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Heijmans, F. Helmerhorst, R. Westendorp, Gender-specific association of the factor V Leiden mutation with fertility and fecundity in a historic cohort. This was studied in subjects who were of childbearing age in a time with minimal fertility control without modern contraceptive methods.
Of subjects the FVL status was analysed, in male and female subjects. Fertility was not affected by FVL status. In female subjects, fecundity was not influenced by FVL status. The FVL mutation induces a hypercoagulable state which increases the risk of venous thrombosis three- to sevenfold among heterozygous carriers and about eightfold among homozygous carriers compared to non-carriers Rosendaal et al. The persistence and high prevalence of the FVL mutation in the general population suggests that it may carry an evolutionary advantage. Briefly, this theory states that ageing is due to the decline of the force of natural selection late in life and that the fixation of alleles with positive effects upon fitness early in life also have deleterious effects late in life.
Some evolutionary benefit of FVL mutation in females may lie in the fact that women who carry the FVL mutation lose less blood in menstruation, have higher haemoglobin levels and possibly have a lower incidence of life-threatening post-partum haemorrhage Lindqvist et al. On the other hand, FVL mutation in females might also be associated with negative outcomes of reproduction such as recurrent abortion, pre-eclampsia, prematurity and small-for-gestational-age neonates De Groot et al.
As the inheritance pattern of FVL can best be described as co-dominant, the status of both maternal and paternal FVL is likely to be of ificance. FVL status in males in relation to reproduction has not been investigated to date. Although it seems unlikely that FVL status per se would influence male fertility, no published data on this topic are available.
Whether the FVL status of the embryo as such has any influence on reproductive success remains to be clarified. A high fecundity rate shorter time to a desired pregnancy may reflect implantation success. A population of males and females with their fertile years in an era in which fertility control was minimal appears suitable for the analysis of the influence of FVL on fertility and fecundity. In this study, we assess fertility and fecundity in a large cohort of subjects born in the late nineteenth and early twentieth centuries, who were of childbearing age in a time where modern contraceptive methods were unavailable.
The Leiden Plus Study consists of two separate cohorts. A detailed description of both cohorts has been presented elsewhere Van Aken et al. In short, subjects of the first cohort were enrolled between December and March During that period, a total of inhabitants of Leiden, The Netherlands, who were aged 85 and over were included. A second cohort of year-olds, consisting of subjects, was enrolled between September and September There were no selection criteria for health or demographics in either cohort.
Of all subjects, a blood sample was obtained. The Registry of Births, Deaths, and Marriages of the municipality of Leiden and the Central Bureau of Genealogy CBG , The Netherlands, provided the date of birth, date of marriage s and birth dates of children of all study participants. The CBG is the major documentation and information centre for family history and heraldry in the Netherlands. For 32 subjects, there was insufficient information available on their marital history or their or dates of birth of progeny. Hence, complete information was available for subjects.
Fecundity was defined as the calculated time interval between the date of first marriage and the date of birth of the firstborn child. This effective fecundability was arbitrarily divided into groups according to probable conception time. If the conception had taken place within the first 3 months of marriage, it can be assumed that these children were most likely born within and days of the marriage date. This was calculated by adding 3 months 91 days to the median duration of a term pregnancy days. Likewise, if conception had occurred within 6 months of marriage, the children would most likely be born between and days after marriage.
For conception within 12 months of marriage, the date of birth was assumed to be within and days of marriage. To minimize the selection of pregnancies conceived before marriage, children born before marriage or within the first 36 weeks days of marriage were excluded from analysis. Women with an age beyond 40 at the time of their marriage were excluded from further analysis due to the rapid decline of fertility and fecundity that can be expected from that age onwards.
Figure 1 illustrates the flow chart of the participating subjects. For the present study, the FVL analysis was done at the same moment in time for all available stored blood samples. All tests were two-tailed.
The year of birth ranged from to The FVL mutation was present in 18 men 4. All were heterozygous for FVL. There were no homozygotes. The year of birth of the firstborn child ranged from to in male subjects and from to in female subjects.
A similar of marriages remained childless in FVL carriers and non-carriers regardless of gender Table I. Characteristics of married male and female subjects married at or before 40 years of age according to their factor V Leiden carrier status. Table II presents the assumed conception time of married men and women dependent on their FVL status.
In female subjects, FVL carriers had similar fecundity rates compared with non-carriers [relative risk RR , 0. Male FVL carriers had a 3. Within 6 months of marriage, the remained similar RR, 2. In an additional analysis, with all births from the first day of marriage onwards included, without the day threshold, the for males remained ificant RR, 1. In the present study of married male and female subjects born between and , fecundity in females was unrelated to FVL status.
In males, there was an unexpected, but highly statistically ificant finding of an increased fecundity shorter time period between marriage and firstborn child in FVL carriers compared with non-carriers. There was no association between FVL mutation and fertility or family size. Heterozygous FVL mutation was found in 4.
There were no individuals homozygous for factor V Leiden, which is within expected s as the population prevalence is 0. Fecundity in females was comparable in FVL carriers and non-carriers. The current study only comprised completed pregnancies; there was no information available on pregnancies ending in miscarriage or fetal loss.
Female FVL carriers may have had higher rates of miscarriages or fetal loss, reducing the amount of children born within the first year and lowering fecundity rates masking an effect of FVL on embryo implantation in females. In male subjects, FVL carriers had a ificantly increased fecundity compared with non-carriers. An explanation for these findings in the male population can only be speculative. The may be real, due to a chance finding or due to a selection bias. In selecting only the births from days after marriage assumed to be conceived after the marriage date , a bias may occur in selecting the less-fertile couples Sallmen et al.
The couples that get married due to an unintended pregnancy will have their babies with a shorter interval after marriage, they will be excluded and presumably, they are the most fertile. However, FVL carriers were evenly distributed in subjects with births that occurred before the first days of marriage and beyond that time in both males and females. Moreover, with all the births from the first day of marriage included, the remained similar.
Although elderly subjects over 85 years of age were selected, the FVL prevalence has been reported to remain stable at this age, and it does not affect population mortality Heijmans et al. Hypothetically, the location of the FVL gene could be in the proximity of an unknown, male-fertility gene elevating the risk of a mutation in that gene, resulting in an increase in sperm s or motility.
Whether FVL has any effect on sperm quality or quantity has never been investigated. Furthermore, FVL may have a positive effect on implantation Majerus, by way of the inheritance of the paternal FVL mutation by the embryo. Indeed, a few small studies have reported a higher-than-expected FVL mutation rate in infants born to mothers in various normal control groups compared with the reported prevalence of FVL mutation in the normal population Currie et al. Further research is required to distinguish whether not only maternal FVL status but also paternal status and subsequently the embryo is of ificance for reproductive success.
Fifty-five percentage of subjects had their first child within 21 months of marriage, corresponding with a calculated conception time within the first 12 months of marriage. In recent times, conception rates are reported considerably higher. From to , fecundity rates in Britain increased ificantly for both men and women. An explanation for this increase in fecundity may be a change in general behaviour due to more knowledge about fertility and therefore a more optimal timing of intercourse.
The readily available and reliable contraception nowadays will enhance family planning with an increased focus to having at a specific time. Furthermore, the recent prospective studies include pregnancies ending in a miscarriage, which was not available in the present study. The current study has some limitations.Any bord wives near Leiden
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