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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 9-15

Breast Cancer and Fertility Part 3: Pregnancy after breast cancer


1 Department of Reproductive Medicine, Mother and Child Hospital, New Delhi, India
2 Dr. Patil's Fertility and Endoscopy Clinic, Bengaluru, Karnataka, India

Date of Web Publication25-Jun-2019

Correspondence Address:
Dr. Nalini Mahajan
Department of Reproductive Medicine, Mother and Child Hospital, D-59 Defence Colony, New Delhi - 110 024
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tofj.tofj_5_19

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  Abstract 


The incidence of breast cancer (BC) in young nulliparous women is on the rise globally. Early diagnosis and improved multimodality treatment have given survivors an opportunity to fulfill their reproductive needs. Concerns of disease recurrence, increased risk of antenatal and neonatal complications, and possibility of cancer inheritance in the baby influence decision making on pregnancy after BC (PAFBC). Fertility itself may be an issue as ovarian reserve is compromised by chemotherapy, and patient may need the help of assisted reproductive technique's. Fortunately, PAFBC treatment does not jeopardize disease outcome. However, the optimal time for conception after completion of treatment needs to be determined. Safety of pregnancy in women with a history of hormone (estrogen and progesterone) receptor positive BC, also remains controversial. Advice on going through with pregnancy should be individualized after evaluating the status of the women, keeping in mind safety of both fetus and the mother. Wishes of the patient need to be respected and the final decision rests with her.

Keywords: Breast cancer, fertility preservation, fertility, pregnancy after breast cancer, BRCA mutation


How to cite this article:
Mahajan N, Patil M. Breast Cancer and Fertility Part 3: Pregnancy after breast cancer. Onco Fertil J 2019;2:9-15

How to cite this URL:
Mahajan N, Patil M. Breast Cancer and Fertility Part 3: Pregnancy after breast cancer. Onco Fertil J [serial online] 2019 [cited 2019 Sep 22];2:9-15. Available from: http://www.tofjonline.org/text.asp?2019/2/1/9/261254



Key Points(Based on ESMO guidelines)

  1. Pregnancy after BC treatment is safe even in women with ER-positive disease and should not be discouraged (III, A).
  2. Optimal timing of PAFBC should take into account the risk of relapse, age of the woman, and decrease in ovarian reserve with CT.
  3. A period of 2 years after completion of treatment in ER-negative tumors and 5 years in ER-positive tumors and when there is nodal involvement is considered adequate and does not decrease DFS or OS (IV, C).
  4. Patients on long-term tamoxifen therapy may be allowed to interrupt treatment after 2–3 years to complete their family after discussion of the risks involved. Tamoxifen therapy should be stopped at least 3 months prior to attempting conception because of teratogenicity and completed after delivery (V, C).
  5. Termination of pregnancy does not alter the course of disease and should not be advised for that purpose (IV, A).
  6. Full oncological evaluation before embarking on pregnancy is mandatory. Evaluation for any obstetric risk factor should be carried out. Cardiac evaluation should be done if patient has received anthracyclines.
  7. There is an increased risk of adverse pregnancy and neonatal outcome – miscarriage, LSCS, preterm delivery, low birth weight, and SGA.
  8. Breastfeeding should be encouraged. It does not increase risk of cancer recurrence.
  9. Safety of ART to achieve pregnancy is established. PR's with autologous oocytes are lower than noncancer patients. PR's with donor oocytes are similar.
  10. oncological Evaluation and Follow-Up After Delivery Should Be Carried Out.



  Introduction Top


Cancer. a life-threatening disease previously associated with age, appears to be increasing in the young. Sonmezer and Oktay[1] reported that a breast cancer (BC) diagnosis was made in over 20% of young women by the age of 30 and over 40% by the age of 40 years. Curative treatment in BC involves gonadotoxic chemotherapy (CT) which can result in partial or total loss of fertility depending on the drug and dosage used. Age of the women, her pretreatment ovarian reserve, and parity are important determinants of posttherapy fertility.[2],[3] Improved multimodality treatments have increased survival rates and longevity. The focus of cancer management has moved toward providing a better quality of life, bringing fertility care to the forefront. Fertility preservation (FP) counseling is being increasingly recommended by oncologists and fertility conservation with gonadotropin-releasing hormone analogs, and/or preservation of oocytes, embryos, and ovarian tissue is being offered to women prior to BC CT.[4],[5],[6],[7]

