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Factor V Leiden: relation to fertility?
CORRESPONDENCE
3
4
5
Sher L. Genetic studies of seasonal affective disorder and seasonality. Compr Psychiatry 2001; 42: 105–10. Madden PAF, Heath AC, Rosenthal NE, Martin NG. Seasonal changes in mood and behaviour: the role of genetic factors. Arch Gen Psychiatry 1996; 53: 47–55. Sher L, Hardin TA, Greenberg BD, Murphy DL, Li Q, Rosenthal NE. Seasonality associated with the serotonin transporter promoter length polymorphism. Am J Psychiatry 1999; 156: 1837.
Factor V Leiden: relation to fertility? Sir—A selective advantage of factor V Leiden has long been sought in an attempt to explain its high prevalence in white populations. Wolfgang Göpel and colleagues (Oct 13, p 1238)1 provide evidence for a fertility-related advantage. With intracytoplasmatic sperm injection as a model for human implantation, they report an association between factor V Leiden and an improved implantation rate at the first attempt. Our data from the Copenhagen City Heart Study (a population-based prospective study of more than 9000 Danes)2 do not, however, support the hypothesis that positive selective forces apply to factor V Leiden for fertility. Heterozygotes and homozygotes have on average 1·52 and 1·65 children, which does not differ from the average 1·55 children of non-carriers. Analysis stratified by sex produces similar results (table). One limitation of our study is the fact that contraceptives are widely used in the Danish population. The number of children among participants does not, therefore, reflect the biological potential, but a more or less deliberate choice. Such regulation of childbirth would make it difficult to truly test Göpel and colleagues’ overall hypothesis that factor V Leiden improves fertility. Our results by no means rule out the validity of Göpel and colleagues’ Number of children
p
All Non-carriers (n=8314) 1·55 (0·01) Heterozygotes (n=689) 1·52 (0·05) Homozygotes (n=20) 1·65 (0·32)
.. 0·33 0·95
Women Non-carriers (n=4691) 1·57 (0·02) Heterozygotes (n=395) 1·54 (0·06) Homozygotes (n=10) 1·50 (0·31)
.. 0·63 0·99
Men Non-carriers (n=3623) 1·53 (0·02) Heterozygotes (n=294) 1·50 (0·08) Homozygotes (n=10) 1·80 (0·57)
.. 0·35 0·94
894
Klaus Juul, Anne Tybjærg-Hansen, *Børge G Nordestgaard Department of Clinical Biochemistry, Herlev University Hospital, Copenhagen; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen; and *Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark 1
2
3
4
5
Göpel W, Ludwig M, Junge AK, Kohlmann T, Diedrich K, Möller J. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358: 1238–39. Dahl M, Tybjaerg-Hansen A, Wittrup HH, Lange P, Nordestgaard BG. Cystic fibrosis Delta F508 heterozygotes, smoking, and reproduction: studies of 9141 individuals from a general population sample. Genomics 1998; 50: 89–96. Heijmans BT, Westendorp RG, Knook DL, Kluft C, Slagboom PE. The risk of mortality and the factor V Leiden mutation in a population-based cohort. Thromb Haemost 1998; 80: 607–09. Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000; 356: 182–83. Emmerich J, Poirier O, Evans A, et al. Myocardial infarction, Arg 506 to Gln factor V mutation, and activated protein C resistance. Lancet 1995; 345: 321–21.
is supported by the wide use of contraceptives and by the very narrow SD of the number of children. Therefore, we do not believe that an improved implantation rate of factor V Leiden carriers in their study is balanced by abortions and miscarriages later in pregnancy, but by family planning of the participants (total number of children also did not differ between carriers and non-carriers in our study). However, a genetic advantage in early implantation has to be associated with a low rate of unsuccessful attempts to get pregnant. This hypothesis was tested in our study and we noted significant differences between carriers and non-carriers of the factor V Leiden mutation, although we are well aware that our results are preliminary because of the limited number of families studied undergoing in-vitro fertilisation and intracytoplasmic sperm injection . We would be interested to know the number of unsuccessful attempts to get pregnant or the time between the decision for and the occurrence of pregnancy and their relation to mutations, which may confer a selective genetic advantage in large cohorts, such as that studied by Juul and colleagues. Such a study design would furthermore circumvent the difficulty of the main confounder, individual family planning, if the total number of children is used as the only outcome parameter. Furthermore, the genotype of the infant should be included in such an analysis, since the fetal carrier status might be of equal importance for implantation and duration of pregnancy to the maternal carrier status. Finally, we do not state that postnatal survival is affected by the factor V Leiden mutation; however, there are numerous studies in which an association between maternal or fetal heterozygous factor V Leiden carrier status and reduced prenatal survival of the fetus are described.1–3 *Wolfgang Göpel, Michael Ludwig, Thomas Kohlmann, Klaus Diedrich, Jens Möller Department of Paediatrics, Social Medicine, Obstetrics and Gynaecology, University of Lübeck, 23538 Lübeck, Germany
Authors’ reply
Values are mean (SE); p values were calculated by Mann-Whitney U test, with non-carriers as reference.
