Management of classic Hodgkin lymphoma during pregnancy

INTRODUCTION — 

Classic Hodgkin lymphoma (cHL) accounts for only 10 percent of all lymphomas, but it is one of the most common types of lymphoma diagnosed during pregnancy, largely because the peak incidence coincides with female reproductive age.

This topic reviews the clinical presentation and management of cHL during pregnancy and the effects of treatment on the developing fetus and delivered infant.

Diagnosis and management of cHL in the nonpregnant adult are discussed separately. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults".)

EFFECTS ON FETAL GROWTH AND DEVELOPMENT — 

Chemotherapy, with or without radiation therapy (RT), is a mainstay of treatment of cHL, but both treatments are potential teratogens. The risk of fetal malformation or death is affected by the stage of fetal development, fetal susceptibility, the treatment, and the dose delivered to the fetus.

First trimester — The first trimester includes implantation (weeks 1 to 2) and embryogenesis (weeks 3 to 8), which are very vulnerable to the effects of chemotherapy and radiation.

●Chemotherapy – The first trimester is the most perilous period for chemotherapy exposure. The major manifestations of drug toxicity in the first trimester are spontaneous abortions during implantation and major morphologic abnormalities during embryogenesis.

The placenta plays a pivotal role in the transfer of chemotherapy to the developing embryo [1]. As such, inadvertent chemotherapy administration in the first two weeks of pregnancy (prior to the development of the placenta) is less likely to be teratogenic [2]. By comparison, single-agent and combination chemotherapy administered in the remainder of the first trimester results in a risk of congenital malformations of approximately 10 percent and 15 to 25 percent, respectively [2].

Some structures (eg, limbs, palate) have limited "windows" of vulnerability during embryogenesis, while other organs, such as the central nervous system, may be affected throughout all phases of embryogenesis, fetal development, and growth.

Placental cells have a multidrug resistance phenotype [3], which may reduce or prevent transfer to the fetus of such natural products as doxorubicin, vinblastine, and vincristine. However, case reports regarding the efficiency of placental transfer of doxorubicin are inconclusive. Fetal drug metabolism and excretion must also consider amniotic fluid recirculation (ie, fetal swallowing of the amniotic fluid). This feature helps to explain the marked teratogenicity of the folate antagonists, aminopterin and methotrexate, when given at regular chemotherapeutic doses.

●Radiation – Radiation exposure of the fetus during the first trimester is associated with teratogenesis and an increased risk of childhood malignancy. The incidence of these effects depends upon the fetal dose of exposure, which in turn is dependent upon the radiation dose, radiation field size, and the distance between the radiation field and the fetus [4]. (See 'Radiation therapy' below.)

Second and third trimesters — The second and third trimesters are periods of continued growth and development of the fetus.

●Chemotherapy – Adverse effects (AEs) of chemotherapy on the fetus are often more subtle during the second and third trimesters [1,5,6]. AEs include low birth weight, intrauterine growth restriction, premature birth, stillborn fetus, impaired functional development, intellectual disability (mental retardation), and diminished learning capability.

Chemotherapy for cHL has been administered successfully during the second and third trimesters with positive outcomes for both the patient and developing fetus, as described below. (See 'Outcomes' below.)

●Radiation – Increasing uterine fundal height affects total dose exposure from internal radiation scatter [7]. The closer the fetus is to the diaphragm, the greater the possible whole-body fetal dose when the patient receives radiation above the diaphragm. However, this effect is potentially counteracted by the larger fetus being more developed and therefore less sensitive to radiation.

Pharmacokinetics in pregnancy — Pregnant patients should be treated with conventional doses of chemotherapy, according to body surface area (BSA).

Dosing should be adjusted with continued weight gains [8]. Little information is available regarding the pharmacokinetics of individual cytotoxic agents in the pregnant patient. Alterations in drug distribution are expected due to the physiologic changes that occur with pregnancy, which include:

●Increases in blood volume and renal and hepatic clearance might be expected to reduce active drug concentrations. (See "Maternal adaptations to pregnancy: Kidney and urinary tract physiology".)

●Diminished gastric motility may affect the absorption of orally administered drugs.

●Plasma albumin decreases in pregnancy, increasing the amount of unbound active drug; however, this effect is counterbalanced by high levels of estrogen, which increase other plasma proteins.

