AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY 26:72-75 © 1991 MUNKSGAARD
Predictors of Pregnancy Success in Repeated Miscarriage M.N. CAUCHI, R. PEPPERELL, M. KLOSS, Royal Women's Hospital, Melbourne
AND
D. LIM
ABSTRACT: Factors that may have a bearing on subsequent pregnancy success or failure in patients with recurrent abortion were examined in 165 women with a history of three or more consecutive miscarriages in the first trimester. The overall success rate was 67.9%. Factors that were found to correlate significantly with success rate were length of abortion history, total number of abortions, interval from last miscarriage to present pregnancy, and whether there was any degree of subfertility. Logistic regression analysis showed that the abortion x years index and maternal age accounted for all the variation observed in our data. Where all other known causes of abortions are excluded, recurrent aborters can be subdivided into two populationsnamely, those with a relatively good prognosis characterized by a short abortion history and absence of subfertility problems, compared to those with a poor prognosis namely those with a long abortion history or presence of subfertility problems. These data clearly demonstrate major differences in success rates in women depending on the number of abortions and the length of abortion history (abortion x year index), particularly in women over the age of 30 years. (Am J Reprod Immunol. 1991; 26:72-75.) INTRODUCTION
Known causes of repeated miscarriage include anatomical, hormonal, endocrinological, and chromosomal disorders. However, in the vast majority of couples with recurrent abortion, a specific cause cannot be identified. A role for immunological causes in the aetiology of recurrent abortion has also been postulated, with a number offactors being reported to have an association with increased pregnancy loss. These include antibodies to phospholipids as measured by anti-cardiolipin antibody or 3:n~ico~gul~nt activity,1--4 absenc~ ofblockin% antibody activity III mixed lymphocyte reaction (MLR), -8 lack of suppressor cells.!" absence of anti-paternallymphocytotoxic antibodies," increased paternal HLA sharing,8,9 and increased homozygosity for HLA loci. ll,12 There is conflicting data in relation to most ofthese parameters, however. Other studies have shown that there is no association of recurrent abortion with increased HLA sharing r ' or lack of maternal serum blocking antibodies in MLR. 13,14 Other factors reported to have an association with an increased risk of abortion include increasing maternal age, primary as compared to secondary abortion, and greater number of previous miscarriages. 14,15
Submitted for publication March 1, i991; accepted August 1, 1991. Address reprint requests to M.N. Cauchi, The Royal Women's Hospital, Swanson St., Carlton 3053, Melbourne, Australia.
732
White cell immunization has been proposed as a method of treatment of women with recurrent abortion; however, there is only one double-blind control study reported to data'" where an improved outcome was seen followin~ immunization. Other studies supporting such a claim 1 ,17 have not been double-blind studies and their control patients have been patients who have not received any treatment at all. All three studies referred to above l4,16,17 have continuing pregnancy rates ofless than 40% in "controls" (i.e., those who were not actively immunized), compared with success rates of 70% or higher following immunization. This low success rate in nonimmunized subjects is much less than that reported by many other workers studying patients with recurrent abortion who have received no immunotherapy whatsoever. 15,18 In a controlled sequential trial we have shown that there is no significant difference between immunized and nonimmunized subjects, and, moreover, the success rate in the nonimmunized control patients was no less than that obtained in the immunized group. 19 In the present study, we have combined the results of two previous studies in an attempt to clarify the role of immunological causes in patients with recurrent abortion. These studies include an uncontrolled study performed initially and the controlled double blind sequential study referred to above. In addition to immunological criteria, we have also analyzed other factors reported to have an association with an increased risk of recurrent abortion such as increasing maternal age, primary as compared to secondary abortion, and greater number of previous miscarriages. MATERIALS AND METHODS