Number of children stratified by sex
findings. They do, however, bring into question the evolutional importance of an early implantation advantage. Obviously, improved implantation in our study could have been balanced by abortions or miscarriages later in pregnancy. Alternatively, the conclusions of Göpel and colleagues could represent a type I error. Thus, their results are rendered non-significant if only one individual changes status in the 2⫻2 table. Finally, the high prevalence of factor V Leiden in the general population may simply reflect that survival is not affected to any substantial extent by the mutation.3 This finding would be in accordance with those from previous studies, in which risk of pulmonary embolism in carriers of factor V Leiden is reported as much smaller than that of more benign deep venous thromboses.4 Furthermore, risk of arterial thrombosis does not seem to be affected by factor V Leiden,5 which lends support to the conclusion that it does not affect survival.
1
Sir—We appreciate the comments of Klaus Juul and colleagues, but we believe that their and our study designs are not comparable. The main limitation of their study design is that their outcome variable (number of children) is affected greatly by individual family planning than by selective genetic advantages. This view
2
3
Meinardi JR, Middeldorp S, de Kam PJ, et al. Increased risk for fetal loss in carriers of the factor-V-Leiden mutation. Ann Intern Med 1999; 130: 736–39. Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997; 177: 402–05. Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999; 353: 1411–12.
THE LANCET • Vol 359 • March 9, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
3
4
5
Sher L. Genetic studies of seasonal affective disorder and seasonality. Compr Psychiatry 2001; 42: 105–10. Madden PAF, Heath AC, Rosenthal NE, Martin NG. Seasonal changes in mood and behaviour: the role of genetic factors. Arch Gen Psychiatry 1996; 53: 47–55. Sher L, Hardin TA, Greenberg BD, Murphy DL, Li Q, Rosenthal NE. Seasonality associated with the serotonin transporter promoter length polymorphism. Am J Psychiatry 1999; 156: 1837.
Factor V Leiden: relation to fertility? Sir—A selective advantage of factor V Leiden has long been sought in an attempt to explain its high prevalence in white populations. Wolfgang Göpel and colleagues (Oct 13, p 1238)1 provide evidence for a fertility-related advantage. With intracytoplasmatic sperm injection as a model for human implantation, they report an association between factor V Leiden and an improved implantation rate at the first attempt. Our data from the Copenhagen City Heart Study (a population-based prospective study of more than 9000 Danes)2 do not, however, support the hypothesis that positive selective forces apply to factor V Leiden for fertility. Heterozygotes and homozygotes have on average 1·52 and 1·65 children, which does not differ from the average 1·55 children of non-carriers. Analysis stratified by sex produces similar results (table). One limitation of our study is the fact that contraceptives are widely used in the Danish population. The number of children among participants does not, therefore, reflect the biological potential, but a more or less deliberate choice. Such regulation of childbirth would make it difficult to truly test Göpel and colleagues’ overall hypothesis that factor V Leiden improves fertility. Our results by no means rule out the validity of Göpel and colleagues’ Number of children
p
All Non-carriers (n=8314) 1·55 (0·01) Heterozygotes (n=689) 1·52 (0·05) Homozygotes (n=20) 1·65 (0·32)
.. 0·33 0·95
Women Non-carriers (n=4691) 1·57 (0·02) Heterozygotes (n=395) 1·54 (0·06) Homozygotes (n=10) 1·50 (0·31)
.. 0·63 0·99
Men Non-carriers (n=3623) 1·53 (0·02) Heterozygotes (n=294) 1·50 (0·08) Homozygotes (n=10) 1·80 (0·57)
.. 0·35 0·94
894
Klaus Juul, Anne Tybjærg-Hansen, *Børge G Nordestgaard Department of Clinical Biochemistry, Herlev University Hospital, Copenhagen; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen; and *Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark 1
2
3
4
5
Göpel W, Ludwig M, Junge AK, Kohlmann T, Diedrich K, Möller J. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358: 1238–39. Dahl M, Tybjaerg-Hansen A, Wittrup HH, Lange P, Nordestgaard BG. Cystic fibrosis Delta F508 heterozygotes, smoking, and reproduction: studies of 9141 individuals from a general population sample. Genomics 1998; 50: 89–96. Heijmans BT, Westendorp RG, Knook DL, Kluft C, Slagboom PE. The risk of mortality and the factor V Leiden mutation in a population-based cohort. Thromb Haemost 1998; 80: 607–09. Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000; 356: 182–83. Emmerich J, Poirier O, Evans A, et al. Myocardial infarction, Arg 506 to Gln factor V mutation, and activated protein C resistance. Lancet 1995; 345: 321–21.