Contemporary medicine has made it possible for women with BC to preserve fertility and conceive safely on completion of treatment. Reports suggest that 40%–50% of survivors desire a family after their BC treatment.[8] Despite this, pregnancy rate (PR) after BC is almost 70% lower than in the general population, the least among all cancer survivor groups.[9],[10] Contributory factors include a fear of recurrence, decreased fertility, associated sexual dysfunction, pregnancy complications, and an apprehension of the detrimental effect of maternal cancer on the child.[11],[12] Lack of counseling further adds to the misconceptions and fears that surround pregnancy after BC (PAFBC).

In spite of reports on the safety of a subsequent pregnancy in both receptor-negative (−ve) and estrogen receptor (ER)-positive (+ve) patients,[13],[14] many physicians are hesitant to encourage conception because of a lack of randomized controlled trials and studies with long-term follow-up. The positive prognostic effect of PAFBC[11],[15] reported in the literature has also been debated. The beneficial effect is attributed to a selection bias or the “healthy mother effect,” i.e., only women with lower stage disease and a good prognosis opt for pregnancy.[8],[16]

This article the third in the series on BC; provides a comprehensive look at pregnancy in cancer survivors and attempts to address issues of concern to both patients and physicians when conception is being considered after completion of BC treatment.


  Methods Top


This review uses published articles in the field of BC, FP, and PAFBC. Cited articles were found by a literature search using PubMed for articles published until January 2019. The reference lists of retrieved studies and review articles were also used to identify additional studies. Guidelines of the European Society for Medical Oncology (ESMO), Royal College of Obstetrics and Gynaecology, National Comprehensive Cancer Network, and The Society of Obstetricians and Gynaecologists of Canada (SOGC), were also taken into account.

The following keywords were used: BC, breast tumor, PAFBC, fertility, FP, cancer survivor, CT, and BRCA mutations.

This review aims to address the following critical questions:

  • Impact of pregnancy on the risk of cancer recurrence
  • Optimal timing for pregnancy after completion of treatment
  • Pregnancy Outcome
  • Assisted reproductive technology (ART)- Requirement and Reproductive Outcome
  • Concerns on breastfeeding
  • Risk to children born after cancer treatment.


Pre-pregnancy evaluation

Before attempting conception, it is mandatory that the patient has a full oncological and gynecological evaluation. Any high-risk factor should be noted. Patients taking tamoxifen should wait for 3 months after discontinuing the drug to attempt pregnancy because of its teratogenic effect.[17] Women who have received anthracycline CT (doxorubicin or epirubicin) should have a thorough cardiac evaluation since anthracyclines can cause left ventricular dysfunction and occasionally cardiomyopathy.[18],[19] A preconception consultation with a maternal-fetal medicine specialist is therefore useful to discuss the possible impact of treatment on pregnancy outcome, assess the need for preconception testing (cardiac, pulmonary, and mental function), and plan for any additional antenatal monitoring that may be warranted. A multidisciplinary team, including an oncologist, breast surgeon, reproductive medicine specialist, obstetrician, and neonatologist, need to work together to ensure a smooth antenatal period and a safe delivery.


  Impact of Pregnancy on the Risk of Breast Cancer Recurrence Top


Safety of pregnancy in BC survivors has been reported widely[13],[20] for both ER-−ve and ER-+ve disease.[21],[22] Apprehensions of an early relapse in ER-+ve BC women due to endocrine stimulation inherent to pregnancy, have been allayed by studies with long-term follow-up of patients. A multicenter retrospective study by Azim et al.[21] found a similar disease-free survival (DFS) in patients who became pregnant 2 years or more from their BC diagnosis to nonpregnant BC survivors, irrespective of the ER status. The median follow-up in this study was 4.7 years' postpregnancy. A subsequent multicentric case–control study was conducted to address the issue of prolonged recurrence risk in ER-+ve BC, which is high even after 5 years. Three hundred and thirty-three patients with PAFBC were matched to 874 nonpregnant controls. A median follow-up of 7.2 years' postpregnancy showed no difference in DFS between pregnant and nonpregnant groups. In ER-+ve patients hazard ratio (HR) was 0.94, 95% confidence interval (CI) = 0.70–1.26, P = 0.68 and ER-−ve patients HR = 0.75, 95% CI = 0.53–1.06, P = 0.10. Overall survival (OS) was similar between pregnant ER-+ve patients and controls while pregnant ER-−ve patients had better OS than controls. Time to pregnancy, miscarriage, breastfeeding, and type of adjuvant CT did not alter the outcome.[22] This study also showed that the improved outcome of patients who conceived before 2 years reported earlier by their group,[21] appeared to be a selection bias. Pregnancy after surgical treatment of BC also does not alter DFS.[23] Based on these reassuring reports, physicians can offer evidence-based advice to BC patients planning pregnancy.