Selection ofPatients Patients were fully investigated prior to being included in either of the two study groups. All patients had anatomical disorders excluded by hysterosalpingography, were shown to be ovulating normally, chromosome analyses of both partners were normal, and immunological investigation showed no evidence of anti-cardiolipin antibody or the presence oflupus anticoagulant.f" The following correlates with success of pregnancy were made: Subfertility index defined by the aborting woman subjectively as follows: 1. Achieves pregnancy with ease 2. Achieves pregnancy with moderate difficulty 3. Requires treatment with Clomiphene 4. Requires in vitro fertilization The abortion history was defined as the number of years taken to achieve the number of pregnancies. The miscarriage to pregnancy interval was defined as the number of weeks between last miscarriage prior to investigation for recurrent miscarriage and LMP of the subsequentpregnanc~
PREDICTORS OF PREGNANCY SUCCESS
73
TABLE I. Comparison Between Successful and Miscarriage Pregnancy Populations Advanced Pregnancy (n Average age No. of abortions Abortion history (years) No. of abortions/year Subfertility index Miscarriage to pregnancy Interval No. of cells injected Abortion x Year Index
x 31.2 3.7 3.1 136.8 1.532 37.9
=
112)
SD 4.7
± ± ± ± ± ±
1.7 54.9 0.74 39.6
77.1 ± 12.6 ±
73.5 11.9
1.1
The number ofabortions per year is defined as the number of miscarriages divided by the number of years over which they occurred. Likewise, the abortion times years index is defined as the number of miscarriages multiplied by the number of years over which they occurred. Primary versus secondary aborters: Primary aborters were defined as those with no previous advanced pregnancy beyond 20 weeks gestation, by the same partner whereas secondary aborters refers to those with previous advanced pregnancies.
Immunization In the first study ("open study") of 119 couples, white cell immunization (husband or third party donor) was offered to all patients who were HLA cross-match negative and who fulfilled the selection criteria. In spite of this a number of patients declined to be immunized or were already pregnant when the results of the crossmatch test became available. In the second study (doubleblind randomized controlled trial), 47 patients were randomly allocated to one of two arms of a protocol and were injected either with the husband's white cells or normal saline. The technique of immunization has been described previously. 19 Statistical Analysis X and modified t tests (which allows for different variances for the two populations) were used to determine significant differences between subjects who achieved a successful or unsuccessful pregnancy. P values obtained using the Wilcoxon Rank Sum Test are also given. Logistic regression analysis on the binary data (success/ failure) for each subject, was performed to obtain regression models to estimate the probability of successful pregnancy. 2
Miscarriage (n x 32.4 4.8 4.9 123.1 1.88 54
=
53)
± ± ± ± ± ±
SD 4.7 2.5 3.5 58.6 1.03 48.8
97.2 ± 30.1 ±
122 36.4
Modified t Test t -1.53 -3.30 -3.52 1.43 2.09 -1.93 1.02 3.42
P .13 .002 .0008 .16 .04 .058
Wilcoxon Test P .07 .003 .001 .04 .098 .085
.31 .0012
.535 .001
The factors that correlated best with subsequent successful pregnancy were as follows (Table 11): normal fertility (subfertility index of 2 or less) (P = .025) number of abortions per year of 1.5 or greater (P = .025) a short abortion history of < 3 years or less (P = .005) total number of abortions < 5 (P = .0005) (P < .025) age: less 30 years abortion x year index (P < .0005) It should be emphasized when interpreting these results that the cut off point for the groups was chosen arbitrarily by examination of the data. These findings should be considered provisional unless and until they are supported by other data. In this analysis the following parameters were not significantly associated with successful pregnancy: primary versus secondary aborters or whether the couple were immunized with husband's or donor white cells. Logistic regression using each predictor variable separately showed that the following variables were significantly associated with successful pregnancy: number of abortions, abortion history, miscarriage to pregnancy interval, subfertility index and abortion x year index (Table III). A subsequent analysis was carried out using all ofthe variables, and including age as a factor with two levels (less than 30 years, greater than or equal to 30 years of age). Using a stepwise procedure it was found that the "best" model (i.e., the simplest, best fitting model for which the addition of extra terms did not result in a significant improvement in fit) was one in which the success rate was constant for women under 30 years of age, and decreased with increasing abortion x years index for women over 30. Figure 1 shows estimates of the probability of success and 95% confidence limits obtained from the logistic regression. For women under 30 years of age the estimate of the probability of success was 0.80 with a 95% confidence interval of(.68, .89).
