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Obstetrics & Gynecology 1999;93:193-198
© 1999 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Association of Antibodies to Beta2-Glycoprotein 1 With Pregnancy Loss and Pregnancy-Induced Hypertension: A Prospective Study in Low-Risk Pregnancy

ANNE LYNCH, MB, MSPH, TIM BYERS, MD, MPH, WOODRUFF EMLEN, MD, DAWN RYNES, MT (ASCP), SUSAN M. SHETTERLY, MS and RICHARD F. HAMMAN, MD, DrPH

From the Department of Preventive Medicine and Biometrics, and the Division of Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado.

Address reprint requests to: Anne Lynch, MB, MSPH Department of Preventive Medicine and Biometrics University of Colorado Health Sciences Center 4200 East 9th Avenue, MSPH Program, Box C245 Denver, CO 80262 E-mail: anne.lynch{at}uchsc.edu


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To determine whether higher levels of anti-ß2-glycoprotein 1 before 25 weeks’ gestation are independently associated with either pregnancy loss or pregnancy-induced hypertension.

Methods: Serum samples for the immunoglobulin (Ig) G and IgM isotypes of anti-ß2-glycoprotein 1, anticardiolipin antibody, and antiphosphatidylserine were collected from 325 low-risk nulliparas who presented for prenatal care before 25 weeks’ gestation. This cohort was followed prospectively for the development of pregnancy loss and pregnancy-induced hypertension.

Results: The adjusted odds ratios (OR) and 95% confidence intervals (CI) of elevated antiphospholipid antibody levels for pregnancy loss were: IgG anti-ß2-glycoprotein 1, OR 1.2 (CI 0.5, 2.8); IgG anticardiolipin antibody, OR 8.4 (CI 2.3, 31); and IgG antiphosphatidylserine, OR 5.2 (CI 1.4, 18.7). The relative risks of pregnancy loss for all IgG antiphospholipid antibodies were higher among women who had blood collected after 10 weeks’ gestation compared with those studied before 10 weeks’ gestation. However, there were only marginal differences in the attributable risks, suggesting that the impact of elevated levels of antiphospholipid antibodies might be similar in early and later stages of pregnancy. None of the antiphospholipid antibodies was associated with pregnancy-induced hypertension.

Conclusion: In this study, elevated levels of IgG anticardiolipin and IgG antiphosphatidylserine antibodies were markers of pregnancy loss, but an elevated level of anti-ß2-glycoprotein was not a strong predictor of fetal loss.

In the past decade, several investigators found an association between elevated levels of antiphospholipid antibodies and adverse fetal outcomes in low-risk pregnancies (reviewed by Lynch et al1). These studies primarily implicated elevated levels of anticardiolipin antibodies as risk factors for pregnancy loss. The development of new assays to detect antibodies to the serum protein ß2-glycoprotein 1 (considered the true antigenic target in subjects with the antiphospholipid antibody syndrome2–4) have prompted the need for prospective studies to assess anti-ß2-glycoprotein 1 as a risk factor for adverse clinical outcomes. We decided to revisit our cohort of healthy pregnant women5 to determine whether higher levels of anti-ß2-glycoprotein 1 (before 25 weeks’ gestation) are more strongly associated with pregnancy loss and pregnancy-induced hypertension than elevated levels of antibodies to either cardiolipin or phosphatidylserine.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
Between August 1990 and July 1991, all consecutive nulliparas seen in the Obstetric Clinic at the University of Colorado Health Sciences Center before 25 weeks’ gestation were invited to participate in the study of antiphospholipid antibodies in low-risk pregnancy. The subjects and methods for this study have been described in detail elsewhere.5 Exclusion criteria were history of more than two spontaneous abortions, history of systemic lupus erythematosus, current treatment with corticosteroids or immunosuppressive agents, and history of thrombosis. This study was approved by the Institutional Review Board. Of the 408 subjects who were originally enrolled, 389 (95.3%) completed follow-up of clinical outcome.

