then handled as a cohort of patients.

Quality assessment

Two review authors used Murad et al.’s tool to assess case studies’ and case series’ quality in duplicate, resolving discrepancies by consensus [24]. The tool’s leading explanatory questions cover four domains: selection, ascertainment, causality, and reporting. As recommended by Murad et al., we did not aggregate scores but discussed the findings as limitations of the evidence.


Search and selection

Fig 1 shows the flowchart of the systematic review. A total of 1 957 records were identified in seven databases. Finally, 40 publications reported the pregnancy outcomes of the spouses of male patients. The most common cause of exclusion on full-text assessment was reporting pregnancy outcomes of female CML patients exclusively (57 records).

Out of the 40 publications, we excluded two papers [17, 25]. In the conference paper of Siddique et al. [25], we were unable to separate pregnancy outcomes of IMA-treated males from that of females in a cohort of patients conceiving a total of ten times (the outcomes included three elective terminations; no malformations were recorded). The reason for exclusion was similar in the case of the study by Hensley and Ford [17]: data of IMA-treated CML and gastrointestinal stromal tumor cases were not separable (the outcomes included two elective terminations and two spontaneous abortions; no malformations were recorded).

We carefully checked the remaining 38 publications (24 full-text papers and 14 conference abstracts) to find overlaps of cases; finally, 27 non-overlapping cohorts of patients or case studies were identified.

Characteristics of the studies included

Tables 1 and 2 show the summary of the studies included [10, 11, 2661]. Seven papers were non-English language articles: one was written in Bulgarian [40], one in French [41], one in Japanese [61], and another four in Chinese [43, 53, 58, 59]. We did not identify any comparative (controlled) studies: all evidence came from descriptive studies (case studies or case series studies). Eleven cohorts of patients were recruited from Europe, another eleven from Asia, two from the US, one from Africa, and there were two multinational studies.

Table 1. Characteristics of the studies reporting on male patients with planned treatment discontinuation before conception.

Table 2. Characteristics of the studies reporting on male patients not discontinuing tyrosine kinase treatment before conception.

Planned treatment discontinuation

Nine pregnancies from nine males in three cohorts of patients were reported (Table 1) [10, 11, 26, 38, 41, 49]. Six cases were pre-treated with IMA, another three with DAS. One pregnancy, where the father was pre-treated with IMA, ended up in spontaneous abortion; otherwise, all were uneventful (no malformations were recorded). Detailed follow-up data were not available for the cases. No information is available on NIL, DAS, or BOS. We were unable to separate the outcomes of planned treatment discontinuation (four of 49 males) from those of no treatment discontinuation in one cohort of patients [59].

No treatment discontinuation

Studies observed a total of 374 males who had conceived under the effect of TKIs (Table 2). A total of 428 pregnancies were reported, 400 of which (93.5%) ended up in a successful delivery with live fetus (17 spontaneous abortions, 10 elective terminations, and 1 case of stillbirth) (Fig 2A). Offspring from ten live births (2.5% of total life births) had any malformation (the type of TKI was not specified in one case) (Fig 2B).

Fig 2. Characteristics of male patients not discontinuing tyrosine kinase treatment before conception.

A: Distribution of pregnancy outcomes among all pregnancies (n = 428). B: Malformations among live births (n = 400). PJS: pyeloureteral junction syndrome.


A total of 327 pregnancies conceived under the effect of IMA, 14 of which (4.3%) did not end up in live birth (six elective and seven spontaneous abortions, one stillbirth). The outcomes were not reported by TKI agents separately in one study [59].

Six of 313 live births (1.9%) developed any malformation, these included cases with congenital hip dysplasia [10, 11, 26], gut malrotation [29], hydronephrosis with pyeloureteral junction syndrome [32, 47], complex cardiopathy [32, 47], hypospadiasis, and hydrocephalus [38, 49].

In addition to sporadic cases of breach [27]; pregnancy-induced hypertension [27], podalic position with threatening miscarriage [31, 51], and a total of nine cases of premature delivery were reported. Regarding postnatal complications; cases of jaundice [10, 11, 26], intrauterine growth retardation [32, 47], and neonatal respiratory distress syndrome [32, 47] were reported. In the long-term, one case of neuroblastoma was identified in a child with family history positive for the tumor [42].


