Primary ciliary dyskinesia (PCD) is an umbrella term for disorders affecting the structure and/or function of cilia. These defects are due to changes (variants) on genes responsible for producing proteins required for building ciliary structures or for supporting functional processes that help cilia work appropriately.
Because both upper (sinuses and ears) and lower airways (lungs) rely extensively on ciliary activity for effective mucociliary clearance, PCD is often thought of as a respiratory disease. However, due to the genetic nature of the disorder, ANY system that relies on adequate functioning of cilia or cilia-related proteins can be impacted. While there is not a large body of reliable information on reproductive health in PCD, recent studies have helped illuminate our understanding of reproductive health in PCD, as well as offering new insights into some long-standing, but possibly erroneous beliefs.
Infertility/Subfertility vs. Sterility
Individuals with PCD may experience infertility (inability to conceive naturally) or subfertility (delayed natural conception) due to genetic changes that impact the function of cilia in the Fallopian tubes in women and the sperm tails (flagella*) in men.
Sterility refers to inability to procreate due to sperm or egg cells that are not viable—not capable of reproduction. PCD does not result in sterility. Both the egg and sperm are viable in PCD (it is possible for people with PCD to have fertility/sterility issues totally unrelated to their PCD, of course)—if the sperm and egg connect, conception can occur because the egg and sperm themselves are fine. Rather, in PCD, the problem is one of mechanics, getting the egg and sperm where they need to be.
This distinction is important because reproductive technologies and assistance may be helpful for individuals with infertility or subfertility due to PCD, while they are often less helpful for individuals who are sterile.
PCD Infertility Myths (vs. Facts vs. What we Just Don’t Know Yet)
At the time of diagnosis with PCD, many individuals are told that they will be infertile (males) or sub-fertile with a higher risk of ectopic/tubal pregnancy (females). It turns out that these long-standing beliefs are not entirely accurate. We still have a lot to learn about infertility issues in PCD, but as we learn more about PCD genetics it appears that infertility in PCD may be related to genetic profile—with some genetic variants more likely to result in infertility/subfertility. As we learn more about PCD genetics, it appears that some of the ‘conventional wisdom’ about PCD infertility may need to be reconsidered.
Myth 1: All Males with PCD are Infertile
In the past, conventional wisdom suggested that all males with PCD are infertile due to impaired sperm tail activity. However, there are numerous documented cases of spontaneous conception by men with PCD. Were these cases just outliers, exceptions to the rule? A recent PCD fertility study from France, the largest of its kind to date, suggests otherwise. In this study, 24.5% of males with PCD were able to conceive with no assistive reproductive technology (ART) (like in-vitro fertilization (IVF) or IVF with intracytoplasmic sperm injection (ICSI)). While infertility is still more common than not for males with PCD, a 25% chance of spontaneous conception is significantly better than no chance. Additionally, among the 75% who experienced infertility, roughly half benefitted from some form of ART, which resulted in successful conception.
(Possible) Myth 2: Females with PCD are Infertile/Subfertile and have a Higher Risk of Tubal Pregnancy
The picture for female infertility/subfertility in PCD is not quite as clear. Cilia line the Fallopian tubes that carry the egg from the ovaries to the uterus. In normal conception, the egg and sperm meet in the Fallopian tube and the fertilized egg is moved through the Fallopian tube to the uterus where it implants for a successful pregnancy. Impaired ciliary movement due to PCD is thought to interfere with this process and contribute to infertility or subfertility.
Additionally, medical literature suggests that women with PCD are at higher risk for ectopic (tubal) pregnancy, presumably because lack of ciliary function means the fertilized egg implants in the Fallopian tube and the pregnancy grows there, rather than in the uterus. Ectopic pregnancies are a potentially dangerous complication of pregnancy.
While large-scale fertility studies in PCD are needed to confirm or refute these beliefs, smaller studies suggest that the female fertility picture in PCD is not quite as bleak as previously believed. A small, very interesting study from Germany reported on a group of women with PCD who had spontaneously conceived despite having seriously impaired ciliary motility. By analyzing the protein composition of both respiratory and oviductal (tubal) cilia, they were able to conclude that there was no difference in the structure/function of the cilia, suggesting that the cilia in the Fallopian tubes of these women was as severely impaired as their respiratory cilia, yet the women were able to conceive naturally. The authors suggest that other factors required for egg transport through the Fallopian tube, including muscle activity and hormonal changes, may compensate for the lack of ciliary motility.
The French study cited earlier also looked at infertility in females with PCD and found that of the 36 women included, 14 (38.9%) had spontaneously conceived. The median age at spontaneous conception was 36 years and 8% reported miscarriage (compared to 10-20% for the general population). No ectopic pregnancies were reported. 22 women (61.1%) with PCD met the criteria for infertility or subfertility. Of these, six had become pregnant with the aid of ART.