RESULTS
DISCUSSION
There were significant differences between the group that had a subsequent successful pregnancy and those who miscarried again (Table I). The miscarriage group had a significantly higher number of abortions, longer abortion history, high subfertility index and a longer interval between each miscarriage and subsequent pregnancy. The average abortion x years index was more than two times higher for those who subsequently miscarried again as compared with those whose next pregnancy was successful.
Several studies have endeavored to determine correlates with successful pregnancy in recurrent aborters; however, the literature is conflicting in relation to the significance of a number of these parameters. Our study has confirmed the findings of Cowchock et al. 14 in that there was no correlation between subsequent successful pregnancy and a) degree ofHLA sharing, b) presence of anti-paternal antibody, and c) primary versus secondary aborters. We also agree with Cowchock et al. that a long abortion history is likely to be associated with a poor
74
CAUCHIET AL.
TABLE II. Factors Correlating With Success in Subsequent Pregnancy
Total Age Less than 30 years 30 years or older Subfertility index 2 or less More than 2 No. abortion/year 1.5 or more Less than 1.5 Abortion history (years) 3 years or less More than 3 years Miscarriage to pregnancy interval 20 weeks or less 21-49 weeks or more 50 or more No. abortions Less than 5 50rmore Abortion x year index < 20 ~ 20 Previous children None 1 or more Immunization Immunized Not immunized
1st Study Successful % No.
2nd Study (Controlled Trial) Successful Total No. %
(Combined Data) Successful Total No. %
2
P
37 81
31 48
(84) (59)
19 28
14 19
(74) (68)
56 109
45 67
(80) (61)
6.41
Predictors of Pregnancy Success in Repeated Miscarriage M.N. CAUCHI, R. PEPPERELL, M. KLOSS, Royal Women's Hospital, Melbourne
AND
D. LIM
ABSTRACT: Factors that may have a bearing on subsequent pregnancy success or failure in patients with recurrent abortion were examined in 165 women with a history of three or more consecutive miscarriages in the first trimester. The overall success rate was 67.9%. Factors that were found to correlate significantly with success rate were length of abortion history, total number of abortions, interval from last miscarriage to present pregnancy, and whether there was any degree of subfertility. Logistic regression analysis showed that the abortion x years index and maternal age accounted for all the variation observed in our data. Where all other known causes of abortions are excluded, recurrent aborters can be subdivided into two populationsnamely, those with a relatively good prognosis characterized by a short abortion history and absence of subfertility problems, compared to those with a poor prognosis namely those with a long abortion history or presence of subfertility problems. These data clearly demonstrate major differences in success rates in women depending on the number of abortions and the length of abortion history (abortion x year index), particularly in women over the age of 30 years. (Am J Reprod Immunol. 1991; 26:72-75.) INTRODUCTION
Known causes of repeated miscarriage include anatomical, hormonal, endocrinological, and chromosomal disorders. However, in the vast majority of couples with recurrent abortion, a specific cause cannot be identified. A role for immunological causes in the aetiology of recurrent abortion has also been postulated, with a number offactors being reported to have an association with increased pregnancy loss. These include antibodies to phospholipids as measured by anti-cardiolipin antibody or 3:n~ico~gul~nt activity,1--4 absenc~ ofblockin% antibody activity III mixed lymphocyte reaction (MLR), -8 lack of suppressor cells.!" absence of anti-paternallymphocytotoxic antibodies," increased paternal HLA sharing,8,9 and increased homozygosity for HLA loci. ll,12 There is conflicting data in relation to most ofthese parameters, however. Other studies have shown that there is no association of recurrent abortion with increased HLA sharing r ' or lack of maternal serum blocking antibodies in MLR. 13,14 Other factors reported to have an association with an increased risk of abortion include increasing maternal age, primary as compared to secondary abortion, and greater number of previous miscarriages. 14,15
Submitted for publication March 1, i991; accepted August 1, 1991. Address reprint requests to M.N. Cauchi, The Royal Women's Hospital, Swanson St., Carlton 3053, Melbourne, Australia.