Blood was collected at the first prenatal visit by routine venipuncture and serum separated and frozen at -70C. These samples remained frozen, apart from a single freeze-thaw cycle in 1992 for measurement of anticardiolipin antibody. Of the 389 original subjects with samples collected before 25 weeks’ gestation, 64 had insufficient amounts of serum for the current study, leaving 325 subjects with samples available for analysis of antiphospholipid antibodies. Subjects with missing samples did not differ in demographic features from subjects included in this study. The analyst was blinded to the clinical status of each subject. Anticardiolipin antibody and antiphosphatidylserine were measured according to the method of Harris,6 and standardized to positive control sera donated by the Antiphospholipid Standardization Laboratory. The ß2-glycoprotein 1 enzyme-linked immunosorbent assay involved plating ß2-glycoprotein 1 onto high-binding polystyrene microtiter plate wells (Costar catalog number 3590), according to the method of Roubey et al.7 Sera designated as positive controls were obtained from three sources: Dr. Roubey’s laboratory, INOVA Diagnostics, Inc. (San Diego, CA), and samples that consistently tested positive in our laboratory. Negative controls were sera obtained from subjects who had no known immunologic disease. The intra- and interassay variability was always less than 6%, and negative and positive controls were included with each batch of test sera.

We defined elevated levels of antiphospholipid antibodies as a value of the IgG or IgM isotypes of anti-ß2-glycoprotein 1, anticardiolipin, or antiphosphatidylserine antibodies above the 50th, 75th, 95th, and 99th percentile for the entire cohort. We chose to use percentiles as cutoffs because the data for all antiphospholipid antibodies followed a non-Gaussian distribution (positively skewed). There is currently a paucity of information on how levels of ß2-glycoprotein 1 and other antiphospholipid antibodies are affected by the process of freezing and by the physiologic changes caused by pregnancy. No control samples were available for pregnant subjects with frozen samples. We eliminated this problem by using controls from within our own cohort and compared outcomes in subjects with higher antibody levels with subjects with lower antibody levels.

The primary outcome variable was pregnancy loss, defined as loss of pregnancy at any time after the baseline examination, of which there were 34 in the original cohort. Serum samples were inadequate in six of these subjects, leaving a total of 28 with pregnancy loss for inclusion in the present study. The duration of gestation at pregnancy loss was determined as accurately as possible from evaluation of clinical information in the case records (date of last menstrual period, fundal height, and ultrasound examination). Seventeen of the 18 subjects who had blood collected before 10 weeks’ gestation had pregnancy loss before approximately 14 weeks’ gestation (spontaneous or missed abortions); the remaining subject experienced a pregnancy loss due to placenta previa at 25 weeks’ gestation. Ten subjects had blood collected after the 10th week. All of these subjects had losses after 10 weeks’ gestation. No obvious cause of loss was found in five cases. Four cases had premature rupture of the membranes and one had an intrauterine fetal death secondary to the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome.

The secondary outcome variable was pregnancy-induced hypertension, defined as supine systolic blood pressure at least 140 mmHg or diastolic blood pressure at least 90 mmHg (measured twice, 10 minutes apart).8 Stored serum samples were available for 37 of 42 women with pregnancy-induced hypertension from the original cohort.

Data were analyzed using the SAS statistical program (6.12, SAS Institute, Cary, NC). Initially, univariate analyses were conducted on all risk factors to determine general descriptive statistics. Relative risk (RR) was used to measure the association between elevated antibody levels and the two outcomes. The RR was calculated as the cumulative incidence of outcomes among women with elevated antiphospholipid antibody levels divided by the cumulative incidence of outcomes among women without elevated antiphospholipid antibody levels. The RR for adverse pregnancy outcome from other risk factors (categorized according to Table 1Go) for the two outcomes was also determined. The attributable risk (incidence of the outcome in the exposed group attributable to the exposure) was calculated by subtracting the incidence of the outcomes in the unexposed from the incidence of the outcomes in the exposed groups.