●The "third space" of the amniotic sac.

●The multidrug resistance p-glycoprotein has been detected in fetal tissues and in the gravid endometrium and may offer some degree of protection to the fetus [3].

It is unclear how these physiologic changes affect active drug concentrations and their resulting efficacy and toxicity. The deleterious effects of drug exposure on the fetus are discussed separately. (See "Congenital anomalies: Approach to evaluation".)

CLINICAL PRESENTATION — 

Pregnant patients with cHL generally present like nonpregnant patients. However, the diagnosis of cHL may be delayed because clinical findings can overlap with symptoms experienced in pregnancy.

The most common presentation of cHL is painless lymphadenopathy. Some of the common clinical findings associated with cHL, such as fatigue, shortness of breath, anemia, thrombocytopenia, and pruritus overlap, are often experienced in pregnancy. Importantly, this overlap can lead to delayed diagnosis of cHL. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Clinical presentation'.)

Increasingly, asymptomatic patients are diagnosed with cHL in association with noninvasive pregnancy testing (NIPT) [9]. In a study of 107 pregnant individuals with unexplained abnormal results from cell-free deoxyribonucleic acid (DNA) sequence analysis used to screen for fetal aneuploidy, magnetic resonance imaging (MRI) identified a new cancer in nearly one-half; cHL was the most common malignancy (20 of 52 cases) [10]. Prenatal screening for fetal aneuploidies is discussed separately. (See "Prenatal screening for common fetal aneuploidies: Cell-free DNA test".)

Presentation of cHL in pregnant patients is like that in the general population [7,11-14]. A series of 48 pregnant females (median age 26 years) reported that cHL was diagnosed in 12 patients before conception, 10 during pregnancy, and 27 within nine months after delivery or pregnancy termination [11]. Comparison of each pregnant patient with three nonpregnant control patients with cHL reported that the stage of disease at presentation (table 1) was comparable: 25 percent stage I, 46 percent stage II, 17 percent stage III, and 12 percent stage IV.

The presence of B symptoms (ie, fever, night sweats, or weight loss exceeding 10 percent of body weight) is variable. While most patients from the North American series have presented without B symptoms [7,12,13,15], a report from Mexico described B symptoms in 10 of 14 patients [16]. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'B symptoms'.)

DIAGNOSIS AND STAGING

Diagnosis — The diagnosis of cHL may be suspected in a pregnant patient with painless lymphadenopathy. Fatigue, pruritus, or other findings associated with cHL may be difficult to distinguish from symptoms experienced in pregnancy.

Diagnosis requires pathologic evaluation of a lymph node or other involved tissue. An excisional or incisional lymph node biopsy is preferred, but multiple core needle biopsies are acceptable. Fine needle aspiration is not sufficient to establish the diagnosis and histologic subtype of cHL. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Tissue biopsy'.)

The biopsy may be performed using local or general anesthesia. The risk of anesthesia and biopsy in the pregnant patient is similar to that of healthy pregnant females [17].

Diagnostic criteria and determination of the pathologic subtype of cHL are discussed separately. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Diagnosis'.)

The subtypes of cHL diagnosed during pregnancy are like those in nonpregnant females of reproductive age. As an example, in a series of 40 patients with cHL during pregnancy, nodular sclerosing cHL was diagnosed in 35 patients, mixed cellularity in 2 patients, and 3 were unclassified [14]. A similar predominance of nodular sclerosis type has been noted in other reports [7,12,13].

Staging — Staging is based on the Lugano criteria (table 2). However, positron emission tomography (PET) and computed tomography (CT) should not be used in pregnant patients to avoid teratogenic and growth-retarding effects of ionizing radiation on the developing fetus [18].

Acceptable imaging techniques include:

●MRI – MRI of the chest, abdomen, and pelvis is the preferred imaging technique for staging pregnant patients. MRI can evaluate lymph nodes, liver, and spleen with good accuracy and is thought to be safe in pregnant patients, but there are limited data in this setting [19-21].

●Ultrasound – Abdominal ultrasound is safe for pregnant patients but is much less sensitive than MRI.

Diagnostic imaging during pregnancy is discussed in more detail separately. (See "Diagnostic imaging in pregnant and lactating patients".)

