Pregnancy Outcomes 'Very Good' After Stem Cell Transplant

Liam Davenport

March 29, 2019

FRANKFURT, Germany — Women due to undergo hematopoietic stem cell transplant (HSCT) can be reassured that, even if they have to rely on artificial reproductive techniques (ART) to achieve a later pregnancy, the likelihood of the normal delivery or a normal weight baby is high, says an expert.

However, not all women in Europe have equal access to fertility preservation, with some HSCT patients only offered the techniques if they have a nonmalignant disease.

Nina Salooja, MD, PhD, consultant haematologist at Charing Cross and Hammersmith Hospitals, London, UK, presented data from five studies on almost 550 pregnancies in HSCT survivors.

Speaking here at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019, she showed that the rate of live births was higher, and the rate of miscarriage lower, than in controls.

Despite these good outcomes, achieving pregnancy following HSCT hinges on the availability of fertility preservation techniques, as the procedure — and especially the chemotherapy and radiotherapy — carriers a high risk of infertility, she explained.

For example, total body irradiation was associated with an approximately fourfold increased risk of miscarriage and a reduction in live birth rates of around 20%, while allogeneic HSCT appeared to triple the risk of low birth weight.

Overall, the studies showed that the live birth rates "are actually very, very good, and we shouldn't lose sight of that when I'm talking about all the potential problems," Salooja told the audience.

Various Fertility-Preserving Techniques

In the same session, Nicole Sänger, MD, PhD, head of Gynecological Endocrinology and Reproductive Medicine at Johann Wolfgang Goethe University Hospital, Frankfurt, Germany, looked at the possibilities for fertility preservation in women.

These include the use of gonadotropin-releasing hormone modulator (GnRH) analogues, ovarian tissue, oocyte and embryo cryopreservation, and fertility-sparing surgery.

Sänger said that, while there is conflicting evidence for GnRH analogues, embryo cryopreservation is an established technique.

However, oocyte preservation may be preferred for a number of reasons, particularly for women who do not have a male partner and/or do not want to use donor sperm.

She added that, for patients who have not yet reached sexual maturity, ovarian tissue cryopreservation may be the only method available, although it is still considered an experimental technique in some places.

Session co-chair Andrea Jarisch, MD, a pediatrician at Johann Wolfgang Goethe, told Medscape Medical News that the overriding factor is where the patient is treated, as practice varies from country to country, even in Europe.

She explained that although fertility preservation is performed in all patients undergoing HSCT in, say, France and the United Kingdom, the costs are not covered by health insurance in Germany.

Nevertheless, fertility preservation is being built up as a service in Germany, "and we counsel every patient and offer it where there is a very high risk of infertility, such as prior to stem cell transplantation."

However, Jarisch noted that this applies only to patients in the nonmalignant setting, not those who are receiving HSCT for malignant conditions.

She also underlined that a lot more research is required into the consequences of, for example, cryopreserving ovarian tissue over long periods of time.

In the pediatric setting, "our patients are probably 2 or 3 years old and then it takes 20 years before they want to have the tissue back."

"We need more and more science in this field and to get more information, even over the question as to whether should we do fertility preservation or not," Jarsich commented.

"Do we harm the patient with this procedure, or not? It's very tricky," she added.

Pregnancy Outcomes After HSCT

Salooja noted that there are a number of reasons why clinicians and women may worry about pregnancy outcomes following HSCT, such as the effects of radiation and chemotherapy, and issues with ART.

For example, prior radiation in childhood cancer survivors has been associated with a relative risk of miscarriage (approximately 1.65) and a risk of still birth and neonatal death (9.11).

While the data on the risk of congenital abnormalities suggest there is no increased risk in childhood cancer survivors, Salooja pointed out that the mean dose of radiation in those studies was low.

Moreover, radiation to the uterus decreases its length and overall volume, and leads to decreased endometrial thickness.

The impact can be reduced, however, by post-radiation hormone replacement, as long as the radiation dose was not too high.

In addition, the reduction or absence of blood flow in the uterine arteries in women who received irradiation in childhood has also been observed, even at relatively low doses.

These effects lead to decreased uterus elasticity and volume, with the endometrial damage affecting implantation and placental development.

Vessel damage can also decrease fetal placental blood flow.

The consequences of this can be miscarriage, preterm labor and delivery, preeclampsia, and a doubling of the risk of low-birth-weight babies.

