Acta Obstet Gynecol S c a n d 1990; 69: 597-601
I D I 0PATHIC RE C UR R E NT S PO NTA NEO US A 6 0 RTI0N Evidence of a Familial Predisposition
Ole B. Christiansen, Ole M a t h i e s e n , J. Glenn Lauritsen and Niels G r u n n e t From the Department of Obstetrics and Gynecology, and the Department of Clinical Immunology, Aalborg Hospital, Aalborg, Denmark
Abstract. Pregnancy outcome was investigated: 1 ) in fifteen women suffering from
idiopathic recurrent spontaneous abortion (RSA) and who had experienced pregnancies with two different partners, and 2) in the mothers, the sisters and wives of the brothers of 90 consecutively referred women with RSA. After adjusting for ascertainment bias, the patients with 2 partners had an abortion rate of 72% with the first spouse (significantly increased compared with the expected rate) and a nearly 100% abortion rate with the second spouse. This suggests that, in the main, RSA is not partner-specific. The sisters of the patients had suffered a significantly increased miscarriage rate (25.3%) compared with the observed rate in a Danish control group. The wives of the brothers had an abortion rate of 18.8%.which was not significantly increased vis-a-vis the controls. The sisters showed a lifetime incidence of RSA (10.6%) which was significantly greater than comparable estimates in the literature. These results suggest the existence of a familial predisposition to spontaneous abortion in families where RSA occurs. Key words: recurrent abortion, spontaneous abortion, genetics, immunogenetics.
'The etiology o f idiopathic recurrent spontaneous ahortion (RSA) is. at present. only poorly clarified. 130th immunological and genetic factors have been claimed t o play ii role ( I .2,3). Several of the immunological theories have been based on the concept of increased sharing of histocompatihility antigens ( H L A ) i n couples with idiopathic RSA, which has been claimed t o result in fetal death because of failed maternal immune recognition of the fetus (4). The genetic theories claim that fetal homozygosity for proposed recessive lethal genes results in pregnancy failure. Both theories are founded on the assumption that RSA is ii partner-specific condition. Patients with ;I history of RSA who have experienced pregnancy with two different partners are inforniativc in the investigation of the problem of partner specificity. but only two studies o f such patients have been published. One study reported ambiguous results ( 5 ) whereas the other study (6) seemed to show that RSA was indeed partner-specific. However. against partner specificity must be counted a recent family study (7) which indicated that the disposition to RSA was associated with certain HLAhaplotypes in the patients' families. I n the present study our aim was to test the hy-
pothesis of partner specificity by collecting information bearing on pregnancy outcome in a group of RSA patients who had been pregnant with two different spouses. Furthermore. to investigate ii possible familial predisposition t o miscarriage, we have collected information concerning prcgnancy outcome in first-degree relatives of a larger group comprising all o u r patients. MATERIAL A N D METHODS Study group From June 19x6 t o
June 1989. I14 patients were referred t o us from all over Denmark to participate in a randomized trial concerning leukocyte immunization in the prevention o f RSA. All patients had suffered at least three consecutive confirmed spontaneous abortions. Nineteen couples wcrc excluded because abnormalities had been revealed in the following screening program: hysterosalpingography/hystcroscopy. mid-Meal s-progesterone in three cycles (normal value: >2S nmol/l). s-thyroxine. semen analysis and karyotyping of male and female. The abnormalities leading to exclusion were (no. of patients in parentheses) indications of cervical insufficiency (3), uterine septa (4). uterine fibroids (3), luteal phase insufficiency (3). significant chromosomal abnormalities in one of the spouses ( 5 ) . and severe oligospermia ( I ) . In addition. one consanguineous couple was excluded. Four couples whose families resided
598
0. B. Christiansen et al.
Table I. Outcome of pregnancies of women with recurrent abortions who have experienced pregnancies with two partners ~~
~~
Patient no.
~~
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1 SA 1 SA 1 SA 3 SA 2 SA (21a 7 SA (21a 1 SA (1)' 1 SA (1)' LB, 3 SA (1)' LB, 4 SA (1)' LB, 1 SA (1)' LB, 1 SA LB
1 SA, 1 1 1 1 1 1 LB 1 LB
Second partner
5 SA 9 SA 5 SA 3 SA 1 SA 1 SA 2 SA 2 SA 2 SA 2 SA 2 SA 4sA
5 SA 3 SA 2 SA, 1 LB, 3 SA
aProportion of the abortions from the first marriage which was fixed by method of ascertainment. LB = Live Birth; SA = Spontaneous Abortion.
