Melanie: The decision of whether to become a parent is complex for people living with cystic fibrosis and it's a major factor in reproductive decision-making. Welcome to UAB MedCast. I'm Melanie Cole. And joining me today is Dr. Gretchen Winter. She's an Assistant Professor in Pulmonary and Critical Care Medicine at UAB Medicine.

Dr. Winter, it's a pleasure to have you join us today. Can you start by telling us a little bit about the reproductive goals and family building concerns faced by people living with cystic fibrosis, including fertility, pregnancy, alternative paths to parenthood, the impact of trying these options on the mental and physical health. What do we know about fertility in people with cystic fibrosis?

Gretchen Winter, MD: Yeah. You know, that's a great question. And thank you so much for having me. Just like everyone else with any other disease or no diseases at all, many people choose to become parents and want to have children. And there are concerns specifically unique to patients with cystic fibrosis that need to be considered.

Most men with cystic fibrosis are infertile and women with cystic fibrosis have higher rates of infertility than patients without cystic fibrosis. So because of that, there's obviously concerns about their ability to get pregnant. And then, there's also concerns about the potential of passing down a genetic disease to their children, as well as their ability to continue life-saving medicines while they're pregnant or breastfeeding children. And so, because of those things, it is a complex discussion on whether to become pregnant and how to become pregnant for patients with cystic fibrosis.

Melanie: Well, then, speak about the impact of CFTR modulators and what their impact on fertility is.

Gretchen Winter, MD: So we know that the majority of women with cystic fibrosis are able to conceive and carry a pregnancy to term, but infertility can occur. And there's data that the prevalence of infertility and subfertility in women with cystic fibrosis is about 20% to 35%, which is about 10% to 20% higher than the general population. And there's a lot of potential causes of that, including older maternal age, exocrine pancreatic insufficiency, malnutrition, reduced ovarian reserve. And then, a lot of people feel that might be due to altered bicarbonate secretion that actually alters pH balance and can lead to sperm capacitation failure, potential prevention of egg fertilization, and then this abnormally thick and dehydrated cervical mucus that makes it harder for sperm to penetrate the cervical os.

Now, we know that CFTR modulators have led to improved health and longevity for people living with CF. So first of all, that leads to more women now looking at it and going, "Hey, I've got a longer lifespan ahead of me, so maybe having children and a family is something that I can have in the future" and wanting to pursue those options. Now, we also know that CFTR modulators do increase fertility for women with CF. The exact effect of those CFTR modulators on fertility is not known yet, but it's thought going back to the cervical mucus that we discussed, that these modulators might decrease viscosity and then increase the pH in the cervical mucus, which promotes a more fertile environment. And additionally, CFTR modulators improve the general health and nutrition of patients with CF, so that can positively impact their fertility. And there have been multiple reports of patients who have unexpected pregnancies on CFTR modulators. And anecdotally, many CF centers have seen what we refer to as the Trikafta baby boom with a surge of pregnancies in women on Trikafta.

Now, unfortunately, for men, 97% to 98% of males with CF have infertility due to a congenital absence of their vas deferense. So without that, the sperm cannot make it into their semen and thus can't reach and fertilize an egg through intercourse. And so CFTR modulators cannot reverse that, so they are not thought to improve fertility for men with CF.

Melanie: In my research, I read about the women with CF who've been taking Trikafta and were surprised to become pregnant. As you're telling us about the CFTR modulators, what do we know, Dr. Winter, about the safety in pregnancy and even in breastfeeding and that women living with cystic fibrosis who want to get pregnant need that guidance on whether they should stop taking the modulator therapy while they're trying to conceive or when they become pregnant? What do we know about pregnancy and breastfeeding?

Gretchen Winter, MD: So each of the CFTR modulators has been tested in animal reproductive models and there have been no adverse effects noted on fetal chromosomes, organogenesis or survival. It has been seen that the administration of Ivacaftor to neonatal rats did lead to a development of neonatal cataracts. Thus, all drugs that contain Ivacaftor do require routine ophthalmologic exams in children to make sure they're not developing this cataracts. Now, those are animal studies and there are no well-controlled studies in humans of CFTR modulators in pregnancy. But the available case studies have not shown a negative effect on babies from the use of modulators during pregnancy.

Of note, there have been reported cases of pregnant women who actually clinically declined after stopping their modulators and needed to resume them during pregnancy. And of course, the health benefits to the mother of continuing the drugs must be weighed against any potential risks to her and stopping the therapy and any risks to the fetus if continuing the therapy. So a decision on whether to continue or stop a CFTR modulator during pregnancy should be made after a conversation between the patient and their CF team.

Now, you also asked about the safety and women who breastfeed and we don't have well-established data on the safety of CFTR modulators in pregnancy and lactation much like pregnancy. So CFTR modulators have been shown it's being excreted in breast milk. So because of that, the liver function should be monitored in infants who are breastfed by mothers on modulators. However, current data does not show clear harm to infants whose mothers breastfeed while on CFTR modulators. So for women who choose to breastfeed, they should have a risk-benefit discussion with their CF care team, their OB team, and their pediatrician and mainly to be aware that the baby's LFTs or liver function test will need to be monitored.

