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Relationship of twin zygosity and risk of preeclampsia
Relationship of twin zygosity and risk of preeclampsia Cynthia V. Maxwell, MD,a Ellice Lieberman, MD, DrPH,a Mary Norton, MD,c Amy Cohen, BA,a Ellen W. Seely, MD,b and Aviva Lee-Parritz, MDa Boston, Mass, and San Francisco, Calif OBJECTIVE: Twin gestations are known to be at higher risk for preeclampsia. One theory suggests that maternal recognition of fetal and trophoblastic tissues as foreign may be a factor. If that hypothesis is true, mothers carrying monozygous (MZ) gestations (ie a single fetal graft) might be predicted to have a lower rate of preeclampsia than those carrying dizygous (DZ) gestations. To evaluate this hypothesis, we compared the rate of preeclampsia in mothers with MZ and DZ twin gestations. STUDY DESIGN: Seven hundred sixty-eight twin deliveries from 1994 to 1999 were reviewed. Placental pathology reports were reviewed to determine the chorionic state of each placenta. Monochorionic placentas were assumed to be MZ. Dichorionic placentas were categorized as DZ if the neonates were of different sexes or different blood types. Maternal and fetal data were abstracted from the medical records. Preeclampsia was defined by standard criteria of the National Institutes of Health Working Group on High Blood Pressure. Our analysis was limited to women with pregnancies reaching at least 30 weeks of gestation where zygosity could be determined. RESULTS: Our analysis included 464 twin pregnancies, 154 MZ and 310 DZ. Among nulliparous women, the rate of preeclampsia was 15% (25/170) for DZ twins versus 20% (15/75) for MZ twins (P = .3). Among multiparous women, the rate was 8% (11/140) for DZ twins and 5% (4/79) for MZ twins (P = .4). In a logistic regression performed to control for confounding by maternal age, gestational age at delivery, assisted reproduction, and male sex, dizygotic state was associated with an odds ratio of 1.4 (95% CI = 0.5-3.9) for developing preeclampsia in nulliparous women and 1.2 in multiparous women (95% CI = 0.3-5.0). CONCLUSIONS: These results do not support the hypothesis that zygosity affects the rate of preeclampsia in twin gestations, though the number of subjects in our study was too small to allow definitive conclusions. Larger studies are needed to evaluate this finding. (Am J Obstet Gynecol 2001;185:819-21.)
Key words: Preeclampsia, twins, zygosity, nulliparous, multiparous
Multiple theories have been proposed to explain the etiology of preeclampsia.1, 2 Many investigators believe that an immunologic or immunogenetic event early in gestation triggers a maladaptation of the maternal immune system to the fetal trophoblastic tissue.1 Such an immunologic event could result in part from maternal recognition and subsequent rejection of the paternal contributions to the fetal syncytiotrophoblastic composition. This is supported by studies showing that change in paternity, or “primipaternity,” is a risk factor for the development of preeclampsia.2, 3 It has also been demonstrated that women with multiple gestations have an increased rate of preeclampsia compared with women with
From the Department of Obstetrics, Gynecology and Reproductive Medicine,a the Department of Medicine,b Brigham and Women’s Hospital, Harvard Medical School, and the Department of Obstetrics, Gynecology and Reproductive Sciences,c University of California. Presented at the Twenty-first Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprint requests: Cynthia V. Maxwell, MD, Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Copyright© 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/117352 doi:10.1067/mob.2001.117352
single gestations.4, 5 If the cause of preeclampsia relates to an immunologic reaction, then one would predict that dizygous (DZ) twin gestations, compared with monozygous (MZ) twin gestations, would be at higher risk for preeclampsia given the greater diversity of antigens. Gestational hypertension is thought to differ from preeclampsia in that it lacks many of the same end-organ disturbances and, therefore, the same immunologic events may not be at work. Since an immunologic etiology is not hypothesized, a similar rate of gestational hypertension would be expected in MZ and DZ twins. This study was designed to evaluate whether women carrying MZ and DZ twin gestations differ in their rates of preeclampsia and gestational hypertension. Study design Case records of all twin deliveries were collected for the period between 1994 and 1999. Placental pathology reports were used to determine chorionic state. Monochorionic placentas were assumed to arise from MZ pregnancies. Since dichorionic placentas could arise from either MZ or DZ pregnancies, fetal information was used to help in the differentiation. Same-sex twins were assumed to be DZ when the fetal ABO blood group typing 819