All pregnancies conceived under the effect of NIL ended up in live birth (the outcomes were not reported by TKI agents separately in one study [59]). Two (7.7%) of 26 pregnancies developed malformation; these were a case of pulmonary stenosis [32, 47] and another case in which the malformation was not specified [56].

Regarding feto-maternal complications, one case of premature delivery with severe hyperbilirubinemia [3335] and another case of acute myeloid leukemia were reported [32, 47].


Three out of 46 pregnancies (6.5%) conceived under the effect of DAS ended up in elective termination or spontaneous abortion (the outcomes were not reported by TKI agents separately in one study [59]). One (2.3%) of 43 live births developed syndactyly [37]; otherwise, no malformations were reported.

Regarding feto-maternal complications, one case of preeclampsia [36, 37] and another case of placenta accrete [35] were reported.


Out of 16 pregnancies, four ended up in elective termination and another one in spontaneous abortion, in which basal deciduitis was confirmed [60]. All the other pregnancies were uneventful.


No information is available.

CML status and conception

Out of 428 pregnancy cases, CML status of 175 fathers were not reported. Among the patients, 250 were in the chronic phase, whereas three patients conceived in the active phase:

  • Case 1, aged 31 years, was treated with alternated NIL/IMA in the accelerated phase when conceived (uneventful pregnancy and follow-up) [10, 11, 26].
  • Case 2, aged 34 years, was treated with IMA in the blast phase when conceived (uneventful pregnancy, premature delivery at the 34th week) [45].
  • Case 3, aged 24 years, treated with IMA 800 mg in the accelerated phase when conceived (elective termination) [38, 49].

Out of the ten malformations, the phase of CML is unknown for five cases, and fathers were in the chronic phase for another five (complete hematological response: two cases; no complete hematological response: one case; and unknown hematological response: two cases). Data on cytogenetic and molecular responses are scarcely reported. However, note that most of the males who had not achieved a complete cytogenetic or molecular response at conception had healthy offspring. Table 3 summarizes data on CML status at conception.

Table 3. CML status at conception in males with no treatment discontinuation.

Quality assessment

The quality of the studies included is summarized in Table 4.


An interesting issue is the safety of exposure to TKIs in men to conceive a pregnancy. Studies suggest it is acceptable to continue TKI with counseling regarding uncertainty, but there are no clear data on safety for men on TKIs to conceive pregnancy (as presented in Table 2). Limited case reports exist of successful, healthy pregnancies conceived by men taking TKI, including second-generation agents (DAS, NIL, and BOS), but there are no reports of successful pregnancies of partners of men on PON. US Food and Drug Administration enrolls TKIs in the ‘D’ pregnancy category, which means that there is potential evidence of risk on fetal development but, due to the potential benefits of use, the drug may be applied during pregnancy. The labeling does not concern paternal issues, although potentially harmful factors affecting the father and the mother may be associated with fetal development [62].

Congenital anomalies are the leading cause of death in infancy in the US [63]. Based on data from the European Surveillance of Congenital Anomalies (EUROCAT, covering approximately 1.5 million births), major congenital anomalies were reported in 23.9 per 1 000 births (2.39%) between 2003 and 2007; 80% of these cases were live births. Congenital heart defects are the most common anomalies (6.5 per 1 000 births) [64]. In line with these, we observed a total of ten malformations (2.5%), including two heart defects, among the children of those fathers who did not discontinue TKI treatment. Malformations having a little impact on health and function, i.e., the ‘minor’ anomalies, are included in this number as well (Table 2 and Fig 2) [65]. Taken together, the rate of malformations seems comparable with the European average. However, we must keep in mind that the pattern and incidence of congenital anomalies may vary by region and time, whereas our study population was recruited from many sites worldwide and over a long period, embracing 15 years. The incidence of malformations with IMA (1.9%) is even closer to the European average, but that with NIL is surprisingly high (7.7%). Notably, the latter value must be interpreted with caution due to the low case numbers (Fig 2) and knowing that NIL proved neutral regarding male fertility in rats [12].

The effect of CML status is hard to be assessed since we lacked data in 41% of the cases. If we consider the available data only, five malformations were recorded in patients being in the chronic phase, four of which in those who achieved a complete hematological response. Importantly, several cases without achieving a complete cytogenetic or major molecular response ended up in uneventful pregnancies (Table 3).

