fbpx Sickle Cell Disease and Its Effects on Female Fertility
A white stylized profile of a woman sits against a teal background.
A white stylized profile of a woman sits against a teal background.

Sickle Cell Disease and Its Effects on Female Fertility

Some evidence suggests SCD and its treatments can negatively affect women's reproductive health.
Written by

James Anderson

Sickle cell disease (SCD) affects an estimated 100,000 people in the United States, and many of them may want to become pregnant at some point.

Although there is insufficient data regarding fertility in women with SCD, studies suggest women with the blood disorder conceive at about the same rate as women without it, according to Antoine-Jean Ribeil, M.D., Ph.D., an associate professor in medicine at the Boston University School of Medicine and the clinical director of the Sickle Cell Disease Center at the Boston University Medical Center.

Nevertheless, in some cases, SCD can create obstacles to fertility for women. This is due to the possible contraindications associated with major treatments for the illness and the debilitating consequences of this disease. It's important to note that SCD is actually a group of disorders, including sickle cell anemia, that cause red blood cells to form a "sickle" shape, as opposed to the regular, flexible, round shape.

Those crescent-shaped cells stick to one another inside blood vessels, resulting in decreased blood flow and diminished oxygen delivery throughout the body, which can cause pain and a whole host of often cumulative problems.

With child and adolescent mortality due to sickle cell disease on the decline over the past few decades, fertility has increasingly become a concern for women of reproductive age who have the disease and want to become pregnant.

Pregnancy itself poses potential problems for women with SCD, but a few precautionary notes are worth considering to ensure an individual can first become pregnant without undue difficulty when navigating the effects of the disease and the treatments for it.

Possible effects of SCD on fertility

The medical community acknowledges "the paucity of knowledge on fertility in women with SCD," according to the authors of a systematic review of literature on fertility challenges for women with SCD published in 2017 in the journal Expert Review of Hematology. Still, they also suggested that those women "have additional risk factors that can impact their ability to conceive and include chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling leading to ischemia and reperfusion injury to the ovary."

In addition, evidence suggests the onset of menarche (menstruation) and puberty can be delayed if you have SCD.

"Delayed puberty is more frequent in sickle cell anemia HbSS phenotype compared to the HbSC phenotype," Ribeil said in an email. "However, the patients should be aware that normal maturation will occur."

But other problems pertaining to getting pregnant can arise.

Fertility requires three physiological components, according to Emily Jungheim, M.D., M.S.C.I., the chief of reproductive endocrinology and infertility in the department of obstetrics and gynecology at Northwestern University's Feinberg School of Medicine in Evanston, Illinois.

"You need eggs, you need sperm and you need a uterine cavity," Jungheim said. "And in a woman with sickle cell disease, there's nothing wrong with her uterus or her fallopian tubes, and there's nothing, quite frankly, wrong with her eggs. The problem is oftentimes these women aren't ovulating."

She said women who are chronically ill often don't ovulate regularly.

"And in the case of someone who has sickle cell, what you would see most often is that they're not ovulating, simply because they're not getting the appropriate input into their ovaries to stimulate growth of follicles," Jungheim said. "That's required to get a mature egg that can then be ovulated."

Women with SCD who are ovulating may experience unpredictable ovulation.

"It's difficult to time intercourse before conception when you don't know if or when you're going to ovulate," Jungheim said. "It just makes it quite difficult to be able to conceive naturally. And so women in that scenario may need medications to help them ovulate so that they can predict [the] timing of sperm exposure so they can conceive."

Insufficient or largely absent estrogen production due to a lack of input from the hypothalamus also leaves the ovaries in a state that approximates constant rest and negatively affects both reproduction and bone health, Jungheim said.

Determination of premature ovarian insufficiency in women with SCD has been based on estimates from observational studies looking at total pregnancy rates, which have been lower than the general population. However, the data are not adequate to draw firm conclusions, according to the authors of a 2020 paper published in the journal Transplantation and Cellular Therapy. As of their writing, no study had "specifically found premature ovarian insufficiency in women with SCD who had no history of potentially sterilizing treatments."

Possible effects of SCD treatments on fertility

Therapeutics for sickle cell disease that can mitigate or resolve some or most of the issues associated with the illness are available, however, they can present a new set of fertility impediments.