abroad were excluded because of difficulties in obtaining appropriate family information. The remaining 90 couples attended a standardized intcrview at the hospital with one of the authors. Concerning their own reproductive histories, the patients were asked specifically if all their pregnancies had been with the same partner, and if not, they were asked to account for the pregnancy outcome with the respective spouses. For each fcmale relative in the three groups: mothers, full sisters, and full brothers' wives, the patients were asked to account for the numbers of live births and pregnancy losses. If it was stated that a relative had experienced intra-uterine pregnancy, a questionnaire was mailed to the woman herself requesting information concerning the number of live births, stillbirths, miscarriages and ectopic pregnancies which she had experienced. Furthermore. information on gestational age at the termination of all pregnancies was requested. Finally the relatives were asked to state what investigations had been carried out to confirm pregnancy ending in first-trimester miscarriage (hCG tests, ultrasound scans, uterine aspiration). Further information was obtained from Danish hospital records to confirm as many of the reported miscarriages as possible. For a reported miscarriage to be accepted for the statistical evaluation, it had to be documented that there had been at least 6 weeks of menostasia and that one positive urinary hCG test had been performed. Only intra-uterine conceptions lost between 6th and 28th week (calculated from the last menstrual period) were included in the statistics as spontaneous abortions. The spontaneous abortion rate was calculated as the number of spontaneous abortions as a fraction of the total number of livebirths, stillbirths, and spontaneous abortions. This was based on the assumption that the spontaneAria Obsiei Gynerol Scand 69 (1WJ
Controls As controls regarding the rate of spontaneous abortions. a group of 631 Danish women between the ages of 20 and 4Y
Pregnancy outcome First partner
ous abortion rate of pregnancies terminated by induced abortion was equal to the overall abortion rate.
years who had achieved at least one conception was used. The women constituted a stratified, random sample of approximately 1.4 women per thousand in Denmark who defined a representative sample of women from Denmark's 275 municipalities. The women had been interviewed with the purpose of generating, retrospectively, detailed reproductive data including total number of pregnancies and numbers of spontaneous abortions, induced abortions, livebirths and stillbirths. Only data concerning the women's first six pregnancies have been recorded - these, however, comprised 1,614 (97.1%) of the total of 1,662 pregnancies. Parts of the data have been published previously (8), whereas unpublished data from the study have been obtained from the Danish Data Archives, Odense, by kind permission of Professor J. Olsen, Department of Social Medicine, University of Aarhus. SIatistics Fisher's exact test or (when appropriate) the XI-test with Yates' correction was applied to compare the size of subgroups of patients and to compare rates of abortions between groups. Mantel-Haenszel's test was applied when comparing age-standardized abortion rates. 95% confidence intervals (CI) were indicated in connection with rates. The unpaired Student's t-test was applied when comparing mean values. Mean values are given ? standard error of mean (SEM). A p-value 4 . 0 5 was considered significant.
RESULTS Patients T h e 90 patients had experienced a total of 337 miscarriages, 9 intra-uterine deaths after the 28th week, 6 induced abortions, 8 ectopic pregnancies a n d 29 live births. The mean number of intra-uterine fetal losses per patient was 3.8 (range 3 t o 10). Fifteen patients had been pregnant with two different spouses. Sixty-three patients were primary aborters whereas 27 patients were secondary aborters, having given birth t o a t least one live infant before beginning t o miscarry repeatedly. Tweenty secondary aborting patients had experienced all their pregnancies in t h e same marriage, whereas 7 secondary aborters (included in Table I) had been pregnant with two partners. The frequency of secondary aborters was thus 20/75 = 26.7% (CI 17.1-38.1) among patients with one partner a n d 7/15 = 46.7% (CI 21.3-73.4) among patients with t w o partners (not different, p = 0.08; Fisher's exact test).