The safety of pregnancy in BC survivors with BRCA mutation is still not established as there is very little literature available. A multicenter retrospective cohort study[24] attempted to look at the prognostic impact of pregnancy in BRCA-mutated patients. Unfortunately, in this study, the patient numbers were too small to draw a definite conclusion. It is logical to presume that the prognostic effect of pregnancy would not be different between patients with and without BRCA mutations.[25]


  Overall Risk of Recurrence in Breast Cancer Top


The timing of BC recurrence varies based on tumor characteristics and treatment strategies. It has been observed that the recurrence occurs earlier in ER-−ve patients.[26] Colleoni et al.[27] reported that overall the annualized hazard of recurrence was highest in the first 5 years (10.4%), with a peak between years 1 and 2 (15.2%). ER-+ve patients had a lower annualized hazard in the first 5 years compared to ER-−ve patients (9.9% vs. 11.5%; P = 0.01). However, beyond 5 years, patients with ER-+ve disease had higher hazards (P < 0.001) which remained high beyond 10 years, even in patients with no positive axillary nodes.


  Optimal Timing for Pregnancy After Breast Cancer Treatment Top


Recommendations on the timing of PAFBC are extremely challenging. Optimal timing of pregnancy is understandably based on the time period associated with risk of recurrence which is highest in first 5 years and peaks at 1–2 years.[27] Ives et al.[16] noted that survival rates were better in women who delayed pregnancy for 2 years or more after completion of BC treatment. A population-based, retrospective cohort study from Canada, comprising 7553 BC women aged 20–45 years reported that pregnancy did not have a negative impact on survival, risk of death being lowest if pregnancy occurred 6 months or more after BC diagnosis.[28] An increased risk of recurrence was shown by Kranick et al.[29] if conception occurred within 6–12 months after BC diagnosis, while the study by Lambertini et al.[22] showed that the timing of pregnancy did not appear to have a major impact on outcome.

The Green-top guidelines[30] based on some well-designed observational studies recommend that patients should be advised to postpone pregnancy for at least 2 years after completing treatment to avoid early relapse (evidence level 3). If there is axillary node involvement, pregnancy should be deferred to 5 years (based on opinion only). Women with ER-+ve disease should be advised to wait for 5 years till tamoxifen treatment is complete. This recommendation has been the subject of debate, as there is lack of published data regarding the impact of postponing pregnancy on disease outcome.[16] In women with BRCA gene mutations, the risks associated with subsequent pregnancy are uncertain (evidence level 2).

Guidelines from the Society of Obstetricians and Gynaecologists of Canada (2002) also recommend waiting at least 3 years before attempting pregnancy and for 5 years if there is nodal involvement (recommendation based on opinion only).[31],[32] The ESMO guidelines[9] also recommend waiting for 2 years after BC treatment (Evidence level IV, C) based on retrospective cohort studies or case–control studies. However, a pregnancy that occurs spontaneously within the first 2 years after completing treatment does not suggest that cancer is more likely to recur, and therefore, a therapeutic abortion should not be advised as pregnancy termination does not alter the outcome.