Limitations of the evidence

First, controlled studies are lacking: only case reports and case series studies, which cannot confirm a cause-effect relationship [66], are available. Rechallenge may provide an opportunity to confirm real causality; however, it is not an option in our scenario. Evidence acquired from uncontrolled studies is inherently weak [67]. Hence, we discarded the idea of performing meta-analysis because pooling would not have strengthened the evidence.

Second, reports from large registries with representative populations are lacking, though there are promising initiatives [68, 69].

Third, case reports and case series studies are particularly vulnerable to dissemination bias, questioning the representativeness of the sample. It is impossible to judge whether investigators are more likely to report complicated pregnancies or uncomplicated cases. We tried to reduce publication bias by including non-English language reports [70].

Fourth, the quality of reporting proved to be poor (Table 4)—none of the reports adhered to reporting guidelines [71]. Detailed, long-term follow-up data of the offspring were also lacking (Tables 2 and 4).

Fifth, the recommended sequence of treatment modalities in resistant cases and the first choice of therapy in CML vary with time and across countries. Some cases were pre-treated with non-TKI chemotherapeutics (ancillary therapies, such as interferon) or different TKI agents, raising concerns about stochastic toxicity.

Implications for clinical practice

The detailed analysis of more than 400 conceptions revealed that the rate of malformations is lower than 3%, comparable with that measured in the general population. However, due to the studies' uncontrolled nature, the level of evidence is low (by the GRADE system). Since discontinuing TKIs may result in CML's progression towards the acute phase while conceiving under the effect of TKIs seems safe, the risk-benefit ratio of TKI discontinuation has not been justified. Semen cryopreservation before TKI treatment may be a much safer alternative. However, due to the weak evidence, we must emphasize the importance of individual risk assessment in daily practice.

Implications for research

Since none of the studies identified recruited a control group, it is impossible to differentiate the effects of (1) TKIs, (2) ancillary therapies, (3) CML status, and (4) other noxae on pregnancy outcomes. Based only on the frequency of undesirable pregnancy outcomes in our study, we know that statistically strong evidence (powered to the adverse events of TKIs regarding pregnancy) would require a large sample size [72]. CML registries carry the potential to achieve the required size. Controlled observational studies are awaited to verify the safety of TKIs, particularly for the new generation TKIs.