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Table I. Classification of zygosity for all twins >30 weeks of gestation Zygosity Monozygous Dizygous Same sex Discordant sex Unknown zygosity
Table II. Maternal characteristics by twin zygosity Maternal characteristic
No. (%) of twin pairs
Monozygous (n = 154)
Parity Nulliparous Multiparous Age Gestational age Assisted reproduction Preterm labor Male fetus
154 (22) 310 (44) 78 232 240 (34)
75 (49%) 79 30.6 35.1 10 (6.7%) 53 (34%) 80 (52%)
Dizygous (n = 310)
170 (55%) 140 33.2 35.3 180 (60%) 83 (27%) 272 (88%)
P value
.2 .0001 .5 .001 .09 .001
Table III. Number (%) of hypertensive outcomes for MZ and DZ twins according to parity Nulliparous* MZ (n = 75) DZ (n = 170) No pregnancy-related hypertension Gestational hypertension Preeclampsia
48 (64%) 12 (16%) 15 (20%)
116 (68%) 29 (17%) 25 (15%)
Multiparous† MZ (n = 79) DZ (n = 140) 69 (87%) 6 (8%) 4 (5%)
118 (84%) 11 (8%) 11 (8%)
*P = .6 for difference in hypertensive outcomes for MZ and DZ twins. †P = .7 for difference in hypertensive outcomes for MZ and DZ twins.
was discordant. For discordant-sex twins, the placentas were assumed to be DZ. Maternal data were abstracted from medical records and included age, gravidity, parity, ABO blood group, complications of pregnancy, and other risk factors for preeclampsia, including history of previous preeclampsia, chronic hypertension, renal disease, systemic lupus erythematosus, and obesity. Fetal data were also obtained and included gestational age at delivery, sex, birth weight, presence of anomalies, and ABO blood group. Preeclampsia was defined by the standard criteria outlined by the 2000 Working Group on Hypertension in Pregnancy.6 Briefly, preeclampsia was diagnosed by the following criteria: elevated blood pressure (2 sitting blood pressure readings taken at least 6 hours apart that were both greater than 140 mm Hg systolic and 90 mm Hg diastolic); nondependent peripheral edema; and proteinuria (greater than 300 mg of protein found in a 24hour urine collection or greater than or equal to 2+ proteinuria on dipstick). Data on elevated liver function tests, thrombocytopenia, hemolysis, abnormal renal function, and occurrence of eclampsia were also collected. Gestational hypertension was defined as hypertension without proteinuria after the 20th week of gestation. The current analysis included only women delivering after 30 weeks’ gestation since the majority of cases of preeclampsia develop late in the third trimester of pregnancy. Of the 48 women delivering before 30 weeks in whom zygosity could be determined, only one was diagnosed with preeclampsia. Analyses were limited to the group of twins for whom zygosity could be determined. Statistical analyses were performed by using the Student t test, the Fisher exact test, and the χ2 test. Logistic regres-
sion was performed to control for confounding by the following variables: maternal age, gestational age at delivery, fetal sex, and use of assisted reproduction. A P value of < .05 was considered statistically significant. Odds ratios were calculated from logistic regression coefficients, and confidence intervals were calculated from the standard errors of these coefficients. Approval for the review of medical records and laboratory reports was obtained from the Human Research Committee of the Brigham and Women’s Hospital. Results There were 768 twin deliveries identified during the study period. Of these, 704 (91.5%) occurred at 30 weeks of gestation or greater. One hundred and fifty-four (22%) pairs of MZ twins and 310 (44%) pairs of DZ twins of at least 30 weeks’ gestation were identified (Table I). Of the DZ twins, 78 pairs were concordant for sex. Mothers with MZ and DZ twins included in the analyses differed with respect to maternal age and rate of assisted reproduction (Table II). Mothers carrying DZ twins were more likely to be older and to have undergone assisted reproduction compared with those carrying MZ twins. The proportion of women with preterm labor was similar for both MZ and DZ gestations. For both nulliparous and multiparous women, rates of chronic and gestational hypertension were similar for MZ and DZ pregnancies (Table III). As expected, nulliparous women had a significantly higher rate of preeclampsia compared with multiparous women, 14% versus 6%, P = .002. The crude rates for preeclampsia in nulliparous women were 20% for MZ twins compared with 15% for DZ twins (P = .3). The crude rates for multiparous women
