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Beyond the issues of paternal age discussed earlier, there is the evidence that structural chromosomal abnormalities, which occur in 0.25 percent of births, more frequently have their origin in paternal chromosomes. In a 2006 report, 72 percent of de novo unbalanced chromosomal rearrangements were of paternal origin.⁴⁷⁴ The likelihood of having a translocation doubled every 10 years after the age of 25.⁴⁷⁵ An American Cancer Society Study of 2,532 cases of hematological cancers noted that men over 35 had a 63 percent higher risk of having affected offspring when compared with those under 25.⁴⁷⁶ A small, but statistically significant increased risk of nonchromosomal congenital malformations associated with advanced paternal age was reported by the National Birth Defects Prevention Study.⁴⁷⁷ Malformations included were cleft lip, diaphragmatic hernia, right ventricular outflow tract obstruction, and pulmonary stenosis.

About 10 percent of couples have infertility. A World Health Organization multicenter study concluded that the problem appeared predominantly in males in 20 percent of cases, predominantly in females in 38 percent, and in both partners in 27 percent. In the remaining 15 percent of cases, no definitive cause for the infertility was identified.⁴⁷⁸ Care should be exercised in the preconception counseling of a couple with a history of infertility. In the absence of a recognizable cause, karyotyping of both is recommended. Unrecognized spontaneous abortions may have occurred without the patient's awareness, caused by overt structural chromosome rearrangements or microdeletions or duplications (see Chapters 11 and 13). Microarrays performed after routine cytogenetics on products of conception in 2,389 cases revealed significant copy number changes or whole‐genome uniparental disomy in 1.6 percent and 0.4 percent of cases, respectively.⁴⁷⁹ A study of 1,300 infertile men revealed chromosomal abnormalities in 10.6 percent and Y‐microdeletions in 4.0 percent.⁴⁸⁰ Recognized habitual abortion due to the same causes would also require cytogenetic analysis. Such studies may reveal a parent (rarely both) with a chromosomal rearrangement with significant risks for bearing a child with intellectual disability and/or malformations, who could benefit from prenatal or preimplantation diagnosis.

Other examples of disorders characteristically associated with recurrent pregnancy loss or infertility include premature ovarian failure in fragile X syndrome carriers (see Chapter 16), and the X‐linked disorders steroid sulfatase deficiency⁴⁸¹ and incontinentia pigmenti.⁴⁸² Thrombophilia as a significant cause remains uncertain.^{483, 484} In about 8 percent of women experiencing recurrent abortion a mutation in the SYCP3 gene (which encodes an essential component of the synaptonemal complex, key to the interaction between homologous chromosomes) was noted.⁴⁸⁵ An extensive list of genes related to premature ovarian failure have been recognized,⁴⁸⁶ especially noteworthy in a highly consanguineous population.⁴⁸⁷ Consequently, next‐generation sequencing⁴⁸⁸ or whole‐exome sequencing,^489–492 cost issues aside, would be indicated.

Although the investigation to determine the cause of male or female infertility can be extensive, several observations are pertinent here. We recognized that congenital bilateral absence of the vas deferens (CBAVD),⁴⁹³ which occurs in 1–2 percent of infertile males, is primarily a genital form of CF (see Chapter 15). Men with CBAVD⁴⁹⁴ should have CF gene analysis (sequencing, poly T variant analysis, deletion analysis). A meta‐analysis concluded that among CBAVD patients, 78 percent had one recognizable CFTR gene mutation whereas 46 percent were noted to have two mutations.⁴⁹⁵ The mutation detection rate is likely to exceed 92 percent including large gene rearrangements.⁴⁹⁶ Of interest is the observation of Traystman et al.⁴⁹⁷ that CF carriers may be at higher risk for infertility than the population at large. Men who test negative for a CFTR mutation should have the ADGRG2 gene on the X chromosome sequenced.^{498, 499}

Some patients with CBAVD (21 percent in one study⁵⁰⁰) also have renal malformations. These patients may have a normal sweat test and thus far no recognizable mutations in the CF gene.^{500, 501} Renal ultrasound studies are recommended in all patients with CBAVD who have normal CFTR analyses. The partner of a male with CBAVD and a recognized mutation(s), after gene analysis, should routinely be offered sequencing and deletion analysis of the CFTR gene. Such couples frequently consider epididymal sperm aspiration,^{502, 503} with pregnancy induced by IVF. Precise prenatal and/or preimplantation genetic testing can be achieved only if specific mutations have been recognized.