59!9
Familial predisposition to abortion
Table II. Age-specific and summarized accumulated lifetime incidences of spontaneous abortion in sisters and wives of brothers to patients with recurrent abortions compared with controls
Age’
Sisters ( N =
Brothers’ wives ( N = 52Ib
SA
TIP
ARO
20-29 30-34 35-39 40-49
9 5 13 10
13 37 55 41
69.2 13.5 23.6 24.4
Total
37
146
25.3’
ARE
12.5
SA
TIP
ARO
1 12 3 3
10 46 25 20
10.0 26.1 12.0 15.0
19
101
18.8
Controls ( N = 631 )b ARE
13.0
SA
TIP
ARO
33 67 52 36
274 471 392 357
12.0 14.2 13.3 10.1
188
1494
12.6
SA = Spontaneous Abortions; TIP = Total Intra-uterine Pregnancies (except legal abortions); ARO = Abortion Rate - Observed (%); ARE = Abortion Rate - Expected (%) (after age-standardization). ‘Age at time of questionnaire; bWomen with 2 one intrauterine pregnancy; *p 90%) could be demonstrated between the preliminary statements of the patients and the accepted statements of the relatives themselves. The resulting assignments
of the pregnancy outcome of the 59 sisters and 52 sisters-in-law who had experienced at least one intrauterine pregnancy are given in Table 11. Fifty-one of the 56 (91.1 YO) pregnancy losses assigned to the patients’ sisters and sisters-in-law had (besides a positive pregnancy test), according to the relatives’ statements, been verified by uterine aspiration. In Danish hospital records, it was possible to verify 46 of these aspirations and subsequent histological pregnancy confirmations. The remaining five aspirations were reported to have been undertaken abroad and therefore no attempt was made to make further verification. Thirty-six of the 59 miscarriages assigned to the patients’ mothers (61 .O%) had, according to their own statements, been verified by aspiration. The age-specific and summarized abortion rates (lifetime incidences) per 100 intra-uterine conceptions in the sisters and sisters-in-law were compared with the rates of the controls (Table 11). When the summarized abortion rates were compared, the sisters’ rate (25.3%; CI 18.5-33.2) was significantly increased compared with controls (p < 0.001), whereas the rate of the brothers’ wives (18.8%; CI 11.0-27.0) was not significantly elevated. When agestandardized comparisons between each of the two study groups and the controls were performed, the abortion rate of the sisters still proved to be significantly greater than the rate of the controls (p < 0.001), and the rate of the brother’s wives was still not significantly elevated (p> 0.1). The abortion rate of the patients’ mothers was 59/360 = 16.4% (CI 12.7-20.7). The lifetime incidences of RSA in those women who were multigravida (having experienced more than one intra-uterine pregnancy) Actu Obsrer Gynecol Scund 69 (1W)
600
0. B. Christiansen et al.
in all three groups of female relatives were 7 out of 87 mothers (8.0%;CI 3.3-15.9), 5 out of 47 sisters (10.6%;CI 3.6-23.1) and 2 out of 32 sisters-in-law (6.3%; CI 0.8-20.8). When, after age-standardization, the rates of the sisters and sisters-in-law were compared with the lifetime-incidence of RSA (1.41%)among 5,901 multigravidas in a Norwegian population study (lo), only the rate of the sisters proved to be significantly elevated (p < 0.001).
1.41% among women who had experienced more than one pregnancy. Compared with the latter group, the sisters had a significantly increased RSA rate, whereas the rate of the brothers’ wives did not prove to be significantly increased. Estimating abortion rates in families is subject to a potential risk of introducing bias. It is possible that not all fetal losses in the families have been reported, because the ascertainment of the miscarriages among relatives with only miscarriages was dependent on the patients’ knowledge of these. On DISCUSSION the other hand, it must: be presumed that the paTable I indicates that, in general RSA, does not tients’ knowledge of the number of liveborn children appear to be partner-specific, since in a substantial of the first-degree relatives was complete. The numnumber of women with RSA, the tendency to mis- ber of abortions assigned to the relatives may thus be carry in the second partnership had already started too low, resulting in an underestimate of the aborin pregnancies with the first partner. The tendency tion rate. The estimate of the mothers’ lifetime into give birth to infants with decreased birth weight in cidence of miscarriage must be considered uncerthe first partnership also supports the concept of tain, because of the difficulty of recalling events diminished reproductive fitness even with the first happening 3 0 4 0 years ago, the lower hospitalization spouse. rate and the poorer possibilities of diagnosing early The rate of clinically recognized spontaneous pregnancy which were available in previous generabortion per 100 pregnancies has been reported in ations. Consequently, we have chosen not to perthe literature to lie between 10.0% and 16.1% form statistical comparisons between the reproduc( 1 1,12,13,14). A thorough prospective study per- tive data of the mothers and of the controls. The formed by Regan (12) gave evidence of an abortion miscarriages which were assigned to the sisters and rate of 10% in a large group of women. the summa- sisters-in-law, on the other hand, must be considered rized abortion rate of the controls in the present as assigned with a high degree of certainty because study (12.6%)was comparable to these figures. Ta- of the high rate (91.1%) of postabortive uterine ble I1 shows that there was a significant aggregation aspiration and histological examination of the uterof spontaneous abortions among the patients’ sis- ine aspirate which has been undertaken in these ters. This might indicate that, in several case, the groups. The increased abortion rate found in the tendency to miscarry was an inherited condition in patients’ sisters cannot therefore be a mere overthose women’s families. The abortion rate of the estimate, but must be considered as real. Our conbrothers’ wives - although showing a tendency to clusion, that there is a familial predisposition to reelevation -was not significantly greater than the rate current abortions, is based primarily on this. In a previous study (7,16) we found evidence