Cystic fibrosis results in the production of an abnormally thickened mucous secretions in various body organs, including lungs, pancreas, bowel and biliary ducts. This causes obstruction and chronic inflammation and progressive organ failure.4 Q4 How can cystic fibrosis cause infertility?A4. Cystic fibrosis in the male is associated with bilateral absence of the vas deferens which is the tube that conveys the sperm from the testicles to the urethra. In the female, cystic fibrosis causes infertility via cervical canal or fallopian tubal obstruction due to the production of viscid and tenacious cervical and tubal secretions.
5 Q5 What is the first step in initiating PGT treatment?A5. Cystic fibrosis is one of the most common indications for PGT, and almost 10% of all PGT cycles performed worldwide are to avoid a pregnancy affected with cystic fibrosis. It is important that couples considering PGT receive adequate genetic counseling before starting the treatment process to understand the testing and the available reproductive options.
References
1 1 Welsh MJ, Denning GM, Ostedgaard LS, Anderson MP. Dysfunction of CFTR bearing the delta F508 mutation. J Cell Sci Suppl. 1993; 17:235–9.
2 2 van der Ven K, Messer L, van der Ven H, Jeyendran RS, Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum Reprod. 1996; 11: 513–7.
3 3 Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, White MB, Milunsky A. Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA. 1992; 267:1794–7.
4 4 Grangeia A, Sá R, Carvalho F, Martin J, Girodon E, Silva J, Ferráz L, Barros A, Sousa M. Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens. Genet Med. 2007; 9:163–72.
5 5 Girardet A, Viart V, Plaza S, Daina G, De Rycke M, Des Georges M, et al. The improvement of the Best Practice Guidelines for Preimplantation Genetic Diagnosis of cystic fibrosis: towards an international consensus. Eur J Hum Genet. 2016; 24(4): 469–78.
6 6 Davis L, Champion S, Fair S, Baker V, Garber A. A cost‐benefit analysis of preimplantation genetic diagnosis for carrier couples of cystic fibrosis. Fertil Steril. 2010; 93:1793–1804.
7 7 Chamayou S, Sicali M, Lombardo D, Alecci C, Ragolia C, Maglia E, et al. Universal strategy for preimplantation testing for cystic fibrosis based on next generation sequencing. J Assist Reprod Genet. 2019; 37(1):213–212. DOI: 10.1007/s10815‐019‐01635‐2.
8 8 Guggino WB, Cebotaru L. Adeno‐associated Virus (AAV) genetherapy for cystic fibrosis: current barriers and recent developments. Expert Opin Bio Ther. 2017; 17:1265–73.
7 The patient on medication
Pedro Meloand Arri Coomarasamy
University of Birmingham and Birmingham Women’s Hospital, Birmingham, UK
Case History 1: A 26‐year‐old woman with Crohn’s disease presents for IVF treatment. She has never had abdominal surgery, and her gastrointestinal symptoms have been well controlled with azathioprine and adalimumab. However, her general practitioner has expressed concerns about continuing these two drugs in pregnancy.
Case History 2: Despite advice to avoid herbal medicines, a woman undergoing IVF treatment insisted on taking echinacea as she believed this herbal remedy boosted her immune system and reduced the risk of implantation failure, which she had suffered in two previous IVF cycles.
Background
Drugs may be harmful in pregnancy, with women and clinicians alike fearing their impact upon fetal development and growth. Congenital developmental disorders have been the subject of tales dating all the way back to prehistoric times and were initially attributed to supernatural causes [1]. In the 19th century, the concept of teratology as the study of developmental malformations in an embryo or fetus was first introduced by I. G. de Saint‐Hillaire [2]. Later on, in the 1930s, Hale described a set of experiments where pigs deprived of vitamin A exhibited a lack of eyeballs, pioneering experimental teratology as a modern science aimed at identifying possible causes of congenital defects [3]. The widely known thalidomide episode in the 1960s, where pregnant women exposed to this antiemetic gave birth to babies with limb deformities, remains a prime example of drug toxicity and its potential catastrophic effects in the offspring of healthy mothers [4].
Today, caution is advised to clinicians prescribing drugs for women who are pregnant or trying to conceive. This stems, to an extent, from a paucity of good‐quality data on safety of medications in pregnant women, who are often excluded from preapproval drug studies [5]. Yet pregnant women, and those trying to conceive, are frequently prescribed drugs with teratogenic potential. This may be due to preexisting medical conditions where the therapeutic benefits of a certain drug are thought to outweigh the teratogenic risk attributed to the medication [6–13]. For example, in the UK, 1 in every 164 women received a United States Food and Drug Administration (FDA) Pregnancy Risk category X prescription in early pregnancy between 1991 and 1999 [6]. Furthermore, over‐the‐counter medications are also used by a majority of women in early pregnancy [14,15].
Women planning to get pregnant, and particularly those undergoing assisted reproductive technology (ART) treatment, often present to their clinicians asking about drug safety in the preconception period and early pregnancy.
Management options
Drugs in the preconception stage and early pregnancy
Historically there has been a reluctance from researchers to enroll pregnant women in research trials, mostly due to fears of harm to the fetus [10]. Pregnant women are thus underrepresented in interventional studies, with efficacy and safety data often being extrapolated from analyses conducted in nonpregnant women. Cohort, registry and case‐control studies are the main sources of safety data of drugs in pregnancy, frequently relying on linkage methodology [7–10,15,16], while controlled interventional studies in pregnancy are often underpowered and focus mostly on labor and delivery rather than drug pharmacokinetics or teratogenicity [11,14,17]. In recent years, however, there has been an increasing number of scientists advocating a fair and representative inclusion of pregnant women in research [17,18].
In 1979, the FDA introduced a five‐letter risk classification to inform clinicians and women about a drug’s potential to cause congenital abnormalities if used in pregnancy (Table 7.1) [19]. This has recently been updated to a labeling system containing narrative summary information thought to be more patient‐friendly [20]. In the UK, the British National Formulary (BNF) simply categorizes drugs into those which may have harmful effects in pregnancy (indicating the potential abnormalities and trimester of risk) and those which are not known to be harmful in pregnancy [21].
The effects of drugs on pregnancy in general, and embryo development in particular, depend on a myriad of factors such as dose, duration of treatment, gestation of use, genetic susceptibility and placental clearance function [22]. In the first two weeks following fertilization, there is an “all‐or‐nothing” effect whereby drugs will either induce miscarriage or allow gestation to continue, although during this period certain exposures can still negatively affect surviving embryos [23]. The time of greatest teratogenic risk extends from the third to the eleventh week of pregnancy, when the basis of organogenesis is established [21]. Following the first trimester of gestation, adverse drug effects may result in growth restriction or disorders of the central nervous system and other organs,