Melanie: Well then, Dr. Winter, tell us about the counseling that women should receive that are living with cystic fibrosis if they're on CFTR modulators during pregnancy.

Gretchen Winter, MD: Absolutely. There are a few things to consider. So first they should know that maternal use of CFTR modulators during pregnancy can actually result in a false negative newborn screening test. So if the father of the infant is a CF carrier or if his genotype is unknown, then the children should undergo genotyping if they have a negative newborn screen. Additionally, as mentioned before, mothers who take a medication containing Ivacaftor should be advised to consider an ophthalmologic screen for their infants. And finally, mothers with CF should also be counseled that their infants might need that liver function testing as they were exposed to CFTR modulators, both in utero and if through breast milk.

Melanie: Well, then what would you like women with cystic fibrosis to know about contraception, Dr. Winter? Is there a certain method of birth control that's most effective for women? Does Trikafta decrease the effectiveness of the pill or other hormonal contraceptive devices? Tell us a little bit about that edge of this.

Gretchen Winter, MD: Yeah, that is a great question. So unfortunately, 25% to 50% of pregnancies and women with CF are unplanned, which is thought to be because many women with CF mistakenly believe that they can't get pregnant. They think that because 98% of men with CF are infertile, that 98% of women are as well, which is not true. So a lot of them don't use contraceptives, because they think they don't need them. Studies actually show that sexually active young women with CF are less likely to use contraception than women without CF. So the first thing is to inform our patients that they can in fact get pregnant and that they do need to be using contraception if they don't want that to happen.

Now, in terms of what form, there are a number of different forms of contraception available for patients with CF and without CF. There are sterilization methods, including vasectomies for men. And for women, there's tubal ligation or tubal occlusion devices. And then, there are intrauterine devices as well. Those include both a hormonal and a copper IUD. And then, there are a number of hormonal methods and those include birth control pills, patches, and insertable ring, injections and implants. And then, of course there are your barrier methods, like condoms, spermicides, the sponge, diaphragms, and any other vaginal barrier device. And finally, there are the behavioral methods, including abstinence, withdrawal and natural family planning.

Now, the most effective methods are the hormonal implants, intrauterine devices and sterilization. But the decision on what form of contraception to be used really needs to be discussed between the patient and their CF team. And it can be based not just on the efficacy of each method, but the potential side effects and then the patient's preference for what to use. All of them are pretty effective if used appropriately and as prescribed.

Now, for patients who do use hormonal contraception, Trikafta is not expected to decrease the effectiveness of birth control. And of the CFTR modulators, only Orkambi actually interacts with hormonal contraception. So patients on Orkambi should use an alternate form of birth control other than hormonal contraception. And we have seen patients who develop a rash while they're on Trikafta and the birth control pill. So if they do develop that rash, we suggest that they're switched to a different form of birth control.

Melanie: What are some other options that exist for people with cystic fibrosis that do want to have children?

Gretchen Winter, MD: So men and women with CF can take advantage of assistive reproductive technology, including IVF and intrauterine insemination. I do note that CFTR modulators do not seem to negatively impact the sperm of men with CF, so their sperm can be used for these therapies if they desire. And then of course, surrogacy is an option for people who want to have a baby that is carried by another person during pregnancy. Most surrogacy in the US is what's referred to as gestational surrogacy, which is when the intended parents use their own eggs and sperm to create an embryo that is then placed in the surrogate's uterus. And finally, adoption is also another way to build a family for someone who doesn't want to use surrogacy or other assistive reproductive technology.

Melanie: This is such an interesting topic. And as we wrap up, Dr. Winter, can you briefly touch on screening for depression, anxiety during pregnancy and postpartum for people living with cystic fibrosis? As you in this field, please reiterate for other providers how with increased health and survival due to modulation, family planning topics are going to become more common for people living with cystic fibrosis.

Gretchen Winter, MD: Well, we know that patients with cystic fibrosis, much like patients with any other chronic disease, do have significant rates of anxiety and depression and other mental health issues. And so we screen for those routinely, whether someone is pregnant, postpartum or not. I think it's very important to recognize that pregnant patients and postpartum patients do you have high risks of anxiety, depression, postpartum depression, even postpartum psychosis associated with pregnancy, which is a lot of trauma for the body to go through, not to mention that the mental effects and the fear and stress associated with that. So just as we should be screening every pregnant and postpartum woman, and just as we should be screening every patient with cystic fibrosis, we should continue to screen, look for, and provide whatever therapies are necessary to help for these mental health disorders when they arise.

Melanie Cole, MS (Host): Thank you so much for joining us today, Dr. Winter. And for more information, please visit our website at uabmedicine. org. That concludes this episode of UAB MedCast.

I'm Melanie Cole.