for of the controls. If inheritance of the abortion trait were common through female gametes but only in- the hypothesis that the risk of miscarriage in families frequently occurred through male gametes, this of patients with RSA segregates with chromosome would support the previous finding that, as a general no. 6 which bears the genes which code for the major histocompatibility complex and we have proposed rule, RSA does not seem to be partner-specific. The lifetime incidences of RSA in those sisters the existence of a HLA-linked spontaneous abortion and sisters-in-law of the probands who were mul- susceptibility region. Recent studies (17,18) have tigravida were 10.6% and 6.3% respectively. Preva- discovered immunological active antigens located on lence of RSA in the female population has been the human trophoblast. These antigens, which may investigated in very few (foreign) studies, which play a role in the survival of pregnancy, are encoded makes statistical evaluation of the mentioned rates by genes mapping in the HLA region. Further chardifficult. In a retrospective study, Roman et al. (15) acterization of trophoblast antigens and studies on reported a RSA prevalence of 0.96% in women who the segregation of their different forms in families had experienced 3 or 4 pregnancies, while Stray- with multiple cases of RSA will determine whether Pedersen & Lorentzen-Styr (10) found a rate of these antigens consitute the basis for the hereditary Acta Obstet Cynecol Scand 69 (1990)
Familial predisposition to abortion predisposition t o R S A which is suggested by the results of the present study. ACKNOWLEDGMENTS This study was supported by grants from the Research Fund of Aalborgs Frivillige Bloddonorer. the Christmas Lottery of Aalhorg Stiftstidende and the Research Fund of Nordjyllands Amt.
REFERENCES I . Schacter B, Weitkamp LR, Johnson WE. Parental HLA compatibility. fetal wastage and neural tube defects: Evidence for a T/t-like locus in humans. Am J Hum Genet 1984;36: 1082-91. 2. Lockshin MD, Druzin ML, Goel S, et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985;313: 152-6. 3. Gill TJ. Genetic factors in fetal losses. Am J Reprod lmmunal Microbiol 1987; 15: 133-7. 4. Mclntyre JA, Page Faulk W. Recurrent spontaneous abortion in human pregnancy: Results of immunogenetical, cellular and humoral studies. Am J Reprod lmmunol 1983;4: 165-70. 5. Coulam CB. Mclntyre JA, Page Faulk W. Reproductive performance in women with repeated pregnancy losses and multiple partners. Am J Reprod Immunol Microbiol 1986; 12: IU-12. 6. Reginald PW, Beard RW, Chapple J , et al. Outcome of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage. Br J Obstet Gynaecol 1987;94: 643-8. 7. Christiansen OB,Riisom K, Lauritsen JG, Grunnet N, Jersild C. Association of maternal HLA haplotypes with recurrent spontaneous abortion. Tissue Antigens 1989;34: 190-9. 8. Rachootin P, Olsen J. Prevalence and socioeconomic correlates of subfecundity and spontaneous abortion in Denmark. Int J Epidemiol 1982; 11: 245-9. Y. The [Danish] National Board of Health. The Medical
601
Birth Register and the Registry of Congenital Malformations 1986.Copenhagen, 1988;91. 10. Stray-Pedersen B, Lorentzen-Styr A. The prevalence of toxoplasma antibodies among 11.736 pregnant women in Norway. Scand J Infect Dis 1979; 11: 159-65. 11. Naylor AF, Warburton D. Sequental analysis of spontaneous abortion. 11. Collaboration study data show that gravidity determines a very substantial increase in risk. Fertil Steril 1979;31: 282-6. 12. Regan L. A prospective study of spontaneous abortion. In: Beard RW. Sharp F, eds. Early pregnancy loss: mechanisms and treatment. London: SpringerVerlag, 1988;23-37. 13. Wilcox AJ. Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319: 189-94. 14. Leridon H. Facts and artefacts in the study of intrauterine mortality: a reconsideration from pregnancy histories. Population Studies 1976;30: 319-35. 15. Roman E, Doyle P, Beral V, Alberman E, Pharoah P. Fetal loss, gravidity and pregnancy order. Early Human Development 1978;2: 131-8. 16. Christiansen OB, Mathiesen 0, Grunnet N, Jersild C, Lauritsen JG. Is there a common genetic background for pre-eclampsia and recurrent spontaneous abortions? Lancet 19%; 1: 361-2 (letter). 17. Ellis SA, Palmer MS, McMichael AJ. Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA class I molecule. J Immunology 1990; 144: 731-5. 18. Kovats S, Main EK, Libranch C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science; 248: 220-3. Submitted for publication March 5 , 1990 Accepted November 22, 1990 Ole B. Christiansen, M.D. Department of Obstetrics and Gynecology Aalborg Hospital, P.O. Box 561 DK-9100 Aalborg Denmark
Acra Obsfet Gynecol Scand 69 (1990)
I D I 0PATHIC RE C UR R E NT S PO NTA NEO US A 6 0 RTI0N Evidence of a Familial Predisposition
Ole B. Christiansen, Ole M a t h i e s e n , J. Glenn Lauritsen and Niels G r u n n e t From the Department of Obstetrics and Gynecology, and the Department of Clinical Immunology, Aalborg Hospital, Aalborg, Denmark
Abstract. Pregnancy outcome was investigated: 1 ) in fifteen women suffering from
idiopathic recurrent spontaneous abortion (RSA) and who had experienced pregnancies with two different partners, and 2) in the mothers, the sisters and wives of the brothers of 90 consecutively referred women with RSA. After adjusting for ascertainment bias, the patients with 2 partners had an abortion rate of 72% with the first spouse (significantly increased compared with the expected rate) and a nearly 100% abortion rate with the second spouse. This suggests that, in the main, RSA is not partner-specific. The sisters of the patients had suffered a significantly increased miscarriage rate (25.3%) compared with the observed rate in a Danish control group. The wives of the brothers had an abortion rate of 18.8%.which was not significantly increased vis-a-vis the controls. The sisters showed a lifetime incidence of RSA (10.6%) which was significantly greater than comparable estimates in the literature. These results suggest the existence of a familial predisposition to spontaneous abortion in families where RSA occurs. Key words: recurrent abortion, spontaneous abortion, genetics, immunogenetics.