732
White cell immunization has been proposed as a method of treatment of women with recurrent abortion; however, there is only one double-blind control study reported to data'" where an improved outcome was seen followin~ immunization. Other studies supporting such a claim 1 ,17 have not been double-blind studies and their control patients have been patients who have not received any treatment at all. All three studies referred to above l4,16,17 have continuing pregnancy rates ofless than 40% in "controls" (i.e., those who were not actively immunized), compared with success rates of 70% or higher following immunization. This low success rate in nonimmunized subjects is much less than that reported by many other workers studying patients with recurrent abortion who have received no immunotherapy whatsoever. 15,18 In a controlled sequential trial we have shown that there is no significant difference between immunized and nonimmunized subjects, and, moreover, the success rate in the nonimmunized control patients was no less than that obtained in the immunized group. 19 In the present study, we have combined the results of two previous studies in an attempt to clarify the role of immunological causes in patients with recurrent abortion. These studies include an uncontrolled study performed initially and the controlled double blind sequential study referred to above. In addition to immunological criteria, we have also analyzed other factors reported to have an association with an increased risk of recurrent abortion such as increasing maternal age, primary as compared to secondary abortion, and greater number of previous miscarriages. MATERIALS AND METHODS
Selection ofPatients Patients were fully investigated prior to being included in either of the two study groups. All patients had anatomical disorders excluded by hysterosalpingography, were shown to be ovulating normally, chromosome analyses of both partners were normal, and immunological investigation showed no evidence of anti-cardiolipin antibody or the presence oflupus anticoagulant.f" The following correlates with success of pregnancy were made: Subfertility index defined by the aborting woman subjectively as follows: 1. Achieves pregnancy with ease 2. Achieves pregnancy with moderate difficulty 3. Requires treatment with Clomiphene 4. Requires in vitro fertilization The abortion history was defined as the number of years taken to achieve the number of pregnancies. The miscarriage to pregnancy interval was defined as the number of weeks between last miscarriage prior to investigation for recurrent miscarriage and LMP of the subsequentpregnanc~
PREDICTORS OF PREGNANCY SUCCESS
73
TABLE I. Comparison Between Successful and Miscarriage Pregnancy Populations Advanced Pregnancy (n Average age No. of abortions Abortion history (years) No. of abortions/year Subfertility index Miscarriage to pregnancy Interval No. of cells injected Abortion x Year Index
x 31.2 3.7 3.1 136.8 1.532 37.9
=
112)
SD 4.7
± ± ± ± ± ±
1.7 54.9 0.74 39.6
77.1 ± 12.6 ±
73.5 11.9
1.1
The number ofabortions per year is defined as the number of miscarriages divided by the number of years over which they occurred. Likewise, the abortion times years index is defined as the number of miscarriages multiplied by the number of years over which they occurred. Primary versus secondary aborters: Primary aborters were defined as those with no previous advanced pregnancy beyond 20 weeks gestation, by the same partner whereas secondary aborters refers to those with previous advanced pregnancies.