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were 5% for MZ twins compared with 8% for DZ twins (P = .4, Table III). In a logistic regression controlling for maternal age, presence of a male fetus, and assisted reproduction, dizygotic gestations compared with monozygotic were associated with an odds ratio of 1.4 (CI = 0.5-3.9) for developing preeclampsia in nulliparous women. For multiparous women, the odds ratio was 1.2 (CI = 0.3-5.0). Comment Several studies have identified twin gestations to be at risk for hypertensive complications of pregnancy.5 Evidence suggests that higher-order pregnancies may also be at increased risk for the severe form of preeclampsia,7 which may be related to problems with placentation in early development. Alternatively, the increase in preeclampsia in twin pregnancies may be related to a maternal immune reaction to the complement of fetal trophoblast in multiple gestations. If immunologic factors contribute significantly to the increase in preeclampsia, as well as the finding by multiple investigators that paternity plays a significant role in the development of preeclampsia,2, 8 then there may be even greater rates of this pregnancy-related syndrome in dizygotic twin gestations. Our study did not show significant differences in the rates of preeclampsia between MZ and DZ twin pregnancies among nulliparous or multiparous women. In regression analyses controlling for confounding factors, the odds ratio from the regression analyses were 1.4 (95% CI = 0.5-3.9) for nulliparous women and 1.2 (95% CI = 0.35.0) for multiparous women. This is consistent with the findings from earlier investigations conducted in the 1970s.9-11 Our study supports the conclusions of these older studies with the advantage of a data set that provides more precise delineation of zygosity and is able to consider potential confounding by variables such as assisted reproduction and fetal sex. The finding that dizygotic pregnancy is not associated with a higher rate of preeclampsia does not support the hypothesis that increased placental immunogenicity derived from paternal antigens contributes to the development of preeclampsia. However, the number of subjects was relatively small and our power to detect a difference was limited. Our study had a 15% power to detect moderate differences in the association of the magnitude we observed; therefore, it is not possible to draw definitive conclusions from it. The rates of gestational hypertension were similar for
MZ and DZ twins. As this type of nonproteinuric pregnancy-associated hypertension lacks most of the end-organ sequelae of preeclampsia and is likely to be pathogenetically distinct from it, immunogenetic factors would not be expected to play a significant role in its development. Several authors have pointed to the role of donor oocytes and sperm as risk factors for the development of preeclampsia.12, 13 However, our study contained too few cases of donor-assisted reproduction to address this question. In summary, this study did not show significant differences in the rate of preeclampsia and gestational hypertension when comparing MZ and DZ twin pairs for both nulliparous and multiparous mothers. A larger study would be needed to provide a definitive answer. The authors acknowledge Ms Cecilia Valera for her assistance in obtaining pathology reports, Ms Ada Maxwell, and Ms Leigh Ann Cumming for their assistance with literature review. REFERENCES
1. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359-75. 2. Dekker GA, Robillard PY, Hulsey TC. Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies. Obstet Gynecol Surv 1998;53:377-82. 3. Trupin LS, Simon LP, Eskenazi B. Change in paternity: a risk factor for preeclampsia. Epidemiology 1996;7:240-44. 4. Coonrod DV, Hickok DE, Zhu K, Easterling TR, Daling JR. Risk factors for preeclampsia in twin pregnancies: a population-based cohort study. Obstet Gynecol 1995;85:645-50. 5. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twin versus singleton gestations. Am J Obstet Gynecol 2000;182:938-42. 6. National Institutes of Health, National Heart, Lung and Blood Institute, National High Blood Pressure Education Program, NIH Publication No. 00-3029. Bethesda (MD):NIH; July 2000. 7. Mastrobattista JM, Skupski DW, Monga M, Blanco JD, August P. The rate of severe preeclampsia is increased in triplet as compared to twin gestations. Am J Perinatol 1997;14:263-5. 8. Dekker GA, Tubbergen P, Valk M, Althuisius SM, Lachmeijer AM. Change in paternity: a risk factor for preeclampsia in multiparous women? [abstract] Am J Obstet Gynecol 1998;178 Suppl:120S. 9. Starkie CM, Crawford JS. Twins, immuno-incompatibility and pre-eclampsia. Int J Gynaecol Obstet 1976;14:559. 10. McFarlane A, Scott JS. Pre-eclampsia/eclampsia in twin pregnancies. J Med Genet 1976;13:208-11. 11. Campbell DM, MacGillivray I, Thompson B. Twin zygosity and pre-eclampsia. Lancet 1977;2:97. 12. Serhal PF, Craft I. Immune basis for pre-eclampsia: evidence from oocyte recipients [letter]. Lancet 1987;744. 13. Need JA, Bell B, Meffin E, Jones WR. Pre-eclampsia in pregnancies from donor inseminations. J Reprod Immunol 1983;5:329-38.