Staging in pregnant patients may be inaccurate because of limitations of imaging techniques. Furthermore, patients who are treated during pregnancy cannot be accurately staged after delivery.

Other studies included in the staging evaluation are:

●Complete blood count with differential count.

●Erythrocyte sedimentation rate (ESR); note that the ESR is often significantly elevated during normal pregnancy.

●Serum chemistries include glucose, electrolytes, kidney function, and liver enzymes (including lactate dehydrogenase [LDH]).

Bone marrow examination is not needed for staging in most patients with cHL but can be safely performed during pregnancy if needed. The role of bone marrow examination for staging cHL is discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Other procedures'.)

Further details of clinical evaluation and laboratory studies used for evaluating cHL are discussed separately. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Evaluation'.)

OVERVIEW OF MANAGEMENT — 

Management of cHL in pregnancy differs from that in nonpregnant patients because of concerns about the well-being of both the patient and the developing embryo/fetus.

Whenever possible, management should be delivered in consultation with a high-risk obstetrician or expert in maternal-fetal medicine.

Management of cHL in pregnant patients requires a balance between maximizing the chance of cure and minimizing potential harm to the developing fetus. Certain approaches that are routinely used in nonpregnant patients must be avoided in the pregnant patient because of known or uncertain risks to the developing fetus [22].

●Imaging – Positron emission tomography (PET) and CT should not be used in pregnant patients to avoid the teratogenic and growth-retarding effects of ionizing radiation on the developing embryo/fetus. MRI and ultrasound are alternative imaging methods that are considered safe for use during pregnancy. (See 'Staging' above.)

●Timing – The staging and treatment of cHL can be deferred in some cases of de novo cHL.

A decision to defer management must consider the impact of delay on treatment outcomes. Patient input is an important factor in selecting management, and the choice should be made by shared decision-making. The advantages and disadvantages of treatment during pregnancy versus deferral of treatment are discussed below. (See 'Timing of management' below.)

●Management – Management of newly diagnosed (de novo) cHL is guided by the trimester in which it is diagnosed.

Management of relapsed or refractory cHL is discussed below. (See 'Relapsed/refractory cHL' below.)

●Treatments – Radiation therapy should not be used during pregnancy because of potential effects on the growth and development of the fetus. Some treatments, such as brentuximab vedotin, should be avoided because there is little experience with their use in pregnant patients.

ELECTIVE TERMINATION OF PREGNANCY — 

The role of elective termination of pregnancy in a patient with cHL varies according to whether it is a new diagnosis (de novo) of cHL or it is relapsed or refractory (r/r) cHL.

The choice of elective abortion requires joint decision-making with the patient and clinicians, including an expert in maternal-fetal medicine/high-risk pregnancy. Knowledge of state laws, risk to maternal life, and the possible need to have the patient cared for out-of-state should be taken into consideration.

●de novo cHL – Elective termination of the pregnancy is rarely medically indicated with newly diagnosed cHL since chemotherapy has been successfully administered in pregnancy but generally only after 20 weeks gestation. A decision to continue or terminate the pregnancy should be individualized and made by a fully informed patient in conjunction with the clinician. Management of cHL diagnosed in the first trimester is discussed below. (See 'First trimester' below.)

●r/r cHL – By contrast, pregnancy termination is often needed with r/r cHL because high-dose chemotherapy, autologous hematopoietic cell transplantation, or other intensive approaches may be required.

Other factors to be considered are whether the patient is willing to assume a possible risk of fetal toxicity or other complications from cHL treatment during pregnancy, the effect of treatment on future fertility, and the patient's prognosis and ability to care for offspring.

The effects of the treatment of cHL on future fertility are discussed separately. (See "Cancer survivors: Overview of fertility and pregnancy outcomes".)

NEWLY DIAGNOSED cHL — 

Management of newly diagnosed (de novo) cHL in pregnancy is guided by the trimester in which it is diagnosed.

First trimester — For most patients diagnosed with de novo cHL in the first trimester, we suggest deferring treatment until at least the second trimester, unless the delay threatens the pregnant patient's immediate well-being.

