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Pregnancies following diagnosis of chronic lymphocytic leukemia (CLL) are rare events, mainly because the disease is typically diagnosed in the elderly. Literature on the topic is based only on case reports, and limited data are available on the influence of pregnancy on CLL course. In this retrospective study, we aimed to summarize the clinical and laboratory course of 10 women with CLL who became pregnant. None of the patients had significant changes in blood count during or after pregnancy or had complications such as infection, autoimmune phenomenon, or preeclampsia. Four out of 10 pregnancies were terminated with an early miscarriage. Following labor, 1 patient started anti-CLL treatment due to preexisting anemia, but none of the women required therapy during CLL progression during the first 2 years of follow-up. We conclude that based on our serial, pregnancy does not negatively impact on CLL course.
As a consultant hematologist specializing in chronic lymphocytic leukemia (CLL), I was approached by a 40-year-old lady who came for a second opinion. She reported being diagnosed with CLL, stage A, 8 years earlier, and since then, she has been on a watch-and-wait follow-up policy. Her physical examination was normal; her blood count showed a white blood count (WBC) of 120,000 mm3, her lymphocyte percentage was 72%, and her hemoglobin and platelets were within the normal range. She came to ask what the literature describes regarding the course of CLL during pregnancy and labor and whether it affects the future fetus? Her local hematologist recommended she avoid pregnancy due to scarce literature on the topic.
In the current work, we aimed to give the best answers for similar cases of young CLL females below 45 years old wishing for a normal life, including pregnancies and children. Due to missing evidence-based medicine, their family doctors and sometimes the local hematologist struggle with what to recommend without risking them.
CLL is the most frequent leukemia in the Western world, yet it is a disease of the elderly with a median age at diagnosis of 72 years old and is more frequent in males [1, 2]. Only 2% are women below 40 years old [3, 4], and this explains the rarity of pregnancy cases.
Reviewing the literature on the topic, it is mainly based on anecdotal case reports . Few of them also report details on therapy given during pregnancy such as leukapheresis 6 and chemotherapy 5. The largest serial published arrived from Australia, where they describe the course of 5 patients with CLL, their pregnancy course and labor, including a literature review and management discussion 10.
It should also be noted that most reported cases are relatively old and that the CLL approach has dramatically changed in the last 10 years, mainly due to novel agents and supportive care, which are now available [11–14]. In a non-biased and constitutive order, we aimed to analyze cases of pregnancy in a large registry cohort of patients with CLL, report on pregnancy outcome, and effect on CLL or pregnancy course.
Material and Methods
The cohort is based on data obtained from electronic medical records after receiving approval from the Ethical Committee for members of Maccabi, the second-largest healthcare organization in Israel, with approximately 2.5 million insured patients 15. All patients included were diagnosed with CLL based on the IWCLL criteria (1) between 1998 and 2022, for whom we had complete data on clinical, laboratory, and therapy given. Patients were identified using the ICD9 code (204.10–12) that is added to their medical records after confirmation of diagnosis by an expert hematologist. A diagnosis was also recorded in the Maccabi Health System (MHS) hematologic neoplasm registry. As with previous retrospective studies of CLL performed on the MHS database, patients had to meet in addition one of the following criteria to ensure the validity of the cohort: (i) received anti-CLL therapy at least once since diagnosis, or (ii) if treatment-naive, at least one CBC result indicating an absolute lymphocyte count above 5 × 109/L at any time during the study. Once all CLL patients were identified, we searched for pregnant women by looking for female CLL patients with a corresponding ICD9-CM pregnancy code: V22 (normal pregnancy) and/or V23 (supervision of high-risk pregnancy).
To determine the outcome of delivery, we used the ICD9-CM code of V27 (outcome of delivery), and codes V30–V39 for the classifying liveborn infants according to type of birth. To identify abortions, we used the following ICD9 codes: 632 (missed abortion), 634 (spontaneous abortion), 635 (legally induced abortion), 636 (illegal abortion), and 637 (unspecified abortion). Complications that occurred during labor and delivery were tracked using ICD9-CM codes 660–669, including cesarean delivery without mention of indication (code 669.7).
During the study period, 1,836 (40%) women with CLL were in the Maccabi Health Maintenance Organization (HMO) database. We identified 67 (1.8%) women below the age of 45 years old, and 10 of them became pregnant after being diagnosed with CLL. We summarized all clinical and laboratory data on pregnancy and the CLL course.
We identified ten women with CLL who became pregnant after being diagnosed with CLL. The median age at diagnosis of this young cohort of patients was 34 years old (24–43). The median age at 1st pregnancy post-CLL diagnosis was 37 years old (29–43), and the median interval from diagnosis of CLL till pregnancy was 34 months (1–156). Out of 10 pregnancies, 4 resulted in miscarriage, all during the second trimester, and 6 gave birth: 4 in normal labor and 2 with cesarean section. Two women underwent planned C-section identified using ICD9 code V30. None of the women underwent C-section due to complication (ICD9 code 669.7). Of note, 3 out of 10 women gave birth before they were diagnosed with CLL.
None of the patients was hospitalized during pregnancy or was diagnosed with infection, including pneumonia, sinusitis bronchitis, or cellulitis, and no antibiotic was prescribed. We have not identified cases diagnosed with preeclampsia or eclampsia in our cohort.