Significant male infertility is mainly associated with XXY males (see Chapter 12), autosomal translocations, Kallman syndrome, Y‐microdeletions, autosomal inversions, CBAVD, mixed gonadal dysgenesis, and X‐linked and autosomal gene mutations.⁵⁰⁴ We reported a 28‐year‐old with azoospermia and bilateral congenital cataracts associated with a contiguous deletion including the Nance–Horan gene at Xp23.13 and implicating the SCML1 gene.⁵⁰⁵ The global prevalence of Yq microdeletions approximates 7.5 percent in infertile males.⁵⁰⁶ Genes including DAZ (“deleted in azoospermia”), YRRM (Y chromosome RNA recognition motif),^{507, 508} and others may be deleted singly or together in the region of Yq11.23.⁵⁰⁹ Couples must be informed that male offspring of men with these interstitial deletions in the Y chromosome will have the same structural chromosome defect. The female partner of the male undergoing intracytoplasmic sperm injection (ICSI) needs explanations about procedures and medications for her that are not risk free. Patients should realize that ICSI followed by IVF is likely to achieve pregnancy rates between 20 and 24 percent,⁵¹⁰ a success rate not very different from the approximately 30 percent rate in a single cycle after natural intercourse at the time of ovulation.⁵¹⁰ Pregnancy follow‐up data from cases culled from 35 different programs reported in a European survey⁵¹¹ and a major American study of 578 newborns showed no increased occurrence of congenital malformations.²¹⁴ However, a statistically significant increase in sex chromosome defects has been observed.⁵¹² Prenatal diagnosis is recommended in all pregnancies following ICSI.

Even “balanced” reciprocal translocations in males may be associated with the arrest of spermatogenesis and resultant azoospermia.⁵¹³ In one series of 150 infertile men with oligospermia or azoospermia, an abnormal karyotype was found in 10.6 percent (16/180), 5.3 percent (8/150) had an AZF‐c deletion, and 9.3 percent (14/150) had at least a single CF gene mutation.⁵¹⁴ This study revealed a genetic abnormality in 36/150 (24 percent) of men with oligospermia or azoospermia. A Turkish study of 1,696 males with primary infertility showed 8.4 percent with a chromosomal abnormality and 2.7 percent with a Y‐chromosome microdeletion.⁵¹⁵

Rarer disorders may need to be considered in the quest to determine the cause of infertility including, for example, the blepharophimosis, ptosis, epicanthus inversus syndrome, which may respond to treatment.⁵¹⁶

In a study of 75,784 women to determine all‐cause and cause‐specific mortality, those with infertility had a 10 percent increased risk of death from any cause.⁵¹⁷ Death from breast cancer was more than doubled. In a major prospective Danish study, 3,356 women who had children born after frozen embryo transfer were compared with 910,291 fertile women. The incidence rate of childhood cancer was 17.5 per 100,000 for children born to fertile women, and 44.4 per 100,000 in children born after the use of frozen embryos.⁵¹⁸ The statistically significant increased risk was primarily leukemia and sympathetic nervous system tumors. The cause(s) remain unknown. A US study did not find a significant association, but had a shorter follow‐up period (<5 years), follow‐up loss, and incomplete maternal data.⁵¹⁹ In a retrospective study using insurance data, the records of 19,658 infertile women and 525,695 fertile women were examined to determine severe maternal morbidity.⁵²⁰ The overall incidence of severe maternal morbidity among women receiving fertility treatment was 7.0 percent compared with 4.3 percent in fertile women.