Therapy should not be delayed for patients with a medical emergency, such as airway obstruction, spinal cord compression, symptomatic bulky subdiaphragmatic disease, or progressive cHL. Although termination of the pregnancy is only rarely required, it may be necessary for the management of a life-threatening medical emergency early in the first trimester. (See 'Elective termination of pregnancy' above.)

Deferring treatment until after the first trimester enables adequate fetal growth and development. Most patients with asymptomatic, stable, nonbulky, supradiaphragmatic disease can safely defer therapy until after the first trimester [14]. However, management of bulky disease in the abdomen or pelvis, severely symptomatic patients, or progressive disease must be individualized and should seek input from an expert in high-risk pregnancies.

Second trimester

Timing of management — The decision to treat cHL during pregnancy versus deferring treatment until after delivery must be individualized.

The timing of treatment should be made by shared decision-making with a well-informed patient and treating clinician, ideally with input from an expert in maternal-fetal medicine/high-risk pregnancies. Considerations include the gestational age at diagnosis; the number, size, and location(s) of disease; severity of symptoms; and patient preference.

No prospective trials in pregnant patients have compared outcomes with deferred therapy versus immediate treatment. It is uncertain whether deferral of therapy affects long-term survival because most reports are small case series from before the routine use of contemporary treatment methods.

There are advantages and disadvantages to both approaches:

●Treatment during pregnancy – Treatment during pregnancy enables prompt control of symptoms and/or complications, but this must be balanced against the recognition that staging may be inaccurate and that treatment may pose a risk to the developing fetus.

•Staging – Staging may be inaccurate because positron emission tomography (PET) and CT cannot be used during pregnancy. However, the disease stage does not affect the choice of treatment or its duration in a pregnant patient.

Patients who are treated during pregnancy cannot be accurately staged after delivery.

•Treatment – In selected patients, chemotherapy can be safely administered during pregnancy.

Risk to the fetus decreases as the pregnancy proceeds, but chemotherapy generally should not be given before 20 weeks gestation, at the earliest. The choice of treatment for cHL in pregnant patients is discussed below. (See 'Choice of treatment' below.)

●Deferral – A decision to defer therapy until after delivery must be individualized. Deferral allows conventional imaging techniques and accurate staging postpartum, but it delays control of symptoms and risks disease progression during pregnancy.

Pregnant patients diagnosed with asymptomatic, clinically stable, low disease burden, supradiaphragmatic cHL in the latter half of the second trimester or in the third trimester may be able to safely defer treatment until after delivery. However, the patient should be closely monitored for progression or disease-related complications.

•Monitoring – The patient should be monitored closely during pregnancy. Monitoring is easier in patients with disease that can be assessed by physical examination, but serial abdominal ultrasound can be used to monitor for the development or progression of subdiaphragmatic disease.

The development of medical emergencies or complications related to cHL while monitoring the patient may require prompt intervention.

•Treatment – Management of patients who defer treatment until after delivery is like that for nonpregnant patients. However, it is uncertain if disease control and/or survival are affected by deferral of therapy.

PET/CT can be used postpartum for staging, but patients should avoid contact with infants for 12 hours following PET. Response-guided therapy and treatments that are not used during pregnancy (eg, radiation therapy [RT], brentuximab vedotin, nivolumab) can be used postpartum.

Postpartum treatment of cHL is guided by disease stage and prognostic factors:

-(See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

-(See "Classic Hodgkin lymphoma (cHL): Treatment of unfavorable prognosis early (stage I-II) cHL in adults", section on 'Chemotherapy-only'.)

-(See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

Choice of treatment — For treatment of cHL during pregnancy, we suggest two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by four cycles of AVD (doxorubicin, vinblastine, dacarbazine; no bleomycin), based on efficacy and a long track record of safe administration of these agents in pregnancy.

The patient is evaluated clinically after treatment with two cycles of ABVD. Patients with no evidence of disease progression then receive four cycles of AVD. Patients with progressive disease during treatment are managed as refractory disease. (See 'Relapsed/refractory cHL' below.)

There is a long track record of safely treating cHL in pregnant patients with ABVD [23] (table 3). The choice of two cycles of ABVD followed by four cycles of AVD is extrapolated from the RATHL trial of cHL in nonpregnant patients [24]. In RATHL, four cycles of AVD after a complete response (CR) with two cycles of ABVD achieved comparable outcomes with less toxicity compared with four additional cycles of ABVD after CR, as discussed separately. (See "Classic Hodgkin lymphoma (cHL): Treatment of unfavorable prognosis early (stage I-II) cHL in adults", section on 'Chemotherapy-only'.)