Key words: Preeclampsia, twins, zygosity, nulliparous, multiparous
Multiple theories have been proposed to explain the etiology of preeclampsia.1, 2 Many investigators believe that an immunologic or immunogenetic event early in gestation triggers a maladaptation of the maternal immune system to the fetal trophoblastic tissue.1 Such an immunologic event could result in part from maternal recognition and subsequent rejection of the paternal contributions to the fetal syncytiotrophoblastic composition. This is supported by studies showing that change in paternity, or “primipaternity,” is a risk factor for the development of preeclampsia.2, 3 It has also been demonstrated that women with multiple gestations have an increased rate of preeclampsia compared with women with
From the Department of Obstetrics, Gynecology and Reproductive Medicine,a the Department of Medicine,b Brigham and Women’s Hospital, Harvard Medical School, and the Department of Obstetrics, Gynecology and Reproductive Sciences,c University of California. Presented at the Twenty-first Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprint requests: Cynthia V. Maxwell, MD, Department of Obstetrics, Gynecology and Reproductive Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Copyright© 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/6/117352 doi:10.1067/mob.2001.117352
single gestations.4, 5 If the cause of preeclampsia relates to an immunologic reaction, then one would predict that dizygous (DZ) twin gestations, compared with monozygous (MZ) twin gestations, would be at higher risk for preeclampsia given the greater diversity of antigens. Gestational hypertension is thought to differ from preeclampsia in that it lacks many of the same end-organ disturbances and, therefore, the same immunologic events may not be at work. Since an immunologic etiology is not hypothesized, a similar rate of gestational hypertension would be expected in MZ and DZ twins. This study was designed to evaluate whether women carrying MZ and DZ twin gestations differ in their rates of preeclampsia and gestational hypertension. Study design Case records of all twin deliveries were collected for the period between 1994 and 1999. Placental pathology reports were used to determine chorionic state. Monochorionic placentas were assumed to arise from MZ pregnancies. Since dichorionic placentas could arise from either MZ or DZ pregnancies, fetal information was used to help in the differentiation. Same-sex twins were assumed to be DZ when the fetal ABO blood group typing 819
820 Maxwell et al
October 2001 Am J Obstet Gynecol
Table I. Classification of zygosity for all twins >30 weeks of gestation Zygosity Monozygous Dizygous Same sex Discordant sex Unknown zygosity
Table II. Maternal characteristics by twin zygosity Maternal characteristic
No. (%) of twin pairs
Monozygous (n = 154)
Parity Nulliparous Multiparous Age Gestational age Assisted reproduction Preterm labor Male fetus
154 (22) 310 (44) 78 232 240 (34)
75 (49%) 79 30.6 35.1 10 (6.7%) 53 (34%) 80 (52%)
Dizygous (n = 310)
170 (55%) 140 33.2 35.3 180 (60%) 83 (27%) 272 (88%)
P value
.2 .0001 .5 .001 .09 .001
Table III. Number (%) of hypertensive outcomes for MZ and DZ twins according to parity Nulliparous* MZ (n = 75) DZ (n = 170) No pregnancy-related hypertension Gestational hypertension Preeclampsia
48 (64%) 12 (16%) 15 (20%)
116 (68%) 29 (17%) 25 (15%)
Multiparous† MZ (n = 79) DZ (n = 140) 69 (87%) 6 (8%) 4 (5%)
118 (84%) 11 (8%) 11 (8%)
*P = .6 for difference in hypertensive outcomes for MZ and DZ twins. †P = .7 for difference in hypertensive outcomes for MZ and DZ twins.