'The etiology o f idiopathic recurrent spontaneous ahortion (RSA) is. at present. only poorly clarified. 130th immunological and genetic factors have been claimed t o play ii role ( I .2,3). Several of the immunological theories have been based on the concept of increased sharing of histocompatihility antigens ( H L A ) i n couples with idiopathic RSA, which has been claimed t o result in fetal death because of failed maternal immune recognition of the fetus (4). The genetic theories claim that fetal homozygosity for proposed recessive lethal genes results in pregnancy failure. Both theories are founded on the assumption that RSA is ii partner-specific condition. Patients with ;I history of RSA who have experienced pregnancy with two different partners are inforniativc in the investigation of the problem of partner specificity. but only two studies o f such patients have been published. One study reported ambiguous results ( 5 ) whereas the other study (6) seemed to show that RSA was indeed partner-specific. However. against partner specificity must be counted a recent family study (7) which indicated that the disposition to RSA was associated with certain HLAhaplotypes in the patients' families. I n the present study our aim was to test the hy-
pothesis of partner specificity by collecting information bearing on pregnancy outcome in a group of RSA patients who had been pregnant with two different spouses. Furthermore. to investigate ii possible familial predisposition t o miscarriage, we have collected information concerning prcgnancy outcome in first-degree relatives of a larger group comprising all o u r patients. MATERIAL A N D METHODS Study group From June 19x6 t o
June 1989. I14 patients were referred t o us from all over Denmark to participate in a randomized trial concerning leukocyte immunization in the prevention o f RSA. All patients had suffered at least three consecutive confirmed spontaneous abortions. Nineteen couples wcrc excluded because abnormalities had been revealed in the following screening program: hysterosalpingography/hystcroscopy. mid-Meal s-progesterone in three cycles (normal value: >2S nmol/l). s-thyroxine. semen analysis and karyotyping of male and female. The abnormalities leading to exclusion were (no. of patients in parentheses) indications of cervical insufficiency (3), uterine septa (4). uterine fibroids (3), luteal phase insufficiency (3). significant chromosomal abnormalities in one of the spouses ( 5 ) . and severe oligospermia ( I ) . In addition. one consanguineous couple was excluded. Four couples whose families resided
598
0. B. Christiansen et al.
Table I. Outcome of pregnancies of women with recurrent abortions who have experienced pregnancies with two partners ~~
~~
Patient no.
~~
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1 SA 1 SA 1 SA 3 SA 2 SA (21a 7 SA (21a 1 SA (1)' 1 SA (1)' LB, 3 SA (1)' LB, 4 SA (1)' LB, 1 SA (1)' LB, 1 SA LB
1 SA, 1 1 1 1 1 1 LB 1 LB
Second partner
5 SA 9 SA 5 SA 3 SA 1 SA 1 SA 2 SA 2 SA 2 SA 2 SA 2 SA 4sA
5 SA 3 SA 2 SA, 1 LB, 3 SA
aProportion of the abortions from the first marriage which was fixed by method of ascertainment. LB = Live Birth; SA = Spontaneous Abortion.