is supported by the wide use of contraceptives and by the very narrow SD of the number of children. Therefore, we do not believe that an improved implantation rate of factor V Leiden carriers in their study is balanced by abortions and miscarriages later in pregnancy, but by family planning of the participants (total number of children also did not differ between carriers and non-carriers in our study). However, a genetic advantage in early implantation has to be associated with a low rate of unsuccessful attempts to get pregnant. This hypothesis was tested in our study and we noted significant differences between carriers and non-carriers of the factor V Leiden mutation, although we are well aware that our results are preliminary because of the limited number of families studied undergoing in-vitro fertilisation and intracytoplasmic sperm injection . We would be interested to know the number of unsuccessful attempts to get pregnant or the time between the decision for and the occurrence of pregnancy and their relation to mutations, which may confer a selective genetic advantage in large cohorts, such as that studied by Juul and colleagues. Such a study design would furthermore circumvent the difficulty of the main confounder, individual family planning, if the total number of children is used as the only outcome parameter. Furthermore, the genotype of the infant should be included in such an analysis, since the fetal carrier status might be of equal importance for implantation and duration of pregnancy to the maternal carrier status. Finally, we do not state that postnatal survival is affected by the factor V Leiden mutation; however, there are numerous studies in which an association between maternal or fetal heterozygous factor V Leiden carrier status and reduced prenatal survival of the fetus are described.1–3 *Wolfgang Göpel, Michael Ludwig, Thomas Kohlmann, Klaus Diedrich, Jens Möller Department of Paediatrics, Social Medicine, Obstetrics and Gynaecology, University of Lübeck, 23538 Lübeck, Germany
Authors’ reply
Values are mean (SE); p values were calculated by Mann-Whitney U test, with non-carriers as reference.
Number of children stratified by sex
findings. They do, however, bring into question the evolutional importance of an early implantation advantage. Obviously, improved implantation in our study could have been balanced by abortions or miscarriages later in pregnancy. Alternatively, the conclusions of Göpel and colleagues could represent a type I error. Thus, their results are rendered non-significant if only one individual changes status in the 2⫻2 table. Finally, the high prevalence of factor V Leiden in the general population may simply reflect that survival is not affected to any substantial extent by the mutation.3 This finding would be in accordance with those from previous studies, in which risk of pulmonary embolism in carriers of factor V Leiden is reported as much smaller than that of more benign deep venous thromboses.4 Furthermore, risk of arterial thrombosis does not seem to be affected by factor V Leiden,5 which lends support to the conclusion that it does not affect survival.
1
Sir—We appreciate the comments of Klaus Juul and colleagues, but we believe that their and our study designs are not comparable. The main limitation of their study design is that their outcome variable (number of children) is affected greatly by individual family planning than by selective genetic advantages. This view
2
3
Meinardi JR, Middeldorp S, de Kam PJ, et al. Increased risk for fetal loss in carriers of the factor-V-Leiden mutation. Ann Intern Med 1999; 130: 736–39. Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997; 177: 402–05. Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999; 353: 1411–12.
THE LANCET • Vol 359 • March 9, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.