None of the patients received treatment for CLL before or during pregnancy. One patient started therapy a month after delivery due to preexisting anemia, while 2 patients had disease progression during follow-ups 43 and 60 months after labor.
We have looked at blood counts before, during, and after pregnancies. None of the CLL patients had a significant change in WBC, lymphocyte %, hemoglobin, and platelet levels (Fig. 1). Platelet counts range from 85,000 to 376,000 mm3. These levels are in the normal range or may be attributed to thrombocytopenia during pregnancy. We have not observed any case of severe or acute thrombocytopenia and therefore, none of the women had a suspicion of developing immune thrombocytopenic purpura during or after pregnancy. The median hemoglobin level was 12.1 g/dL (range 8–14.2 g/dL). The lowest decrease in hemoglobin level during pregnancy was 2 g/dL in patient number 2 (Fig. 1). Still, none of them had increased LDH above baseline level, and therefore we have not seen cases of autoimmune hemolytic anemia. Coombs test was negative in seven women, while in other 3 patients we have not identified that the test has been performed. Of note is that none of the patients received steroids during pregnancy.
The median follow-up for CBC post-labor was 3 weeks. The median time for next hematologist visit was 11 weeks.
Follow-up of our cohort demonstrated that only one woman has been in pregnancy following the index pregnancy. However, she had miscarriage in the next pregnancy due to spontaneous abortion.
Pregnancy following the diagnosis of hematological malignancies is a rare event. The primary goal of treatment is to preserve the mother’s health, and challenges involves diagnostic dilemma as well as decision whether to terminate the pregnancy (mainly in first or second semester) or the deliver chemotherapy 16. Most of the available data are based on clinical cases of young women who were diagnosed with lymphoma or leukemia during pregnancy [16, 17]. This is of major interest for women with CLL as leukemia, due to its chronic nature, will be of lifelong nature.
In addition, the effect of pregnancy on leucocyte count was investigated mainly in healthy women [18, 19]. Indeed, it was reported that during pregnancy, there is a physiological effect on the white cell count, mainly due to an absolute increase in neutrophils. In contrast, the absolute lymphocyte count and the ratio of B and T cells remain unchanged 10. In previous case reports on patients with CLL and elevated WBC, high absolute lymphocyte count should not necessarily be a trigger for treatment unless there is placental insufficiency, inter-uterine growth restriction, or other antenatal complications that may be CLL-related [8, 9].
In the current study, we have analyzed WBC levels in a cohort of 10 women with CLL. We have not observed a significant WBC or lymphocyte percentage increase during pregnancy and the year following labor. Similar results were monitored for hemoglobin levels and platelet counts (Fig. 1). In addition, only 1 patient required therapy within a year following pregnancy, but this patient already had symptomatic anemia due to her leukemia before pregnancy. We feel this represents reassuring results that pregnancies in young women with CLL do not accelerate disease progression.
None of the patients we have reported required therapy for their CLL during pregnancy. One of the important questions to be answered is which therapy for CLL would be best recommended during pregnancy, mainly in the novel era of novel agents, as currently, no gold standard is available for these cases. Limited evidence for the use of leukapheresis in reducing the white cell count could be considered a temporary therapy in extreme cases 6. Yet, accumulated data are already available regarding the use of anti-CD20 during pregnancy during 2nd and 3rd semesters 20.
Based on previously reported cases in the literature of pregnancy complicated with preeclampsia [5, 8], infection [8, 21], or autoimmune phenomenon 22, we have looked for these diagnoses in our cohort, but we have not identified them.
Of note is that 4 out of 10 pregnancies terminated in abortion. This percentage is higher than in a healthy population, but our cohort is too small for a definitive conclusion or explanation from this point of view.
Our study has several limitations due to its retrospective and anonymous nature. We had no data regarding the newborn. This missing piece of data are still of significant interest for the reassuring young woman with CLL that not only do pregnancies have no negative impact on their disease but also their fetus. Future studies should aim to analyze the newborns outcome.
In conclusion, we summarized 10 cases of young patients who became pregnant after being diagnosed with CLL. Also, the cohort size is small. Nevertheless, this is the most extensive series of pregnant women with CLL. Based on our results, the impact of CLL on pregnancy outcomes is still unclear but our piece of data suggests that pregnancy probably has no negative impact on the CLL course. These may contribute to another level of safety by not preventing pregnancy for young women with CLL.
Statement of Ethics
The cohort is based on data obtained from electronic medical records after receiving approval from the Ethical Committee for members of Maccabi Health System, number: 134/21. Patient consent was not required on the ground of local or national guidelines. The need for informed consent was waived by the Ethical Committee for members of Maccabi Health System, number: 134/21.
Conflict of Interest Statement
The authors have no conflicts of interest.
The study was supported by a grant from Kahn Sagol Maccabi Research and Innovation Center, Maccabi Healthcare Services, Tel-Aviv, Israel.
T.T. designed, organized, and wrote the manuscript. H.A. prepared the data and preprocessed the data. G.M., S.G., and T.P. organized and wrote the manuscript. L.R. performed the data analysis and wrote the manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.