was discordant. For discordant-sex twins, the placentas were assumed to be DZ. Maternal data were abstracted from medical records and included age, gravidity, parity, ABO blood group, complications of pregnancy, and other risk factors for preeclampsia, including history of previous preeclampsia, chronic hypertension, renal disease, systemic lupus erythematosus, and obesity. Fetal data were also obtained and included gestational age at delivery, sex, birth weight, presence of anomalies, and ABO blood group. Preeclampsia was defined by the standard criteria outlined by the 2000 Working Group on Hypertension in Pregnancy.6 Briefly, preeclampsia was diagnosed by the following criteria: elevated blood pressure (2 sitting blood pressure readings taken at least 6 hours apart that were both greater than 140 mm Hg systolic and 90 mm Hg diastolic); nondependent peripheral edema; and proteinuria (greater than 300 mg of protein found in a 24hour urine collection or greater than or equal to 2+ proteinuria on dipstick). Data on elevated liver function tests, thrombocytopenia, hemolysis, abnormal renal function, and occurrence of eclampsia were also collected. Gestational hypertension was defined as hypertension without proteinuria after the 20th week of gestation. The current analysis included only women delivering after 30 weeks’ gestation since the majority of cases of preeclampsia develop late in the third trimester of pregnancy. Of the 48 women delivering before 30 weeks in whom zygosity could be determined, only one was diagnosed with preeclampsia. Analyses were limited to the group of twins for whom zygosity could be determined. Statistical analyses were performed by using the Student t test, the Fisher exact test, and the χ2 test. Logistic regres-
sion was performed to control for confounding by the following variables: maternal age, gestational age at delivery, fetal sex, and use of assisted reproduction. A P value of < .05 was considered statistically significant. Odds ratios were calculated from logistic regression coefficients, and confidence intervals were calculated from the standard errors of these coefficients. Approval for the review of medical records and laboratory reports was obtained from the Human Research Committee of the Brigham and Women’s Hospital. Results There were 768 twin deliveries identified during the study period. Of these, 704 (91.5%) occurred at 30 weeks of gestation or greater. One hundred and fifty-four (22%) pairs of MZ twins and 310 (44%) pairs of DZ twins of at least 30 weeks’ gestation were identified (Table I). Of the DZ twins, 78 pairs were concordant for sex. Mothers with MZ and DZ twins included in the analyses differed with respect to maternal age and rate of assisted reproduction (Table II). Mothers carrying DZ twins were more likely to be older and to have undergone assisted reproduction compared with those carrying MZ twins. The proportion of women with preterm labor was similar for both MZ and DZ gestations. For both nulliparous and multiparous women, rates of chronic and gestational hypertension were similar for MZ and DZ pregnancies (Table III). As expected, nulliparous women had a significantly higher rate of preeclampsia compared with multiparous women, 14% versus 6%, P = .002. The crude rates for preeclampsia in nulliparous women were 20% for MZ twins compared with 15% for DZ twins (P = .3). The crude rates for multiparous women
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were 5% for MZ twins compared with 8% for DZ twins (P = .4, Table III). In a logistic regression controlling for maternal age, presence of a male fetus, and assisted reproduction, dizygotic gestations compared with monozygotic were associated with an odds ratio of 1.4 (CI = 0.5-3.9) for developing preeclampsia in nulliparous women. For multiparous women, the odds ratio was 1.2 (CI = 0.3-5.0). Comment Several studies have identified twin gestations to be at risk for hypertensive complications of pregnancy.5 Evidence suggests that higher-order pregnancies may also be at increased risk for the severe form of preeclampsia,7 which may be related to problems with placentation in early development. Alternatively, the increase in preeclampsia in twin pregnancies may be related to a maternal immune reaction to the complement of fetal trophoblast