Human Reproduction, Vol. 16, No. 10, 2238-2241,
October 2001
© 2001 European Society of Human Reproduction and Embryology
Fetal antecedents of male factor sub-fertility: how important is birthweight?
Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Aberdeen, Scotland
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Abstract |
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BACKGROUND: Severely reduced fetal growth has been linked to gonadal dysfunction. The aim of this study was to explore the link between birthweight and subsequent male infertility using the Aberdeen Maternity and Neonatal Databank (AMND). METHODS AND RESULTS: Assuming 80% power at the 5% significance level, a minimum of 126 men (63 in each group) was required to show a mean difference of 0.5 (SD = 1) in the standardized birthweight scores between cases and controls. Men born locally with unexplained male factor infertility (n = 79) were identified from the infertility clinic database. Men with normal semen parameters, born in Aberdeen and attending the infertility clinic with their partners (n = 104), served as controls. The pregnancy records of these men's mothers were obtained from the AMND and a standard case–control analysis performed. In addition to standardized birthweight scores, the following variables were studied: crude birthweight, social class, maternal age, parity, obstetric history, antepartum and peripartum events. CONCLUSIONS: No differences were found between the two groups, suggesting that low birthweight is unlikely to affect male fertility in later life.
Key words: birthweight/fetal antecedents/male subfertility
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Introduction |
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Male infertility accounts for 30% of all cases of infertility and contributes to the problem in a further 25% of cases (Templeton and Drife, 1992
). In at least half of the identified cases the causal factors are unknown. Reports of decreasing sperm counts in men (Irvine et al., 1996) have generated considerable interest in this field and led to speculation about the role of preventable factors.
Reduced growth in utero as a cause of chronic disease in adulthood is not a new concept (Barker, 1989). Links between low birthweight and raised blood pressure in adult life have been extensively demonstrated. The association between male gonadal dysfunction and severely reduced fetal growth has also been made (Silver, 1953; Anghern et al., 1979). Francois et al. found standardized birthweight scores to be higher in men with normal semen analysis compared with those with unexplained male subfertility (Francois et al., 1997). Although this study was unable to establish a definite link between low birthweight and male subfertility, it highlighted the need for further work in this area.
The Grampian Region in Scotland is in a unique position to support longitudinal studies. The population can be considered to be fairly stable (60% of primigravida delivering in Aberdeen are born locally). The Aberdeen Maternity and Neonatal Databank (AMND) contains information on all obstetric and fertility related gynaecological events in women who have delivered in Aberdeen City District since 1951 (Samphier and Thompson, 1982). Stringent and consistent data relating to clinical events as well social and lifestyle factors are available. In addition, Aberdeen Maternity Hospital offers secondary as well as tertiary level fertility care to all couples in this region. The Fertility Database contains detailed case records of more than 3000 couples since 1992. This information includes history, examination and results of investigations.
We aimed to match data from the two databases to allow us to compare birthweights, as well as antenatal and perinatal factors, between a group of men with abnormal semen parameters and a control group.
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Methods |
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Men with male factor infertility according to World Health Organization (WHO) guidelines (World Health Organization, 1999
) were identified from the Fertility Database. The computerized records of these men were scrutinized to exclude known causes of subfertility such as vasectomy, reversal of vasectomy, other testicular surgery, testicular maldescent, injury, mumps, testicular torsion or varicocele. Males with `normal' semen parameters according to WHO criteria (World Health Organization, 1999) attending the Fertility Clinic were identified from the Fertility Database as the control group. For each individual, at least two semen analyses were included in the statistical analysis. The mean (SD) abstinence time was 5.1 (2.4) days. Maternal obstetric records of men born in Aberdeen were identified by matching the surnames and dates of birth of the men with the surnames and date of delivery of their respective mothers. A list of relevant obstetric and neonatal factors that could affect intrauterine growth was drawn up and then extracted from the AMND in the form of a Statistical Package for Social Sciences (SPSS) file. The variables examined were: maternal age, maternal height, maternal weight, number of cigarettes smoked/day, husband/partner's social class, antepartum haemorrhage, pre-eclampsia, diabetes, mode of delivery, gestation period at delivery, birthweight, placental weight, standardized birthweight score, Apgar score at 1 min and Apgar score at 5 min. Socio-economic class was evaluated according to the husbands' occupation and was classified according to the Registrars' General Classification using five groups: I-II, professionals; III, skilled manual and non-manual workers; IV, non-skilled manual workers; and V, others such as armed forces.
The Standardized Birthweight Score (SBS) was calculated using the following formula:
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Birthweight scores are standardized for sex, parity and gestational age and allow comparison between subjects and the total population. A score of 0 implies no deviation from the population mean, while scores of –1 or +1 indicate a negative or positive deviation from the mean by 1 standard deviation (SD). For the purposes of this study, we looked specifically at the mean SBS in the two groups as well as the numbers of cases with SBS of –2.5 or –1 (indicating low standardized birthweights) in the two groups.
Statistical Analysis
Assuming 80% power at the 5% significance level, a minimum of 126 men (63 in each group) were required in order to show a mean (SD) difference of 0.5 (1) in the standardized birthweight scores between cases and controls.
Data analysis was performed using SPSS Version 9 for Windows. Statistical significance was set at P 
0.05. Categorical variables were analysed using the 
2 test. Continuous variables were presented as either mean ± SD or median, interquartile range (IQR) and analysed using either the Student's independent t-test or Mann–Whitney U-test depending on the normality of the data.