  1. 1. Hoglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol. 2015;94 Suppl 2:S241–7. pmid:25814090
  2. 2. Smith AG, Painter D, Howell DA, Evans P, Smith G, Patmore R, et al. Determinants of survival in patients with chronic myeloid leukaemia treated in the new era of oral therapy: findings from a UK population-based patient cohort. BMJ Open. 2014;4(1):e004266. pmid:24435897
  3. 3. Mendizabal AM, Garcia-Gonzalez P, Levine PH. Regional variations in age at diagnosis and overall survival among patients with chronic myeloid leukemia from low and middle income countries. Cancer Epidemiol. 2013;37(3):247–54. pmid:23411044
  4. 4. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917–27. pmid:28273028
  5. 5. Hehlmann R, Lauseker M, Saussele S, Pfirrmann M, Krause S, Kolb HJ, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398–406. pmid:28804124
  6. 6. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002;1(7):493–502. pmid:12120256
  7. 7. Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract. 2014;2014:357027. pmid:24963404
  8. 8. Fachi MM, Tonin FS, Leonart LP, Aguiar KS, Lenzi L, Figueiredo BC, et al. Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis. Eur J Cancer. 2018;104:9–20. pmid:30296736
  9. 9. Mealing S, Barcena L, Hawkins N, Clark J, Eaton V, Hirji I, et al. The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis. Exp Hematol Oncol. 2013;2(1):5. pmid:23422286
  10. 10. Abruzzese E, Scortechini AR, Gugliotta G, Pierri I, Musolino C, Iurlo A, et al. Gimema registry of conception/pregnancy in adult patients diagnosed with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKIs). Blood. 2014;124(21).
  11. 11. Abruzzese E, Trawinska MM, de Fabritiis P, Baccarani M. Management of pregnant chronic myeloid leukemia patients. Expert Rev Hematol. 2016;9(8):781–91. pmid:27352939
  12. 12. Palani R, Milojkovic D, Apperley JF. Managing pregnancy in chronic myeloid leukaemia. Ann Hematol. 2015;94 Suppl 2:S167–76. pmid:25814083
  13. 13. Ghalaut VS, Prakash G, Bansal P, Dahiya K, Dokwal S, Ghalaut PS, et al. Effect of imatinib on male reproductive hormones in BCR-ABL positive CML patients: A preliminary report. J Oncol Pharm Pract. 2014;20(4):243–8. pmid:23966360
  14. 14. Mariani S, Basciani S, Fabbri A, Agati L, Ulisse S, Lubrano C, et al. Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty. Fertil Steril. 2011;95(3):1120.e15-7. pmid:20888557
  15. 15. Seshadri T, Seymour JF, McArthur GA. Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. N Engl J Med. 2004;351(20):2134–5. pmid:15537917
  16. 16. Chang X, Zhou L, Chen X, Xu B, Cheng Y, Sun S, et al. Impact of Imatinib on the Fertility of Male Patients with Chronic Myelogenous Leukaemia in the Chronic Phase. Target Oncol. 2017;12(6):827–32. pmid:28791527
  17. 17. Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol. 2003;40(2 Suppl 2):21–5. pmid:12783371
  18. 18. Apperley J. Issues of imatinib and pregnancy outcome. J Natl Compr Canc Netw. 2009;7(10):1050–8. pmid:19930974
  19. 19. Bhandari A, Rolen K, Shah BK. Management of chronic myelogenous leukemia in pregnancy. Anticancer Res. 2015;35(1):1–11. pmid:25550528
  20. 20. Jovelet C, Broutin S, Gil S, Mir O, Paci A. Tyrosine kinase inhibitors and pregnancy: A risk to the fetus? Bull Cancer. 2016;103(5):478–83. pmid:26969425
  21. 21. Lodish MB. Clinical review: kinase inhibitors: adverse effects related to the endocrine system. J Clin Endocrinol Metab. 2013;98(4):1333–42. pmid:23450053
  22. 22. Lorenzi E, Simonelli M, Santoro A. Infertility risk and teratogenicity of molecularly targeted anticancer therapy: A challenging issue. Crit Rev Oncol Hematol. 2016;107:1–13. pmid:27823636
  23. 23. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of internal medicine. 2009;151(4):264–9. pmid:19622511
  24. 24. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ evidence-based medicine. 2018;23(2):60–3. pmid:29420178
  25. 25. Siddique MK, Siddiqui N, Mahmood R, Rehan H. Fertility in patients on imatinib for chronic myeloid leukemia. J Clin Oncol. 2008;26(15_suppl):18031-.
  26. 26. Abruzzese E, Trawinska MM, Perrotti AP, De Fabritiis P. Tyrosine kinase inhibitors and pregnancy. Mediterr J Hematol Infect Dis. 2014;6(1):e2014028. pmid:24804001
  27. 27. Alizadeh H, Jaafar H, Rajnics P, Khan MI, Kajtar B. Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: short report from a single centre. Leuk Res. 2015;39(1):47–51. pmid:25455655