Treatment of cHL in pregnant patients differs in important ways from treatment in nonpregnant patients:

●Response-guided therapy is not used in pregnant patients to avoid radiation exposure from PET/CT. As a result, treatment is not stratified by limited stage (stage I to II) versus advanced stage (stage III to IV) or according to prognostic category (ie, favorable prognosis versus adverse prognosis).

●Brentuximab vedotin and nivolumab are not used because of limited experience with these agents in pregnant patients.

●RT is not used in pregnancy to avoid fetal exposure. However, RT may be needed in rare cases for prompt local control of highly symptomatic disease above the diaphragm. (See 'Radiation therapy' below.)

We obtain a PET/CT soon after delivery to assess the response to therapy. (See 'Management after delivery' below.)

Third trimester — The choice of treatment during the third trimester versus deferring therapy until after delivery is individualized.

This decision is individualized and should be made jointly by the treating clinician, patient, and an expert in high-risk pregnancies. The advantages and disadvantages of prompt treatment versus deferral are discussed above. (See 'Timing of management' above.)

OBSTETRICAL MANAGEMENT

Delivery — We suggest delivery as close to full term as possible without compromising the health of the patient or infant.

Cesarean delivery is not necessary unless it is obstetrically indicated. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)

The timing of delivery of the infant should be a joint decision between the obstetrician, hematologist-oncologist, maternal-fetal medicine expert, and the patient.

Chemotherapy should not be given within three weeks before delivery to avoid cytopenias that might complicate the delivery. Blood counts of both the pregnant patient and the infant should be monitored for cytopenias. Neonates have limited ability to metabolize and excrete drugs, and some who were born to a pregnant patient who received chemotherapy within 30 days of delivery had significant cytopenias [25]. Patients with chemotherapy-associated thrombocytopenia may experience postpartum hemorrhage that requires platelet transfusions and/or other methods to control bleeding. (See "Overview of postpartum hemorrhage".)

The importance of avoiding iatrogenic preterm delivery was illustrated in a multicenter observational study of 70 children who were exposed to cancer staging and treatment during gestation and followed for a median of 22 months (range 17 to 212 months) [26]. Exposure to chemotherapy in utero was not associated with increased central nervous system, cardiac, or auditory impairment. However, cognitive development scores were lower for children born preterm, with intelligence quotient increasing by an average of 11.6 points for each additional month of gestation.

Management after delivery

●Staging – For patients who deferred therapy during pregnancy, staging with positron emission tomography (PET) should be performed as soon as possible after delivery. MRI is acceptable for staging if PET is not available promptly after delivery.

Patients should avoid contact with infants for 12 hours following PET.

PET is useful for accurate staging of cHL, and it can have an impact on treatment choices. For example, PET enables response-guided therapy and can be useful for determining if a patient with limited-stage disease might benefit from radiation therapy (RT) as a component of combined modality treatment (CMT). (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

●Treatment – Nivolumab, brentuximab vedotin, and RT can be safely administered after delivery if needed.

●Breastfeeding – Breastfeeding should be discontinued once staging and therapy begin since contrast and nuclear medicine imaging agents, chemotherapy, and ancillary supportive medications may concentrate in breast milk.

In general, breastfeeding should be avoided in patients while receiving chemotherapy. Many cytotoxic drugs, especially alkylating agents, are excreted in breast milk [27,28]. Neonatal neutropenia has been reported in an infant breastfed during maternal treatment with cyclophosphamide [29].

RADIATION THERAPY — 

Radiation therapy (RT) can offer local disease control, but it is potentially teratogenic, and it may be associated with an increased risk of childhood malignancy in the child and second cancers in the patient.

RT should only be used if it is required to maintain the well-being of the pregnant patient by providing disease control until delivery. If RT during pregnancy is deemed necessary, it should be delayed until the second or third trimester, if possible, and only administered after consultation with a physician with substantial expertise in treating cHL.

