Infertility in Men in Relation to Their Birth Characteristics

Abstract: Background: About 10-15 % of couples worldwide suffer from infertility, the inability to achieve a pregnancy after more than 12 months of unprotected intercourse. Causes can be related to female factors, male factors, or both. In about 20 % of the couples, the cause remains unexplained. Male factor infertility is based on semen sample evaluation and is defined as poor semen quantity or quality, preferably in two or more samples. When assisted reproductive technology (ART) is considered for a couple with male factor infertility, intra-cytoplasmic sperm injection (ICSI) where the sperm is injected into the oocyte, is often needed to achieve embryo development.Men born small for gestational age (SGA), with low birth weight (LBW, £2,5000g) and/or prematurely (before the 37th gestational week) do not become fathers as often as men born with appropriate size for gestational age (AGA) at term. The aims of the present thesis were to investigate if this lower likelihood to become a father for men born SGA, preterm, or with low birth weight could be related to an increased risk of male factor infertility, if ICSI and sperm donation more often were needed and if the chance of conceiving by ART was lower than in men born AGA. An additional aim was to investigate if sperm DNA damage was more common in men born SGA compared with men born with normal size for gestational age.Material and Methods: Paper I and II were based on retrospective case control studies on men becoming fathers by ART in study I, and infertile men, patients at the Centre of Reproductive Medicine, University Hospital, Linköping, Sweden (RMC), in study II. Paper III was based on a cohort study on all men born in Sweden between 1973 and 1993. All three studies used data from national registers held by the National Board of Health and Welfare and Statistics Sweden. Study III also used information from the Swedish National Quality Register of Assisted Reproduction.Paper IV was based on a case series study of sperm DNA fragmentation in infertile patients and sperm donors at RMC, where two different methods of measuring sperm DNA fragmentation were compared, Halosperm® (easier to perform) and Sperm Chromatin Structure Assay (reference method). Paper V was based on a cohort study of men undergoing ART at RMC. The proportion of sperm with DNA fragmentation was compared between men born SGA and men born AGA.Results and conclusions: Men becoming fathers after ART were more often born with low birth weight than men conceiving naturally. Men becoming fathers after ICSI, presuming a poor semen sample, were more often born SGA than men conceiving by conventional IVF, or conceiving without treatment. ICSI had to be performed in 63% of men born SGA but only in 45% of men born AGA. Men with male factor infertility were more often born SGA or with LBW than men with female factor infertility, or when the infertility was unexplained. The results after ART were not affected by birth weight or size at birth.The likelihood of becoming a father was lower for men born SGA or with LBW compared with men born with normal birth weight. These men were also more often single (never married or with a registered partner) and had a higher risk of being born with undescended testicles, which increases the risk of infertility. Men born SGA more often needed ICSI or sperm donation.The two different methods to analyse sperm DNA fragmentation had high correlation and agreement, and Halosperm® could be considered a reliable and more easily handled method in the clinical setting. The median proportion of sperm with DNA fragmentation were higher for men born SGA (16.6%) compared with men born AGA (6.4%). The result was not statistically significant as the absolute number of men born SGA was much smaller than expected in this sample of 550 men. Larger studies are needed to confirm the hypothesis that DNA fragmentation contributes to a lower likelihood to become a father in men born SGA.

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