  28. 28. Assi R, Kantarjian HM, Keating MJ, Pemmaraju N, Verstovsek S, Garcia-Manero G, et al. Management of chronic myeloid leukemia (CML) during pregnancy among patients (pts) treated with a tyrosine kinase inhibitor (TKI): A single-center experience. Blood. 2017;130.
  29. 29. Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol. 2006;24(7):1204–8. pmid:16446320
  30. 30. Babu GK, Thanky A, Jacob LA, Babu MCS, Dasappa L, Ganguly S. Outcome of young adults with chronic myeloid leukemia treated with upfront imatinib: A single institutional experience. Journal of Applied Hematology. 2015;6(4):157.
  31. 31. Breccia M, Cannella L, Montefusco E, Frustaci A, Pacilli M, Alimena G. Male patients with chronic myeloid leukemia treated with imatinib involved in healthy pregnancies: report of five cases. Leuk Res. 2008;32(3):519–20. pmid:17804066
  32. 32. Carlier P, Markarian M, Bernard N, Lagarce L, Dautriche A, Bene J, et al. Pregnancy outcome among partners of male patients receiving imatinib, dasatinib or nilotinib in chronic myeloid leukemia: reports collected by the French network pharmacovigilance centers (vol 295, pg 269, 2017). Archives of Gynecology and Obstetrics. 2017;295(4):1059-. pmid:28255764
  33. 33. Chelysheva E, Turkina A, Kolosheinova T, Gusarova G, Sokolova M, Vakhrusheva M, et al. Pregnancy outcomes and treatment regimens in patients with chronic myeloid leukemia. Haematologica. 2012;97:311–2.
  34. 34. Chelysheva E, Turkina A, Kolosheinova T, Gusarova G, Sokolova M, Vinogradova O, et al. Pregnancy outcomes in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors. Haematologica. 2011;96:294–5.
  35. 35. Chelysheva EY, Turkina AG, Gusarova GA, Kolosheinova TI, Sokolova MA, Khoroshko ND, et al. Pregnancy among the patients with chronic myeloid leukemia on imatinib therapy. Haematologica. 2009;94:262.
  36. 36. Cortes J, O'Brien S, Ault P, Borthakur G, Jabbour E, Bradley-Garelik B, et al. Pregnancy Outcomes among Patients with Chronic Myeloid Leukemia Treated with Dasatinib. Blood. 2008;112(11):1109-.
  37. 37. Cortes JE, Abruzzese E, Chelysheva E, Guha M, Wallis N, Apperley JF. The impact of dasatinib on pregnancy outcomes. Am J Hematol. 2015;90(12):1111–5. pmid:26348106
  38. 38. Dasgupta S, Mukhopadhyay A, Ray UK, Gharami FH, Basu CK, Mukhopadhyay S. Report on imatinib treated CML patients: Pregnancy outcome. European Journal of Cancer. 2013;49:S844.
  39. 39. Gentile M, Guido M, Lucia E, Vigna E, Mazzone C, Recchia AG, et al. Favorable conception and pregnancy involving a male patient affected by chronic myeloid leukemia while taking dasatinib. Leuk Lymphoma. 2014;55(3):709–10. pmid:23741978
  40. 40. Grudeva-Popova J, Alexandrova K, Nenova I. Successful pregnancies of spouses of male patients with chronic myeloid leukemia on imatinib therapy. Clinical and Transfusion Haematology. 2010;46(1–2):90–2.
  41. 41. Guerci-Bresler A, Huguet F, Legros L, Maloisel F, Réa D. Fertilité, grossesse, allaitement et état de santé des nouveau-nés chez les patient (e) s souffrant de LMC-PC et traité (e) s par inhibiteurs de la tyrosine kinase. Recommandations du groupe Fi-LMC Correspondances en Onco-hématologie. 2011;6:92–102.
  42. 42. Iqbal J, Ali Z, Khan AU, Aziz Z. Pregnancy outcomes in patients with chronic myeloid leukemia treated with imatinib mesylate: short report from a developing country. Leuk Lymphoma. 2014;55(9):2109–13. pmid:24237577
  43. 43. Jiang Q, Jiang B, Chen SS, Jiang H, Qin YZ, Lai YY, et al. Pregnancy outcome among patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. Zhonghua xue ye xue za zhi. 2012;33(1):6–9. pmid:22575184
  44. 44. Klamová H, Srbová D, Šišková M, Poláková K, Březinová J, Cetkovský P, et al. Successful management of CML during pregnancy and in post-partum period. Haematologica. 2013;98:551.
  45. 45. Luciano L, Cerchione C, Ciancia R, Pane F. Successful pregnancies in chronic myeloid Leukaemia male patients on imatinib therapy. Haematologica. 2010;95:541.
  46. 46. Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience. J Glob Oncol. 2019;5:1–11. pmid:31584851
  47. 47. Markarian M, Carlier P, Bernard N, Lagarce L, Dautriche A, Béné J, et al. Pregnancy outcome among partners of male patients receiving imatinib, dasatinib or nilotinib in chronic myeloid leukemia (CML): Reports collected by the French regional pharmacovigilance (PV) centers. Fundamental and Clinical Pharmacology. 2016;30:40.