A definitive type of treatment for SCD often entails administration of toxic chemotherapeutic agents, which are deliberately used to deplete the patient's bone marrow cells manufacturing the sickle-shaped blood cells and replenish them with stem cells capable of producing normal hemoglobin, Jungheim said.

"But giving those types of agents, what they do is they deplete the store of oocytes that one might be carrying such that she may have decreased chances of pregnancy later," Jungheim explained. "And so an opportunity for those women may be to bank their oocytes prior to bone marrow transplant so that they could conceive with assisted reproductive technologies later on."

Neurotherapeutic treatments might address the disease and circumvent the need for the oocyte-depleting toxic agents, she qualified.

One reason SCD is so debilitating is the immense pain it can cause. Medications taken to relieve this chronic pain create fertility concerns.

Researchers who published the 2017 review referenced above pointed to previous studies that suggested long-term opioid use contributes to infertility, and they reviewed a 2008 case-control study that compared 47 women on opioid medication to 68 individuals who were not on the painkillers. The study showed not-insignificant reductions in hormones such as estradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women taking the drugs to reduce pain.

But the reviewers, who highlighted other possible fertility problems owing to endocrine abnormalities associated with opioids, further stressed the dearth of research specifically examining the use of those treatments on the fertility of women with sickle cell disease.

"Opioids decrease the overall fertility rate in women, decrease estradiol level by 48 percent to 57 percent, and decrease luteinizing hormone and FSH levels by 30 percent—all thought to be secondary to suppression of the HPA [hypothalamic-pituitary-adrenal] axis and subsequent downregulation of gonadotropin-releasing hormone," the researchers from the 2020 Transplantation and Cellular Therapy article explained. "NSAIDs also decrease ovulation, as COX-2 inhibition reduces prostaglandin synthesis and impairs ovulation, fertilization and implantation."

Hydroxyurea, a popular FDA-approved drug used to treat sickle cell disease and reduce its pain, has been shown to contribute to infertility in men with SCD, but the effects on women with the disease are not as apparent.

Unfortunately, strong literature on gonadotoxicity in women with sickle cell anemia taking hydroxyurea is lacking, according to Kywanna Alfred, M.D., a resident doctor in the department of obstetrics and gynecology at Boston Medical Center.

"We have more data in terms of negative effects of hydroxyurea on the fetus than on oocytes/ovaries," Alfred said by email.

Authors of the 2017 article in Expert Review of Hematology advised discontinuing the use of hydroxyurea during family planning and pregnancy, in part, because of research suggesting it could be teratogenic, or capable of damaging genetic material.

They also commented on regular blood transfusion therapy, another treatment for SCD: "Regular blood transfusion therapy and subsequent endocrine dysfunction secondary to transfusion-related hemochromatosis has been described as the most common cause of primary ovarian insufficiency in individuals with β-thalassemia major [another inherited blood disorder]."

Those transfusions, the authors added, can cause iron overload (hemochromatosis) and cumulative iron deposition that adversely affect the function of the hypothalamic-pituitary-ovarian axis, which plays an integral role in fertility.

Contributors to the above-mentioned 2020 paper in Transplantation and Cellular Therapy also cited hematopoietic (stem) cell transplantation as a known cause of infertility in women, especially due to patients' exposure to alkylating agents and radiation as part of the therapy.

In a 2018 commentary in the Annals of Internal Medicine, Adrienne Mishkin, M.D., M.P.H., Markus Mapara, M.D., Ph.D., and Ran Reshef, M.D., M.Sc., all from Columbia University Medical Center, reiterated those concerns regarding the pre-transplant conditioning regimen.

"Because of the high cost of fertility-sparing treatments, especially for women who must undergo ovarian mobilization and oocyte collection [approximately $10,000 in upfront costs], many patients who undergo transplant do so at the cost of future fertility," they wrote.

While Jungheim said assisted reproductive technology might be an option for some women, ART and the techniques enabling it often remain cost-prohibitive. The Columbia doctors suggested using physician organizations to lobby for mandatory insurance coverage of ART for patients anticipating iatrogenic sterility, the type of infertility caused by medical procedures.

"In recognition of this issue, Rhode Island and Connecticut recently passed legislation requiring private insurance companies to pay for fertility-sparing treatments in advance of medical procedures that are gonadotoxic," the three co-authors explained. "This portends a new opportunity for physician organizations to encourage other states to do the same."