●RT fields – The RT field should be as small as possible to achieve the needed effect. RT to the chest should be avoided to reduce the subsequent risk of breast cancer.

●Fetal exposure – Radiation fields should minimize the fetal dose by maximizing the distance between the inferior border of the field and the uterus. The whole-body fetal dose should be limited to ≤0.10 gray (Gy).

The uterus should be protected during radiotherapy with 10 HVL shielding (half-value layer; ie, the thickness of a material that reduces the intensity of radiation by one-half of its initial level).

Calculation of the maximal dose to the fetus should be performed prior to treatment, and the dose to the fetus should be monitored during treatment [30]. Fetal outcome following radiotherapy is dependent upon gestational age when radiation is given, whole-body fetal dose, and maternal health.

●Outcomes – Higher frequencies of spontaneous abortion and congenital anomalies have not been convincingly demonstrated.

A case series of 16 pregnancies reported 16 full-term infants [7], and a series of 10 pregnancies resulted in one spontaneous abortion in a patient irradiated during the first trimester, three therapeutic abortions, and six normal infants [12].

ANTIEMETICS — 

Antiemetics are often needed to control nausea and vomiting caused by the underlying disease (eg, abdominal involvement) and/or treatment of cHL.

Patients with nausea and vomiting should be evaluated for the severity of symptoms and the state of hydration, as discussed separately. (See "Nausea and vomiting of pregnancy: Treatment and outcome".)

Selective antagonists of the 5-hydroxytryptamine-3 (5-HT3) serotonin receptor have favorable safety and efficacy profiles in nonpregnant patients, but there are limited data regarding their use in pregnant patients. Some studies have suggested a possible risk of fetal anomalies when used early in pregnancy.

A decision to use ondansetron, granisetron, or dolasetron should be individualized and made jointly by the patient and clinician with the recognition that there may be a small risk of cardiovascular anomalies when used in the first trimester.

Administration, adverse effects, and outcomes of treatment with 5-HT3 antagonists in pregnant patients are discussed separately. (See "Nausea and vomiting of pregnancy: Treatment and outcome", section on 'Add a serotonin antagonist'.)

RELAPSED/REFRACTORY cHL — 

Management of relapsed or refractory (r/r) cHL during pregnancy adds additional complexity and risk for pregnant patients.

Termination of pregnancy may be necessary to permit intensive life-saving treatments for r/r cHL, such as hematopoietic cell transplantation or immunotherapy.

Management of relapsed cHL in a pregnant patient must consider the duration of the prior remission, comorbidities, medical fitness, and patient choice, as discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

OUTCOMES

Obstetric outcomes — Antenatal treatment of cHL has been associated with increased obstetrical complications, but the precise risk is not well-defined.

A retrospective study compared obstetrical outcomes for 72 pregnant patients who received antenatal chemotherapy for cHL versus 56 who deferred treatment until after birth (56 patients) and 6 who received radiation therapy alone [31]. Compared with the other cohorts, patients who received antenatal therapy had more obstetric complications, including preterm contractions (12 versus 7 percent) and preterm prelabor rupture of membranes (5 versus 0 percent), and neonatal birthweights were lower.

Lymphoma outcomes — Pregnancy appears to have no significant effect on the course of cHL, based on limited retrospective studies.

Analysis from the International Network on Cancer, Infertility, and Pregnancy database reported no difference in progression-free survival (PFS) or overall survival (OS) of 77 pregnant patients treated between 1969 and 2018 compared with 211 nonpregnant, matched controls [31].

In a study of 90 pregnant patients that included 40 patients with cHL, one-third of patients deferred treatment until after delivery [14]. Gestation went to full term in more than one-half of patients, with delivery occurring at a median of 37 weeks. There were no differences in maternal complications, perinatal events, or median infant birth weight based on deferred versus antenatal therapy. Three-year OS and PFS for patients with cHL were 97 and 85 percent, respectively. Combination chemotherapy administered past the first trimester, and as early as 13 weeks gestation, was associated with few complications and expected maternal survival.

Late effects of antenatal exposure — Limited data are available to address the long-term outcomes of the treatment of cHL in pregnancy.