PCD Infertility/Subfertility: Is it in the Genes?
In attempting to account for the differences between PCD patients who were infertile/subfertile vs. those who had conceived spontaneously, the French authors examined a number of factors. They measured ciliary motility/beat patterns among both groups and found no differences. However, when they analyzed electron microscopy (EM) results from ciliary biopsies, a clear difference emerged. Individuals with EM evidence of inner dynein arm defects with microtubule disorganization (IDA/MTD) and those whose biopsies indicated both inner and outer dynein arms were missing (2DA) were significantly more likely to be infertile/subfertile than those with other EM defects.
Using this information, they looked at the genotypes of the individuals with these EM patterns and were able to identify four genes associated with a higher risk for infertility/subfertility: CCDC39 and CCDC40 (IDA/MTD defects) and DNAAF1 (aka LRRC50) and LRRC6 (inner and outer dynein arms both absent). On the other hand, individuals with PCD caused by variants on RSPH4A appeared to be less likely to experience infertility/subfertility.
This study is pivotal, as it is the first-time genotyping has been successfully used to specifically link certain PCD genes with risk for infertility/subfertility and it demonstrates the need for further data collection and analysis to understand reproductive health issues across the entire genetic spectrum in PCD.
PCD Reproductive Health: Other Considerations
The decision to start a family is a personal one and there is no right or wrong answer. Individuals with PCD have an extra burden, because not only do they need to decide whether they can have children given the issues above, but they also must decide if it is in the best interests of their own health to pursue pregnancy and parenthood. These are very personal decisions, and each prospective parent brings their own values, priorities, support system, and individual circumstances to the equation.
Here are answers (as always with PCD, as far as we know now and subject to change) to a number of common questions related to PCD that may be helpful:
- If I have PCD will my child have PCD?
Except for rare cases of other forms of inheritance almost all currently known genetic causes of PCD are passed from parents to children in a recessive fashion. This means that the child must inherit two non-working copies of the SAME gene—one from each parent–in order to express the disorder. If the child receives one working copy and one non-working copy, they will be a carrier for PCD, but will not be affected.
A parent with PCD has inherited two non-working copies of the gene associated with their PCD from their parents, which is why they have PCD. This means that a PCD parent only has non-working copies to contribute to their offspring. If the child’s other parent has two working copies of this gene, the child will inherit one working and one non-working copy, and so will be a carrier, but will not have PCD. This is the most common situation. All biological children of a parent with recessively-passed PCD will be a carrier for PCD because all will inherit one of the PCD parent’s non-working copies of the gene in question.
In the rare instance where one parent has PCD and one parent is a PCD carrier (one working copy of the gene in question and one non-working copy), the child will either inherit the working copy from the carrier parent and be a carrier themselves or will inherit the non-working copy from the carrier parent and have PCD. But it is critical to note that this is only the case when the SAME GENE is involved.
- Is pregnancy safe in PCD?
Pregnancy puts additional stress on the body. This can be especially challenging for women with underlying conditions like PCD and bronchiectasis. Many women with PCD have successfully navigated pregnancy, but each individual’s health and personal circumstances are unique. Sometimes underlying lung status, like very low lung function, could jeopardize both the mother and the baby’s health and complicate pregnancy. In these cases, your pulmonary advisor may want to check your lung status more often. In some cases, pregnancy may be discouraged due to concerns about declining lung function.
Pregnancy with lung disease presents unique challenges, but both men and women with PCD also need to think about the realities of caring for an infant—whether biological or adopted. Lack of sleep, skipped meals, missed therapies, etc. and the general stress associated with raising young children can take a toll on parents with PCD. Ensuring a support system that will allow you to take care of your health needs is an important consideration.
- Can PCD therapies be done safely during pregnancy?
The general answer to this is yes, but this is a discussion to have with the medical professionals involved in your care—both your pulmonologist and your ob/gyn physician—to determine what is best for your personal circumstances. It is often helpful for these health professionals to be in contact with one another during the pregnancy to facilitate communication should any concerns arise.
Many individuals with PCD have successfully managed pregnancy, adoption, and raising families. We now know that spontaneous conception is more common than previously believed in PCD—so PCD IS NOT effective birth control–and that assistive reproductive technologies are available that can be instrumental in helping individuals with PCD who are experiencing infertility and subfertility achieve pregnancy.
*Flagella are distinct from cilia, but these related structures share proteins. Genetic variants known to cause PCD can also result in defective flagellar motility and sperm that cannot ‘swim’ effectively.