  48. 48. Modi M, Madabhavi I, Lahori M. Pregnancy outcomes in chronic myeloid leukemia (CML): A single-centre experience. American Journal of Clinical Pathology. 2018;149:S45.
  49. 49. Mukhopadhyay A, Dasgupta S, Kanti Ray U, Gharami F, Bose CK, Mukhopadhyay S. Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy. Ir J Med Sci. 2015;184(1):183–8. pmid:24590821
  50. 50. Oweini H, Otrock ZK, Mahfouz RA, Bazarbachi A. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet. 2011;283(1):133–4. pmid:20473616
  51. 51. Pacilli M, Montefusco E, Porrini R, Moscetti A, Veggia B, Antolino G, et al. Conception of healthy childrens under imatinib treatment in two man affected by chronic myeloid leukemia. Haematologica. 2009;94:168–9.
  52. 52. Ramasamy K, Hayden J, Lim Z, Mufti GJ, Ho AY. Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy. Br J Haematol. 2007;137(4):374–5. pmid:17408403
  53. 53. Ruirui G, Zhang G, Li Z, Zhai H, Zu Y, Li M, et al. Clinical observation of fertility circumstance among patients with chronic granulocytic leukemia treated with imatinib. J Clin Hematol (China). 2016;29(6):887–90.
  54. 54. Shash E, Bassi S, Cocorocchio E, Colpi GM, Cinieri S, Peccatori FA. Fatherhood during imatinib. Acta Oncologica. 2011;50(5):734–5. pmid:21517714
  55. 55. Wang A, Zhou L. Pregnancies in patients with chronic myeloid leukemia treated with tysosine kinase inhibitors. Haematologica. 2013;98:555. pmid:23242593
  56. 56. Yamina B, Souad T, Mohand Tayeb A. Impact of tyrosine kinase inhibitors (TKIs) on the fertility of chronic myeloid leukemia patients (CML) in a single center in Algeria. Haematologica. 2015;100:690–1. pmid:25715403
  57. 57. Zhou L, You JH, Wu W, Li JM, Shen ZX, Wang AH. Pregnancies in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor. Leuk Res. 2013;37(10):1216–21. pmid:23937984
  58. 58. Xiaohui C, Huai G, Yubin C. One case report: a male patient with chronic myeloid leukemia treated with imatinib involved in healthy pregnancies [article in Chinese]. Zhong Guo Yi Yao Dao Bao. 2013;10(1):116–7.
  59. 59. Dou XL, Qin YZ, Shi HX, Lai YY, Hou Y, Huang XJ, et al. [Fertility and disease outcomes in patients with chronic myeloid leukemia]. Zhonghua Xue Ye Xue Za Zhi. 2019;40(12):980–5. pmid:32023726
  60. 60. Cortes JE, Gambacorti-Passerini C, Deininger M, Abruzzese E, DeAnnuntis L, Brümmendorf TH. Pregnancy outcomes in patients treated with bosutinib. Int J Hematol Oncol. 2020;9(2):Ijh26. pmid:33005329
  61. 61. Aota Y, Udagawa S, Honda T, Okuda Y, Gotoh A. [Delivery of a Healthy Newborn by the Partner of a Patient with CML Undergoing Treatment with Nilotinib]. Gan To Kagaku Ryoho. 2020;47(5):811–3. pmid:32408325
  62. 62. Baldacci S, Gorini F, Santoro M, Pierini A, Minichilli F, Bianchi F. Environmental and individual exposure and the risk of congenital anomalies: a review of recent epidemiological evidence. Epidemiol Prev. 2018;42(3–4 Suppl 1):1–34. pmid:30066535
  63. 63. Mathews TJ, Driscoll AK. Trends in Infant Mortality in the United States, 2005–2014. NCHS Data Brief. 2017;(279):1–8. pmid:28437240
  64. 64. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv Exp Med Biol. 2010;686:349–64. pmid:20824455
  65. 65. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res A Clin Mol Teratol. 2003;67(3):193–201. pmid:12797461
  66. 66. Grimes DA, Schulz KF. Descriptive studies: what they can and cannot do. Lancet. 2002;359(9301):145–9. pmid:11809274
  67. 67. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128(1):305–10. pmid:21701348
  68. 68. Hoffmann VS, Baccarani M, Hasford J, Castagnetti F, Di Raimondo F, Casado LF, et al. Treatment and outcome of 2904 CML patients from the EUTOS population-based registry. Leukemia. 2017;31(3):593–601. pmid:27568522
  69. 69. Hoglund M, Sandin F, Hellstrom K, Bjoreman M, Bjorkholm M, Brune M, et al. Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry. Blood. 2013;122(7):1284–92. pmid:23843494
  70. 70. Thornton A, Lee P. Publication bias in meta-analysis: its causes and consequences. J Clin Epidemiol. 2000;53(2):207–16. pmid:10729693
  71. 71. Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep. 2013;2013. pmid:24155002
  72. 72. Gelperin K, Hammad H, Leishear K, Bird ST, Taylor L, Hampp C, et al. A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection. Pharmacoepidemiol Drug Saf. 2017;26(2):208–14. pmid:28028914