There is a need to individualize advice on postponing pregnancy because BC treatment increases the risk of infertility and advancing age adds to that risk. Advice should be based on the individual's tumor characteristics, risk of recurrence, age, and ovarian reserve. It has been suggested that patients with good prognosis need not wait 2 years to become pregnant[16] Patients on tamoxifen can be allowed temporary interruption of therapy after 2 years to complete their family after discussing the risks.[33] An ongoing multinational trial (POSITIVE-Pregnancy Outcome and Safety of Interrupting Therapy for Women With Endocrine Responsive BC) is looking into the safety of such an approach.[22] Pregnancy did not adversely affect survival in women with BC. For BC survivors who wish to conceive, the risk of death is lowest if pregnancy occurs 6 months or more after diagnosis.[22]


  Pregnancy Outcome Top


Majority of patients achieve a term delivery; however, PAFBC is associated with an increased risk of adverse obstetric and neonatal outcome. There is an increase in cesarean delivery, very preterm delivery, small for gestational age (SGA) neonates, and low birth weight (LBW) compared to the general population.[34],[35],[36] Anthracyclines doxorubicin (adriamycin), daunorubicin (cerubidine), epirubicin (ellence), and idarubicin (idamycin) damage the heart muscle leading to risk of cardiac complications during pregnancy and labor.[18] Miscarriage rates (MRs) reported range from 12% to 40%.[12],[22] High rate of miscarriage has been attributed in part to induced abortions. Hartnett et al.[37] reported that women who conceived within a year of completing CT with or without radiotherapy had a higher risk of preterm birth and LBW (preterm birth for CT without radiation: RR, 2.4; 95% CI, 1.5–3.9; for CT with radiation: RR, 2.0; 95% CI- 1.2, 3.1) than controls. For children born to women who conceived after 1 year of treatment, risk was similar to women without history of cancer. CT may lead to miscarriage through its immunosuppressive effect, chronic anemia, physical stress, or low weight gain.[37]

Antenatal care

Close monitoring during pregnancy and labor is highly recommended. In addition to standard prenatal care and screening, evaluation of the placenta, fetus, and uterus/cervix must be done frequently. Patients may require hospitalization during the antenatal period if they have suffered any major organ system changes due to extended CT. The presence of severe cardiopulmonary symptoms may require early pregnancy termination or early delivery.


  Assisted Reproductive Technology: Requirement and Reproductive Outcome Top


Women with BC have a higher chance of reduced fertility due to gonadotoxic CT or advanced age, related to extended endocrine therapy. Thus, if they have not opted for preservation of their gametes or embryos prior to treatment or they have any additional infertility factor, they may need the help of ART to conceive. A study on oncological patients[38] going for FP reported that the mean time interval between ovarian stimulation to first frozen embryo transfer was 31 months. The PR per transfer was 43.75%, the live birth rate (LBR) was 22.72%, and the MR was 57.1%. A multicenter retrospective study done specifically on BC patients[39] looked at the impact of ART on pregnancy and long-term outcomes of young BC survivors. 198 patients were evaluated, of whom 25 underwent ART. More than 50% had hormone-sensitive disease, tumor characteristics were similar with histological grade 3 tumors being fewer in the ART group (36% vs. 59%, P = 0.033). It was found that patients in the ART group were older at diagnosis (31.4 vs. 33.7 years, P = 0.009) and conception (38 vs. 35 years, P < 0.001). They also experienced more miscarriages (23.5 vs. 12.6%, P = 0.082). Full-term pregnancies were similar in both groups (77% spontaneous and 76% ART). Follow-up at a mean of 63 and 50 months showed no difference in BC outcome between groups (P = 0.54). Another large study using records from SART database found that LBR following ART with autologous oocytes in BC patients is about 14%, while that with donor oocytes is similar to women without cancer. It is important to note that once women with cancer became pregnant, their likelihood of having a live birth does not differ significantly from women without cancer, whether donor or autologous oocytes were used.[40] The reduced pregnancy and live birth rates in women undergoing ART with their own oocytes after BC treatment underpin the importance of FP in these young patients. The option of donor oocytes, which gives better results may not to be acceptable to many patients because of religious, social, or emotional reasons.


  Breastfeeding Top


“There is no evidence that breastfeeding increases the risk of BC recurring or of a second BC developing, nor that it carries any health risk to the child. Women previously treated for BC, who do not show any evidence of residual tumor, should be encouraged to breastfeed their children” (III-B). (Green-top guidelines, Canada). Breastfeeding may pose an emotional challenge. Apart from concerns of inadequate milk production due to mastectomy or radiation, women fear cancer transmission to the baby. Moran et al.[41] reported that successful lactation can be achieved in the contralateral breast in majority of patients. Functional lactation with significantly reduced milk production was also seen in the treated breast.