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  		Table 1. Unadjusted Relative Risks of Selected Risk Factors for Pregnancy Loss and Pregnancy-Induced Hypertension
 
Separate multivariate logistic regression models were constructed for pregnancy loss and pregnancy-induced hypertension. The RR adjusted for other risk factors of elevated levels of the individual antiphospholipid antibodies for pregnancy loss and pregnancy-induced hypertension was estimated using the odds ratio (OR). The multiplicative interaction of each risk factor with elevated anti-ß2-glycoprotein 1, anticardiolipin anti-body, and antiphosphatidylserine was then tested in these individual models. A full model was constructed containing all antiphospholipid antibodies variables and other risk factors. Backward selection was done on this model, to remove statistically unimportant variables (P > .05).


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
The subjects in this cohort were young, with a mean (± standard deviation) maternal age of 21.6 ± 4.98 years. Gestational age at the first prenatal visit was 13.3 ± 5.3 weeks, and the cohort was mainly single (76.6%) and non-Hispanic white (71.7%). Forty-seven percent reported either current or past cigarette smoking. Previous spontaneous abortions were reported by 20.3% of subjects. The unadjusted RR of other risk factors for pregnancy loss is shown in Table 1Go. Gestation length at blood collection was the only other risk factor significantly associated with pregnancy loss.

The unadjusted RR of pregnancy loss for IgG isotype of anti-ß2-glycoprotein 1, anticardiolipin antibody, and antiphosphatidylserine at values greater than selected cutoff levels is shown in Table 2Go. Although the RR for pregnancy loss was elevated for IgG anti-ß2-glycoprotein 1 levels greater than the 50th and 75th percentiles, neither association was statistically significant. The RR for pregnancy loss was significantly higher for most values of IgG anticardiolipin antibody and IgG antiphosphatidylserine greater than the 50th percentile. No association was found between pregnancy loss and elevated levels of IgM anti-ß2-glycoprotein 1, IgM anti-cardiolipin antibody, or IgM antiphosphatidylserine (data not shown).


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  		Table 2. Unadjusted Relative Risks* of Immunoglobulin G Antiphospholipid Antibodies for Pregnancy Loss
 
Levels of IgG anti-ß2-glycoprotein 1 greater than the 75th percentile and of the other two IgG antiphospholipid antibodies greater than the 95th percentile were selected for entry into the multivariate logistic regression model. The OR of the individual antiphospholipid antibodies for pregnancy loss, adjusted for other risk factors, is shown in Table 3Go. The association of IgG anti-ß2-glycoprotein 1 with pregnancy loss was weak, with an adjusted OR of 1.2. The adjusted ORs of IgG anticardiolipin antibody and IgG antiphosphatidylserine for pregnancy loss were 8.4 and 5.2, respectively. In a full model, including all antiphospholipid antibodies and risk factors, the adjusted OR and 95% confidence interval (CI) for IgG anti-ß2-glycoprotein 1 was 1.2 (0.5, 2.8), for IgG anticardiolipin antibody 5.9 (1.5, 24) and for IgG antiphosphatidylserine 2.9 (0.7, 12). Backward selection was done on this full model, leaving the IgG isotype of anticardiolipin antibody (OR 9.1; CI 2.8, 30; P < .001) and gestation at first blood collection (OR 5.4; CI 2.3, 12.6; P < .001) as the only variables statistically significantly associated with pregnancy loss. The test characteristics for the IgG antiphospholipid antibodies are also shown in Table 3Go.