abroad were excluded because of difficulties in obtaining appropriate family information. The remaining 90 couples attended a standardized intcrview at the hospital with one of the authors. Concerning their own reproductive histories, the patients were asked specifically if all their pregnancies had been with the same partner, and if not, they were asked to account for the pregnancy outcome with the respective spouses. For each fcmale relative in the three groups: mothers, full sisters, and full brothers' wives, the patients were asked to account for the numbers of live births and pregnancy losses. If it was stated that a relative had experienced intra-uterine pregnancy, a questionnaire was mailed to the woman herself requesting information concerning the number of live births, stillbirths, miscarriages and ectopic pregnancies which she had experienced. Furthermore. information on gestational age at the termination of all pregnancies was requested. Finally the relatives were asked to state what investigations had been carried out to confirm pregnancy ending in first-trimester miscarriage (hCG tests, ultrasound scans, uterine aspiration). Further information was obtained from Danish hospital records to confirm as many of the reported miscarriages as possible. For a reported miscarriage to be accepted for the statistical evaluation, it had to be documented that there had been at least 6 weeks of menostasia and that one positive urinary hCG test had been performed. Only intra-uterine conceptions lost between 6th and 28th week (calculated from the last menstrual period) were included in the statistics as spontaneous abortions. The spontaneous abortion rate was calculated as the number of spontaneous abortions as a fraction of the total number of livebirths, stillbirths, and spontaneous abortions. This was based on the assumption that the spontaneAria Obsiei Gynerol Scand 69 (1WJ
Controls As controls regarding the rate of spontaneous abortions. a group of 631 Danish women between the ages of 20 and 4Y
Pregnancy outcome First partner
ous abortion rate of pregnancies terminated by induced abortion was equal to the overall abortion rate.
years who had achieved at least one conception was used. The women constituted a stratified, random sample of approximately 1.4 women per thousand in Denmark who defined a representative sample of women from Denmark's 275 municipalities. The women had been interviewed with the purpose of generating, retrospectively, detailed reproductive data including total number of pregnancies and numbers of spontaneous abortions, induced abortions, livebirths and stillbirths. Only data concerning the women's first six pregnancies have been recorded - these, however, comprised 1,614 (97.1%) of the total of 1,662 pregnancies. Parts of the data have been published previously (8), whereas unpublished data from the study have been obtained from the Danish Data Archives, Odense, by kind permission of Professor J. Olsen, Department of Social Medicine, University of Aarhus. SIatistics Fisher's exact test or (when appropriate) the XI-test with Yates' correction was applied to compare the size of subgroups of patients and to compare rates of abortions between groups. Mantel-Haenszel's test was applied when comparing age-standardized abortion rates. 95% confidence intervals (CI) were indicated in connection with rates. The unpaired Student's t-test was applied when comparing mean values. Mean values are given ? standard error of mean (SEM). A p-value 4 . 0 5 was considered significant.
RESULTS Patients T h e 90 patients had experienced a total of 337 miscarriages, 9 intra-uterine deaths after the 28th week, 6 induced abortions, 8 ectopic pregnancies a n d 29 live births. The mean number of intra-uterine fetal losses per patient was 3.8 (range 3 t o 10). Fifteen patients had been pregnant with two different spouses. Sixty-three patients were primary aborters whereas 27 patients were secondary aborters, having given birth t o a t least one live infant before beginning t o miscarry repeatedly. Tweenty secondary aborting patients had experienced all their pregnancies in t h e same marriage, whereas 7 secondary aborters (included in Table I) had been pregnant with two partners. The frequency of secondary aborters was thus 20/75 = 26.7% (CI 17.1-38.1) among patients with one partner a n d 7/15 = 46.7% (CI 21.3-73.4) among patients with t w o partners (not different, p = 0.08; Fisher's exact test).