in multiple gestations. If immunologic factors contribute significantly to the increase in preeclampsia, as well as the finding by multiple investigators that paternity plays a significant role in the development of preeclampsia,2, 8 then there may be even greater rates of this pregnancy-related syndrome in dizygotic twin gestations. Our study did not show significant differences in the rates of preeclampsia between MZ and DZ twin pregnancies among nulliparous or multiparous women. In regression analyses controlling for confounding factors, the odds ratio from the regression analyses were 1.4 (95% CI = 0.5-3.9) for nulliparous women and 1.2 (95% CI = 0.35.0) for multiparous women. This is consistent with the findings from earlier investigations conducted in the 1970s.9-11 Our study supports the conclusions of these older studies with the advantage of a data set that provides more precise delineation of zygosity and is able to consider potential confounding by variables such as assisted reproduction and fetal sex. The finding that dizygotic pregnancy is not associated with a higher rate of preeclampsia does not support the hypothesis that increased placental immunogenicity derived from paternal antigens contributes to the development of preeclampsia. However, the number of subjects was relatively small and our power to detect a difference was limited. Our study had a 15% power to detect moderate differences in the association of the magnitude we observed; therefore, it is not possible to draw definitive conclusions from it. The rates of gestational hypertension were similar for
MZ and DZ twins. As this type of nonproteinuric pregnancy-associated hypertension lacks most of the end-organ sequelae of preeclampsia and is likely to be pathogenetically distinct from it, immunogenetic factors would not be expected to play a significant role in its development. Several authors have pointed to the role of donor oocytes and sperm as risk factors for the development of preeclampsia.12, 13 However, our study contained too few cases of donor-assisted reproduction to address this question. In summary, this study did not show significant differences in the rate of preeclampsia and gestational hypertension when comparing MZ and DZ twin pairs for both nulliparous and multiparous mothers. A larger study would be needed to provide a definitive answer. The authors acknowledge Ms Cecilia Valera for her assistance in obtaining pathology reports, Ms Ada Maxwell, and Ms Leigh Ann Cumming for their assistance with literature review. REFERENCES
1. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359-75. 2. Dekker GA, Robillard PY, Hulsey TC. Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies. Obstet Gynecol Surv 1998;53:377-82. 3. Trupin LS, Simon LP, Eskenazi B. Change in paternity: a risk factor for preeclampsia. Epidemiology 1996;7:240-44. 4. Coonrod DV, Hickok DE, Zhu K, Easterling TR, Daling JR. Risk factors for preeclampsia in twin pregnancies: a population-based cohort study. Obstet Gynecol 1995;85:645-50. 5. Sibai BM, Hauth J, Caritis S, Lindheimer MD, MacPherson C, Klebanoff M, et al. Hypertensive disorders in twin versus singleton gestations. Am J Obstet Gynecol 2000;182:938-42. 6. National Institutes of Health, National Heart, Lung and Blood Institute, National High Blood Pressure Education Program, NIH Publication No. 00-3029. Bethesda (MD):NIH; July 2000. 7. Mastrobattista JM, Skupski DW, Monga M, Blanco JD, August P. The rate of severe preeclampsia is increased in triplet as compared to twin gestations. Am J Perinatol 1997;14:263-5. 8. Dekker GA, Tubbergen P, Valk M, Althuisius SM, Lachmeijer AM. Change in paternity: a risk factor for preeclampsia in multiparous women? [abstract] Am J Obstet Gynecol 1998;178 Suppl:120S. 9. Starkie CM, Crawford JS. Twins, immuno-incompatibility and pre-eclampsia. Int J Gynaecol Obstet 1976;14:559. 10. McFarlane A, Scott JS. Pre-eclampsia/eclampsia in twin pregnancies. J Med Genet 1976;13:208-11. 11. Campbell DM, MacGillivray I, Thompson B. Twin zygosity and pre-eclampsia. Lancet 1977;2:97. 12. Serhal PF, Craft I. Immune basis for pre-eclampsia: evidence from oocyte recipients [letter]. Lancet 1987;744. 13. Need JA, Bell B, Meffin E, Jones WR. Pre-eclampsia in pregnancies from donor inseminations. J Reprod Immunol 1983;5:329-38.