Another potential adverse event is that women can develop cardiac damage as a result of anthracycline use, with up to 57% of patients having asymptomatic cardiac dysfunction.

This, Salooja said, may become clinically apparent during a time of stress, such as in pregnancy.

Use of ART Following Transplant

Turning to ART following HSCT, Salooja pointed to an abstract that she and colleagues from the EBMT conference presented at the American Society of Hematology annual meeting in December. The research showed that use of ART is relatively common among posttransplant patients.

The study involved 439 men and women who had undergone allogeneic or autologous HSCT between 1995 and 2015. Researchers followed them afterward when either the patients or their partners had a total of 656 pregnancies.

Of 181 women who specified the mode of conception, 33% had used some form of ART.

Among those, the most frequent method (65%) was the use of donor eggs. Other techniques included hormone stimulation, in vitro fertilization (IVF), cryopreserved embryos, and cryopreserved ovarian tissue.

Of 170 men who specified the mode of conception, 55% conceived with ART, with the techniques typically involving the use of sperm cryopreservation prior to HSCT.

The most common method of ART was intracytoplasmic sperm injection (ICSI), in 40% of cases.

Salooja noted that ART has been associated with an increased risk of birth defects in the general population.

A 2016 study by Zhu and colleagues comparing ART and spontaneous conception in almost 8000 women suggested that there is a significantly increased risk of complications following ART, including during pregnancy and in the perinatal phase, alongside neonatal complications.

Salooja underlined, however, that, in the general population, ART is designed to "circumvent the natural selection processes that are characteristic of sexual reproduction".

In other words, there are underlying factors in the non-cancer population "that made someone infertile in the first place," and it is these underlying factors that may be linked to poorer outcomes, rather that the ART.

Potential Problems in Pregnancy After HSCT

The potential issues for couples contemplating having children following HSCT do not end at conception, which may have required ART.

The list of things that "could go wrong" relating to pregnancy after HSCT is daunting, and includes miscarriage, preterm birth, stillbirth and neonatal death, low birth weight, cardiac decompensation, gestational diabetes and hypertension, severe preeclampsia, placental problems, postpartum hemorrhage, and offspring cancer.

The story becomes more optimistic, however, when actual pregnancy outcomes in HSCT patients are examined, Salooja commented.

While there is a lack of large-scale studies, Salooja brought together data from five studies conducted over the past 20 years, involving 549 pregnancies in 362 HSCT survivors.

Live birth rates across the studies were generally high, at 79% to 93% among women who became pregnant after HSCT and 83% to 88% among male survivors whose partners became pregnant.

This compares with a "live birth" rate among 401 nearest-age sibling controls of 72% for women and 78% for men, in a study by Carter and colleagues from 2006.

The exception to these data were the results among patients who had undergone total body irradiation prior to their transplant, in whom the live birth rate was 65%.

Salooja said that the rate of congenital abnormalities, although reported on less often in the studies, also seemed to be comparable — if not better — than the rate seen in controls, and there was no significant difference in the rate of stillbirths.

Hypertension during pregnancy was no more likely among women who had previously undergone HSCT than among women in the control group, and there was no increase in the rate of placental previa/abruption.

Strikingly, the available data suggested that the rate of miscarriage was lower than the rate seen in controls.

The notable exception was, again, a high rate of miscarriage among women who had previously undergone total body irradiation, who had rates of 21-28% vs 6-10% in controls.

The prevalence of low birth weight was higher among women who had undergone allogeneic HSCT, at 23-25% vs 6-7% among controls.

Among women who had received total body irradiation, the rate of low birth weight increased even further, to 42-46%.

Premature birth showed a similar pattern. The rate was 6-10% among controls, but rose to 20-25% among recipients of allogeneic HSCT, and up to 27%-62.5% in women who had undergone total body irradiation.

Salooja ended her talk by noting that, while pregnancy outcomes following HSCT are generally good, for many complications, such as gestational diabetes, severe preeclampsia, and postpartum hemorrhage, "we really just don't know."

As to the question as to whether there is an increased rate of cancer in the offspring "we have no data on this at all."

She added that she would "like to reiterate my personal feeling, which is that we really need to collect prospective long-term data."

Salooja, Sänger, and Jarisch have disclosed no relevant financial relationships.

European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019: Abstracts W4-1, W4-4. Presented March 25, 2019.

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