  Risk of Birth Defects Top


Evidence does not suggest an increased risk of birth defects or genetic diseases in infants delivered by women previously treated with CT.[42],[43],[44],[45] Preimplantation genetic testing can be offered to women with heritable cancer.


  Conclusion Top


Economic and academic progress has led to an increase in the number of nulliparous women diagnosed with BC. Physicians are faced with the unique challenge of offering advice on FP and pregnancy to young women with BC in order that they have a better quality of life after completing cancer treatment. Parenthood represents normalcy and is a strong predictor of emotional well-being in cancer survivors.[46] The reluctance to offer advice on pregnancy arises from the fact that there are no established guidelines on PAFBC. However, evidence from retrospective studies with large cohorts and prolonged follow-up suggest[21],[22] that PAFBC treatment does not increase a woman's risk of disease recurrence even in hormone-sensitive tumors and should not be forbidden solely because of these concerns. The earlier projected benefit of PAFBC on survival rates has not been confirmed by subsequent studies and has been put down to a selection bias – the “healthy mother effect.”[14],[16],[22] Although pregnancy is deemed safe after BC, achieving pregnancy may be a challenge since fertility is diminished due to age and CT induced reduction in ovarian reserve. It has been reported that amongst all cancer groups BC patients have the lowest PR's following treatment. This may necessitate need for ART and highlights the importance of FP in BC. Results of ART in PAFBC patients are low with use of autologous oocytes but similar to noncancer patients with the use of donor oocytes or oocytes and embryos preserved prior to CT, pointing to a compromise in oocyte quality following treatment. A LBR of (44% [CI 12%–77%] compared with 33% (CI 22%–44%) per embryo transfer with oocytes and embryos cryopreserved before CT was reported in cancer versus noncancer patients.[47] Multiple studies have reported that ART per se does not compromise BC outcome.

Regarding optimal timing for achieving a pregnancy, most authors and guidelines agree that it should be 2 years for ER-−ve and 5 years for ER-+ve and node-positive patients, which allows pick-up of patients with early relapse. The DFS and OS in PAFBC patients were found to be similar to nonpregnant BC women in a follow-up for over 7 years.[22] Women on tamoxifen may be allowed to interrupt therapy after 2–3 years to allow pregnancy after a discussion on the risks. Tamoxifen should be discontinued for 3 months prior to starting pregnancy to avoid teratogenicity. There are insufficient studies addressing the risk of subsequent pregnancy in BRCA mutation women. There are no increased risks of congenital malformation in the children born; however, there is an increased risk of surgical delivery, prematurity, SGA, and LBW. MRs are high with many women electing to terminate pregnancy for fear of worsening outcome; however, pregnancy termination does not alter the course of disease. Breastfeeding should be encouraged though milk production may be reduced in the affected breast in women who have undergone breast-conserving surgery.

A multidisciplinary approach involving the patient, her medical and surgical oncologist, obstetrician, and fetal medicine specialist is essential to counsel and manage patient's expectations regarding prognosis and health of the child. Patients social support network adds much-needed value to antenatal care. In conclusion, patients should not be discouraged to attempt PAFBC as it is safe for both mother and her offspring.

Levels of evidence

  • Level I – Evidence from at least one large randomized controlled trial of good methodological quality (low potential for bias), or meta-analyses of well-conducted randomized trials without heterogeneity
  • Level II – Small randomized trials or large randomized trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
  • Level III – Prospective cohort studies
  • Level IV – Retrospective cohort studies or case–control studies
  • Level V – Studies without control group, case reports, and experts opinions.


Grades of recommendation

  1. A – Strong evidence for efficacy with a substantial clinical benefit, strongly recommended
  2. B – Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
  3. C – Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs.,), optional
  4. D – Moderate evidence against efficacy or for adverse outcome, generally not recommended
  5. E – Strong evidence against efficacy or for adverse outcome, never recommended.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Methods
Impact of Pregna...
Overall Risk of ...
Optimal Timing f...
Pregnancy Outcome
Assisted Reprodu...
Breastfeeding
Risk of Birth De...
Conclusion
References

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