Late manifestations of in-utero exposure to antineoplastic agents may include impaired growth, diminished neurologic and/or intellectual function, decreased gonadal and reproductive function, mutagenesis of germline tissue, and carcinogenesis. However, case series have reported relatively good outcomes among children who were exposed to ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) during the second or third trimester [16,25,32].

A series of 43 children exposed to chemotherapy during pregnancy, including 5 who were exposed during the first trimester, reported no significant abnormalities in growth or development compared with a case-control group of 25 children [16]. Evaluation included routine blood work, lymphocyte function, immunoglobulins, cytogenetics, bone marrow examination, school performance, neurologic testing, sexual development, and medical history. Further follow-up of the same cohort with expansion to 26 patients with cHL and a median follow-up of nearly 19 years confirmed good health in the children and grandchildren [32].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Description – Classic Hodgkin lymphoma (cHL) is a common malignancy in pregnancy.

●Effect of treatment on the fetus – Fetal malformation or death from radiation therapy (RT) and chemotherapy varies with gestational age. (See 'Effects on fetal growth and development' above.)

●Presentation – Most patients present with painless lymphadenopathy. Dyspnea, pruritus, nausea, and other symptoms may be dismissed as pregnancy-related, causing delayed diagnosis. Some asymptomatic patients are in association with noninvasive pregnancy testing (NIPT). (See 'Clinical presentation' above.)

●Diagnosis – cHL may be suspected with painless lymphadenopathy, with or without other symptoms.

Diagnosis requires an adequate incisional or excisional tissue biopsy or multiple core biopsies; fine-needle aspiration is not adequate for diagnosis and histologic classification. (See 'Diagnosis' above.)

●Staging – Staging is based on Lugano criteria (table 2), but positron emission tomography (PET) and CT are not used in pregnant patients. If needed, MRI is the preferred imaging technique in pregnancy. (See 'Staging' above.)

●Overview – Pregnant individuals with cHL should be informed about the risks and benefits of chemotherapy during pregnancy versus deferral of treatment. Shared decision-making by the patient and treating clinician is essential; consultation with high-risk obstetricians is important. If the pregnancy is desired, management must consider the well-being of both the patient and the developing embryo/fetus. (See 'Overview of management' above.)

●Abortion – Elective termination of pregnancy is rarely indicated for newly diagnosed cHL, but it may be needed to enable intensive treatments for relapsed cHL. (See 'Elective termination of pregnancy' above.)

●Newly diagnosed cHL – Management is guided by the trimester at diagnosis.

•First trimester – For most patients diagnosed in the first trimester, we defer treatment until at least the second trimester. However, therapy should not be delayed for medical emergencies (eg, airway obstruction, spinal cord compression, symptomatic bulky subdiaphragmatic disease, progressive cHL). Pregnancy termination may be needed to manage a life-threatening medical emergency. (See 'First trimester' above.)

•Second trimester

-Timing – The decision to treat during pregnancy versus deferring treatment until after delivery must be individualized, with shared decision-making by a well-informed patient, treating clinician, and input from high-risk pregnancy experts. The advantages and disadvantages of each approach are discussed above. (See 'Timing of management' above.)

-Choice of treatment – For treatment during pregnancy, we suggest two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by four cycles of AVD (doxorubicin, vinblastine, dacarbazine; no bleomycin) (Grade 2C). There is a long track record of safe administration of ABVD in pregnant patients. (See 'Choice of treatment' above.)

Unlike in nonpregnant patients, we do not use response-guided therapy or stratify treatment by stage or prognostic category, and we do not use RT, brentuximab vedotin, or nivolumab.

•Third trimester – The choice of prompt treatment versus deferral until after delivery is individualized, as discussed above. (See 'Timing of management' above.)

●Obstetrical management

•Delivery – We advise delivery as close to full term as possible without compromising the health of the patient or infant. (See 'Delivery' above.)

•Postpartum – For patients who deferred management, we pursue PET/CT staging and treatment soon after delivery. (See 'Management after delivery' above.)

Breastfeeding should be discontinued once staging and therapy begin.

●Relapsed/refractory cHL – Abortion may be needed to enable intensive life-saving treatments. Management is guided by the duration of prior remission, comorbidities, fitness, and patient preference. (See 'Relapsed/refractory cHL' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Steven Horwitz, MD, and Joachim Yahalom, MD, who contributed to earlier versions of this topic review.