59!9
Familial predisposition to abortion
Table II. Age-specific and summarized accumulated lifetime incidences of spontaneous abortion in sisters and wives of brothers to patients with recurrent abortions compared with controls
Age’
Sisters ( N =
Brothers’ wives ( N = 52Ib
SA
TIP
ARO
20-29 30-34 35-39 40-49
9 5 13 10
13 37 55 41
69.2 13.5 23.6 24.4
Total
37
146
25.3’
ARE
12.5
SA
TIP
ARO
1 12 3 3
10 46 25 20
10.0 26.1 12.0 15.0
19
101
18.8
Controls ( N = 631 )b ARE
13.0
SA
TIP
ARO
33 67 52 36
274 471 392 357
12.0 14.2 13.3 10.1
188
1494
12.6
SA = Spontaneous Abortions; TIP = Total Intra-uterine Pregnancies (except legal abortions); ARO = Abortion Rate - Observed (%); ARE = Abortion Rate - Expected (%) (after age-standardization). ‘Age at time of questionnaire; bWomen with 2 one intrauterine pregnancy; *p 90%) could be demonstrated between the preliminary statements of the patients and the accepted statements of the relatives themselves. The resulting assignments
of the pregnancy outcome of the 59 sisters and 52 sisters-in-law who had experienced at least one intrauterine pregnancy are given in Table 11. Fifty-one of the 56 (91.1 YO) pregnancy losses assigned to the patients’ sisters and sisters-in-law had (besides a positive pregnancy test), according to the relatives’ statements, been verified by uterine aspiration. In Danish hospital records, it was possible to verify 46 of these aspirations and subsequent histological pregnancy confirmations. The remaining five aspirations were reported to have been undertaken abroad and therefore no attempt was made to make further verification. Thirty-six of the 59 miscarriages assigned to the patients’ mothers (61 .O%) had, according to their own statements, been verified by aspiration. The age-specific and summarized abortion rates (lifetime incidences) per 100 intra-uterine conceptions in the sisters and sisters-in-law were compared with the rates of the controls (Table 11). When the summarized abortion rates were compared, the sisters’ rate (25.3%; CI 18.5-33.2) was significantly increased compared with controls (p < 0.001), whereas the rate of the brothers’ wives (18.8%; CI 11.0-27.0) was not significantly elevated. When agestandardized comparisons between each of the two study groups and the controls were performed, the abortion rate of the sisters still proved to be significantly greater than the rate of the controls (p < 0.001), and the rate of the brother’s wives was still not significantly elevated (p> 0.1). The abortion rate of the patients’ mothers was 59/360 = 16.4% (CI 12.7-20.7). The lifetime incidences of RSA in those women who were multigravida (having experienced more than one intra-uterine pregnancy) Actu Obsrer Gynecol Scund 69 (1W)
600
0. B. Christiansen et al.
in all three groups of female relatives were 7 out of 87 mothers (8.0%;CI 3.3-15.9), 5 out of 47 sisters (10.6%;CI 3.6-23.1) and 2 out of 32 sisters-in-law (6.3%; CI 0.8-20.8). When, after age-standardization, the rates of the sisters and sisters-in-law were compared with the lifetime-incidence of RSA (1.41%)among 5,901 multigravidas in a Norwegian population study (lo), only the rate of the sisters proved to be significantly elevated (p < 0.001).
1.41% among women who had experienced more than one pregnancy. Compared with the latter group, the sisters had a significantly increased RSA rate, whereas the rate of the brothers’ wives did not prove to be significantly increased. Estimating abortion rates in families is subject to a potential risk of introducing bias. It is possible that not all fetal losses in the families have been reported, because the ascertainment of the miscarriages among relatives with only miscarriages was dependent on the patients’ knowledge of these. On DISCUSSION the other hand, it must: be presumed that the paTable I indicates that, in general RSA, does not tients’ knowledge of the number of liveborn children appear to be partner-specific, since in a substantial of the first-degree relatives was complete. The numnumber of women with RSA, the tendency to mis- ber of abortions assigned to the relatives may thus be carry in the second partnership had already started too low, resulting in an underestimate of the aborin pregnancies with the first partner. The tendency tion rate. The estimate of the mothers’ lifetime into give birth to infants with decreased birth weight in cidence of miscarriage must be considered uncerthe first partnership also supports the concept of tain, because of the difficulty of recalling events diminished reproductive fitness even with the first happening 3 0 4 0 years ago, the lower hospitalization spouse. rate and the poorer possibilities of diagnosing early The rate of clinically recognized spontaneous pregnancy which were available in previous generabortion per 100 pregnancies has been reported in ations. Consequently, we have chosen not to perthe literature to lie between 10.0% and 16.1% form statistical comparisons between the reproduc( 1 1,12,13,14). A thorough prospective study per- tive data of the mothers and of the controls. The formed by Regan (12) gave evidence of an abortion miscarriages which were assigned to the sisters and rate of 10% in a large group of women. the summa- sisters-in-law, on the other hand, must be considered rized abortion rate of the controls in the present as assigned with a high degree of certainty because study (12.6%)was comparable to these figures. Ta- of the high rate (91.1%) of postabortive uterine ble I1 shows that there was a significant aggregation aspiration and histological examination of the uterof spontaneous abortions among the patients’ sis- ine aspirate which has been undertaken in these ters. This might indicate that, in several case, the groups. The increased abortion rate found in the tendency to miscarry was an inherited condition in patients’ sisters cannot therefore be a mere overthose women’s families. The abortion rate of the estimate, but must be considered as real. Our conbrothers’ wives - although showing a tendency to clusion, that there is a familial predisposition to reelevation -was not significantly greater than the rate current abortions, is based primarily on this. In a previous study (7,16) we found evidence for of the controls. If inheritance of the abortion trait were common through female gametes but only in- the hypothesis that the risk of miscarriage in families frequently occurred through male gametes, this of patients with RSA segregates with chromosome would support the previous finding that, as a general no. 6 which bears the genes which code for the major histocompatibility complex and we have proposed rule, RSA does not seem to be partner-specific. The lifetime incidences of RSA in those sisters the existence of a HLA-linked spontaneous abortion and sisters-in-law of the probands who were mul- susceptibility region. Recent studies (17,18) have tigravida were 10.6% and 6.3% respectively. Preva- discovered immunological active antigens located on lence of RSA in the female population has been the human trophoblast. These antigens, which may investigated in very few (foreign) studies, which play a role in the survival of pregnancy, are encoded makes statistical evaluation of the mentioned rates by genes mapping in the HLA region. Further chardifficult. In a retrospective study, Roman et al. (15) acterization of trophoblast antigens and studies on reported a RSA prevalence of 0.96% in women who the segregation of their different forms in families had experienced 3 or 4 pregnancies, while Stray- with multiple cases of RSA will determine whether Pedersen & Lorentzen-Styr (10) found a rate of these antigens consitute the basis for the hereditary Acta Obstet Cynecol Scand 69 (1990)
Familial predisposition to abortion predisposition t o R S A which is suggested by the results of the present study. ACKNOWLEDGMENTS This study was supported by grants from the Research Fund of Aalborgs Frivillige Bloddonorer. the Christmas Lottery of Aalhorg Stiftstidende and the Research Fund of Nordjyllands Amt.