Immunization In the first study ("open study") of 119 couples, white cell immunization (husband or third party donor) was offered to all patients who were HLA cross-match negative and who fulfilled the selection criteria. In spite of this a number of patients declined to be immunized or were already pregnant when the results of the crossmatch test became available. In the second study (doubleblind randomized controlled trial), 47 patients were randomly allocated to one of two arms of a protocol and were injected either with the husband's white cells or normal saline. The technique of immunization has been described previously. 19 Statistical Analysis X and modified t tests (which allows for different variances for the two populations) were used to determine significant differences between subjects who achieved a successful or unsuccessful pregnancy. P values obtained using the Wilcoxon Rank Sum Test are also given. Logistic regression analysis on the binary data (success/ failure) for each subject, was performed to obtain regression models to estimate the probability of successful pregnancy. 2
Miscarriage (n x 32.4 4.8 4.9 123.1 1.88 54
=
53)
± ± ± ± ± ±
SD 4.7 2.5 3.5 58.6 1.03 48.8
97.2 ± 30.1 ±
122 36.4
Modified t Test t -1.53 -3.30 -3.52 1.43 2.09 -1.93 1.02 3.42
P .13 .002 .0008 .16 .04 .058
Wilcoxon Test P .07 .003 .001 .04 .098 .085
.31 .0012
.535 .001
The factors that correlated best with subsequent successful pregnancy were as follows (Table 11): normal fertility (subfertility index of 2 or less) (P = .025) number of abortions per year of 1.5 or greater (P = .025) a short abortion history of < 3 years or less (P = .005) total number of abortions < 5 (P = .0005) (P < .025) age: less 30 years abortion x year index (P < .0005) It should be emphasized when interpreting these results that the cut off point for the groups was chosen arbitrarily by examination of the data. These findings should be considered provisional unless and until they are supported by other data. In this analysis the following parameters were not significantly associated with successful pregnancy: primary versus secondary aborters or whether the couple were immunized with husband's or donor white cells. Logistic regression using each predictor variable separately showed that the following variables were significantly associated with successful pregnancy: number of abortions, abortion history, miscarriage to pregnancy interval, subfertility index and abortion x year index (Table III). A subsequent analysis was carried out using all ofthe variables, and including age as a factor with two levels (less than 30 years, greater than or equal to 30 years of age). Using a stepwise procedure it was found that the "best" model (i.e., the simplest, best fitting model for which the addition of extra terms did not result in a significant improvement in fit) was one in which the success rate was constant for women under 30 years of age, and decreased with increasing abortion x years index for women over 30. Figure 1 shows estimates of the probability of success and 95% confidence limits obtained from the logistic regression. For women under 30 years of age the estimate of the probability of success was 0.80 with a 95% confidence interval of(.68, .89).
RESULTS
DISCUSSION
There were significant differences between the group that had a subsequent successful pregnancy and those who miscarried again (Table I). The miscarriage group had a significantly higher number of abortions, longer abortion history, high subfertility index and a longer interval between each miscarriage and subsequent pregnancy. The average abortion x years index was more than two times higher for those who subsequently miscarried again as compared with those whose next pregnancy was successful.
Several studies have endeavored to determine correlates with successful pregnancy in recurrent aborters; however, the literature is conflicting in relation to the significance of a number of these parameters. Our study has confirmed the findings of Cowchock et al. 14 in that there was no correlation between subsequent successful pregnancy and a) degree ofHLA sharing, b) presence of anti-paternal antibody, and c) primary versus secondary aborters. We also agree with Cowchock et al. that a long abortion history is likely to be associated with a poor
74
CAUCHIET AL.
TABLE II. Factors Correlating With Success in Subsequent Pregnancy
Total Age Less than 30 years 30 years or older Subfertility index 2 or less More than 2 No. abortion/year 1.5 or more Less than 1.5 Abortion history (years) 3 years or less More than 3 years Miscarriage to pregnancy interval 20 weeks or less 21-49 weeks or more 50 or more No. abortions Less than 5 50rmore Abortion x year index < 20 ~ 20 Previous children None 1 or more Immunization Immunized Not immunized
1st Study Successful % No.
2nd Study (Controlled Trial) Successful Total No. %
(Combined Data) Successful Total No. %
2
P
37 81
31 48
(84) (59)
19 28
14 19
(74) (68)
56 109
45 67
(80) (61)
6.41