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Results |
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A total of 183 men were correctly matched with their mother's obstetric records. This included 79 `cases' and 104 `controls'. All sperm parameters examined were significantly higher in the `controls' than in the `case' group (Table I
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Maternal characteristics in the two groups are shown in Table II
. Maternal age and parity were comparable in the two groups. The mean (SD) maternal age was 25.2 (5.4) years in the study group and 25.9 (5.9) years in the control group. The mean (SD) maternal height in the study group was 158.8 (5.7) cm versus 160.3 (5.5) cm in the control group. Maternal weight was excluded from the analysis due to insufficient data as only eight values were recorded.
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From the data available it appears that there was no significant difference in the incidence of smoking between the study and control groups. The incidence of antepartum haemorrhage and hypertensive disease was also comparable. There was no record of diabetes in women of either group.
Fetal factors are shown in Table III. The majority of confinements in either group ended in spontaneous vaginal delivery. The median (IQR) gestational age at time of delivery for both groups was 41 (39–41) weeks. The mean (SD) birthweight in the study group was 3435 ± 501 g while in the control group it was 3368 ± 524 g (not significant) (Figure 1). The mean (SD) standardized birthweight scores in the study and control groups were 0.009 ± 1.03 and –0.006 ± 1.01 respectively (not significant) (Figure 2). In comparison, the mean (SD) birthweight for the general male population born during the same period was 3365 (536) g (not significant). The corresponding mean (SD) standardized birthweight score was +0.01 (1.00) (not significant).
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The proportion of low birthweight babies (<2500 g) was comparable in both groups (Table III
). The mean placental weight (SD) in the study group was 598 (139) g versus 616 (110) g in the control group (N/S). |
Discussion |
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The results of this study fail to show any correlation between birthweight and subsequent male infertility. The unique nature of the AMND has allowed an accurate and relatively detailed examination of data surrounding antenatal and perinatal events in a manner that studies relying on patient questionnaires would find difficult to achieve.
SBS was used to compare the birthweights between the study and control group. These scores are corrected for gestational age, sex of the baby and parity of the mother (Campbell et al., 1993) and provide the most accurate way to study birthweight in epidemiological studies of this nature. While we felt that that SBS allowed for a more robust measure of growth restriction than crude birthweights, the data were analysed using both parameters. In fact, there were no differences between the study and control groups in terms of either SBS or the crude birthweight.
However, the study does suffer from a number of weaknesses. The control group was identified from the Fertility Clinic database. Men attending the clinic (even as partners of women with known causes of infertility) may not be fully representative of a normal fertile population. Despite having sperm parameters that fall within reference values for fertile men (World Health Organization, 1999), the possibility that some of them could suffer fertility-related problems cannot be excluded.
The limited obstetric records kept between 1951 and 1975 meant that information regarding a number of key maternal factors was unavailable. These include important variables like maternal weight, smoking, alcohol intake and use of drugs, which have all been shown either to affect fetal growth (Kramer, 1998) or, in the case of oestrogenic drugs, increase the risk of male reproductive anomalies (Dieckmann et al., 1953). Our inability to adjust for the effects of these confounders is likely to compromise the reliability of our findings.
In addition, this study was designed to explore differences in standardized birthweight and has limited power to draw any meaningful conclusions about the impact of antenatal and perinatal factors on subsequent male infertility.
Our results differ from those presented by Francois et al. who used a slightly smaller sample size and a different method of data collection (Francois et al., 1997). Details of birthweight and gestational length in their study were obtained using questionnaires; a method which has the potential to introduce recall bias (Schlesselman and Stolley, 1982). The authors of this project concluded that a link between low birthweight and male infertility did exist, and that severe intrauterine growth retardation occurring over a critical period of male gonadal development could be the causal factor.
Another study by Francois et al. suggested an association between unexplained male pseudo-hermaphroditism and reduced prenatal growth (Francois et al., 1999). However, direct comparison of our results with this conclusion is inappropriate due to clinical differences between the study populations.
A number of maternal factors including age, height and weight have been historically linked to birthweight (Nandi et al., 1992; Wessel et al., 1996; Kramer, 1998). Low socio-economic class and low income have also been found to cause low birthweight either by a direct effect (Gould and LeRay, 1988), or by their association with high parity (Wessel et al., 1996). We were unable to compare maternal weight in this study due to lack of data, but could not demonstrate a link between either maternal age or height with subsequent male fertility problems in the offspring. Our data also fail to show a correlation between social class or parity and subsequent male subfertility. Despite the known association between pre-eclampsia and intrauterine growth restriction (Haelterman et al., 1997; Xiong et al., 1999) our results fail to implicate either of these conditions as risk factors for subsequent infertility in the child. There is a suggestion that low birthweight is more common among babies presenting by breech (Rayl et al., 1996). We have failed to show any association between mode of delivery and subsequent semen quality. However, in view of the relatively small numbers studied, our findings relating to the impact of antenatal and perinatal factors should be interpreted with caution.
The Barker Hypothesis (Barker et al., 1989) implies that permanent changes in the structure or function of an organism are due to specific environmental changes in utero. It is evident that these changes must occur over a particular period of development—the `critical window.' The concept of in-utero programming of adult disease suggests that factors responsible for male infertility could operate during a `critical' period of gonadal development even though the final birthweights are normal. (Lucas, 1991; Leon, 1998). Although the design of our study does not allow us to rule out a common intrauterine insult which could explain both pathologies, the lack of association between birthweight and semen quality suggests that the possibility of two separate `critical windows' cannot be ruled out.
The results of this study indicate that birthweight is unrelated to sperm quality in adult life. More work in this area is needed to examine the effects of antenatal and perinatal factors, particularly those affecting testicular development in the early weeks of gestation.
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Notes |
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1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, Scotland. E-mail: ogy162{at}abdn.ac.uk
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Submitted on May 17, 2001; accepted on July 13, 2001.
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