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Developmental Biology - InFertility

Boys Born Small Have a Higher Chance of Infertility

Baby boys born small for gestational age have increased risk of infertility in adulthood...

Baby boys who are born small for their gestational age are at increased risk of having fertility problems in adulthood, according to research published December 13, 2019 in Human Reproduction.

Researchers in Denmark looked at 5594 men and 5342 women born between 1984 and 1987 and followed them through to adulthood until the end of 2017. They found that men who had been born small for gestational age had a 55% increased risk of infertility as adults compared to men born within the appropriate weight range for gestational age. However in women, no such link was found between gestational age and infertility.
"Among the men who were born small for gestational age, we found that 8.3% had been diagnosed or were being treated for infertility by the end of 2017 compared to 5.7% of men born within an appropriate weight."

Anne Thorsted PhD, Department of Public Health, Aarhus University, Denmark.

Small for gestational age is defined as babies having birth weights in the bottom 10% according to each week of gestation compared to other children of the same gestational age. For instance, the weight range for babies born at full term (40 weeks) was between approximately 2500-4500 grams (5.5-9.9 Ibs) in this study, so full-term babies born weighing less than 3000 grams were defined as being small for gestational age and weighed less than 90% of other children of the same gestational age.

Previous research has suggested a link between restricted growth of the fetus in the womb and a two to three times increased risk of penis and testicular problems in boys; in particular, hypospadias (a malformation where the opening of the urethra is not at the tip of the penis), cryptorchidism (undescended testis) and testicular cancer. These conditions are linked to fertility problems. However, there have been few and conflicting studies on the link between birth weight for gestational age and infertility.

In the current study, when researchers excluded men born with hypospadias or cryptorchidism, the link between being born small for gestational age and infertility weakened. They found a statistically non-significant 37% increased risk of infertility among the remaining men, with 7.3% of men born small for gestational age being infertile compared to 5.6% of men born with the appropriate weight.
"This may indicate that part of the association between gestational weight and infertility is mediated by the effects of hypospadias and cryptorchidism, which are known to be related to later risk of infertility."

Thorsted believes it is not yet clear what the potential mechanisms could be for a link between birth weight and infertility.
"A suboptimal growth environment for the fetus, for whatever reason, could itself be detrimental to the development of sperm production and reproductive organs. It could also be speculated that the mother's health and lifestyle during pregnancy could affect both fetal growth and development of reproductive functions. For example, we know if a mother smokes, this can have an impact on the fetus. It may well be that cryptorchidism, hypospadias and infertility have common origins in fetal life.

"Our results show that sometimes we must look at very early life to find explanations of health problems occurring later in life."

Anne Thorsted PhD.

Men and women in the study were all singleton births, born in two Danish regions, Aalborg and Odense, between 1984 and 1987. Researchers obtained information on birth weight and gestational age from birth records, retrieving information on infertility diagnoses and fertility treatments from the Danish National Patient Registry and the Danish In Vitro Fertilisation registry.

Mothers of all participants had completed a questionnaire during pregnancy asking age, lifestyle (smoking and alcohol consumption), health (including body mass index) and sociodemographic status (employment and whether or not the parents lived together). At the end of the follow-up period in 2017, the average age of participants was 32.

Strengths of the study include its large numbers and high participation rate (87%) among pregnant women involved in the "Health Habits for Two" study. Additionally, the availability of data from the Danish registers resulted in a 98% follow-up rate for the participants, reducing the risk of bias and making it a representative sample.

Researchers acknowledge that participants had not reached the end of their reproductive life by 2017 and it would be interesting to see what the situation was in another ten years' time.

Limitations of the study include that different methods were used for estimating gestational age, and that participants were classified as infertile if they either had a diagnosis of infertility or were part of a couple seeking fertility treatment, thus including lesbian and single mothers.

However, when researchers excluded all participants with missing information of cause of infertility, the risk of infertility among men born small for gestational age increased from 55% to 88%, suggesting this might reflect the true risk of infertility in this group more accurately.
About 12.5% of couples are affected by infertility, unable to conceive for one year or longer.
• A third of cases = Male infertility
• A third of cases = Female infertility
• A third of cases = Both infertile/no known cause.

Is birth weight for gestational age associated with infertility in adulthood among men and women?

Being born small for gestational age (SGA) was associated with infertility in adulthood among men.

Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent.

In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants’ 18th birthday and up until 31 December 2017.

Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age.

Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09–2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93–2.01). No association was found between women’s birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73–1.37).

Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared.

Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further.

A Thorsted, J Lauridsen, B Høyer, L Arendt, B Bech, G Toft, K Hougaard, J Olsen, J P Bonde and C Ramlau-Hansen.

This study was supported by Health, Aarhus University. No competing interests are declared.

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Dec 26 2019   Fetal Timeline   Maternal Timeline   News 

Excluding all participants with missing information for cause of infertility,
the risk among men born small for gestational age increased from 55% to 88%.
CREDIT Irish Times (no copyright infringment intended).

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