REFERENCES I . Schacter B, Weitkamp LR, Johnson WE. Parental HLA compatibility. fetal wastage and neural tube defects: Evidence for a T/t-like locus in humans. Am J Hum Genet 1984;36: 1082-91. 2. Lockshin MD, Druzin ML, Goel S, et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985;313: 152-6. 3. Gill TJ. Genetic factors in fetal losses. Am J Reprod lmmunal Microbiol 1987; 15: 133-7. 4. Mclntyre JA, Page Faulk W. Recurrent spontaneous abortion in human pregnancy: Results of immunogenetical, cellular and humoral studies. Am J Reprod lmmunol 1983;4: 165-70. 5. Coulam CB. Mclntyre JA, Page Faulk W. Reproductive performance in women with repeated pregnancy losses and multiple partners. Am J Reprod Immunol Microbiol 1986; 12: IU-12. 6. Reginald PW, Beard RW, Chapple J , et al. Outcome of pregnancies progressing beyond 28 weeks gestation in women with a history of recurrent miscarriage. Br J Obstet Gynaecol 1987;94: 643-8. 7. Christiansen OB,Riisom K, Lauritsen JG, Grunnet N, Jersild C. Association of maternal HLA haplotypes with recurrent spontaneous abortion. Tissue Antigens 1989;34: 190-9. 8. Rachootin P, Olsen J. Prevalence and socioeconomic correlates of subfecundity and spontaneous abortion in Denmark. Int J Epidemiol 1982; 11: 245-9. Y. The [Danish] National Board of Health. The Medical
601
Birth Register and the Registry of Congenital Malformations 1986.Copenhagen, 1988;91. 10. Stray-Pedersen B, Lorentzen-Styr A. The prevalence of toxoplasma antibodies among 11.736 pregnant women in Norway. Scand J Infect Dis 1979; 11: 159-65. 11. Naylor AF, Warburton D. Sequental analysis of spontaneous abortion. 11. Collaboration study data show that gravidity determines a very substantial increase in risk. Fertil Steril 1979;31: 282-6. 12. Regan L. A prospective study of spontaneous abortion. In: Beard RW. Sharp F, eds. Early pregnancy loss: mechanisms and treatment. London: SpringerVerlag, 1988;23-37. 13. Wilcox AJ. Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319: 189-94. 14. Leridon H. Facts and artefacts in the study of intrauterine mortality: a reconsideration from pregnancy histories. Population Studies 1976;30: 319-35. 15. Roman E, Doyle P, Beral V, Alberman E, Pharoah P. Fetal loss, gravidity and pregnancy order. Early Human Development 1978;2: 131-8. 16. Christiansen OB, Mathiesen 0, Grunnet N, Jersild C, Lauritsen JG. Is there a common genetic background for pre-eclampsia and recurrent spontaneous abortions? Lancet 19%; 1: 361-2 (letter). 17. Ellis SA, Palmer MS, McMichael AJ. Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA class I molecule. J Immunology 1990; 144: 731-5. 18. Kovats S, Main EK, Libranch C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science; 248: 220-3. Submitted for publication March 5 , 1990 Accepted November 22, 1990 Ole B. Christiansen, M.D. Department of Obstetrics and Gynecology Aalborg Hospital, P.O. Box 561 DK-9100 Aalborg Denmark
Acra Obsfet Gynecol Scand 69 (1990)