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  		Table 3. Odds Ratios (95% Confidence Intervals) and Test Characteristics for Pregnancy Loss
 
The effect of elevated levels of IgG anti-ß2-glycoprotein 1, IgG anticardiolipin antibody, and IgG antiphosphatidylserine on pregnancy loss was modified by the time of the blood collection (ie, before or after 10 weeks’ gestation). Among subjects who had blood collected between the tenth and 25th weeks, the adjusted ORs for pregnancy loss for elevated anti-ß2-glycoprotein 1, IgG anticardiolipin antibody, and IgG antiphosphatidylserine levels were 3.8, 16.7, and 8.5, respectively. In contrast, among subjects who had blood collected before 10 weeks, the adjusted ORs for elevated levels of IgG anti-ß2-glycoprotein 1, IgG anticardiolipin antibody, and IgG antiphosphatidylserine for pregnancy loss were 0.5, 2.3, and 2.6, respectively. The interaction term P values for IgG anti-ß2-glycoprotein, IgG anticardiolipin antibody, and IgG antiphosphatidylserine were .03, .13, and .36, respectively.

We calculated the attributable risk (risk difference) of pregnancy loss associated with elevated antiphospholipid antibodies among subjects who had blood collected before (n = 100) and after (n = 225) 10 weeks’ gestation (Table 4Go). Unlike the differences in RRs, there were only small differences in the attributable risks.


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  		Table 4. Relative and Attributable Risks of Pregnancy Loss for Subjects Who Had Blood Collection Before and After 10 Weeks’ Gestation
 
None of the antiphospholipid antibodies were associated with pregnancy-induced hypertension in either the univariate or multivariate logistic regression parts of the analyses. The unadjusted RRs and 95% CIs of elevated (greater than the 95th percentile) antiphospholipid antibody levels for pregnancy-induced hypertension were as follows: IgG anti-ß2-glycoprotein 1, 0.5 (0.08, 3.2); IgG anticardiolipin antibody, 0.5 (0.1, 3.2); and IgG antiphosphatidylserine, 0.00 (0, 3.6). Most cases of pregnancy-induced hypertension (70%) occurred after 35 weeks’ gestation, and most subjects had a mild form of pregnancy-induced hypertension. Two factors were associated with this outcome, maternal age (under 20 years) and history of spontaneous abortion, each of which were associated with reduced risk of pregnancy-induced hypertension (Table 1Go).


   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this cohort, the adjusted OR for pregnancy loss was increased with elevated levels of IgG anticardiolipin antibody and IgG antiphosphatidylserine, but elevated levels of anti-ß2-glycoprotein 1 showed a much lower risk of pregnancy loss. Our results did not support anti-ß2-glycoprotein as a more specific marker for pregnancy loss in low-risk pregnancy.

Recent reviews9–11 emphasized that the causes of pregnancy loss differ between the preembryonicembryonic (before 10 weeks) and fetal (after 10 weeks) periods of pregnancy.12 Pregnancy loss is more common in the early stages,9 which explains the association we observed between pregnancy loss and early blood collection. As in other studies that suggested fetal death was more specific for antiphospholipid antibodies,11 the RR of pregnancy loss was higher among women who had blood collected after compared with before 10 weeks’ gestation (Table 4Go). The differences in RR between these two periods clearly indicate effect modification by gestation at blood collection (Table 4Go). There were only small differences between the stratum-specific attributable risks. In both strata, there was a moderately high attributable risk associated with elevated levels of anticardiolipin and antiphosphatidylserine antibodies, but a much lower attributable risk associated with elevated levels of anti-ß2-glycoprotein 1. These results imply that, when all other stratum-specific causes of pregnancy loss have been removed, the absolute risk of pregnancy loss due to elevated levels of antiphospholipid antibodies is similar regardless of when blood was collected. In our cohort, the observed RR of pregnancy loss among subjects who had early blood collection was likely driven toward null due to dilution of the effect by other causes of pregnancy loss during early pregnancy. The same attributable risk produced a much higher RR after 10 weeks’ gestation, when pregnancy loss was less common (Table 4Go). IgG anticardiolipin and IgG antiphosphatidylserine might be important markers of adverse fetal outcome in early and late pregnancy.

Despite the potentially important, evolving clinical importance of anti-ß2-glycoprotein 1 as a marker for antiphospholipid antibody syndrome, IgG anticardiolipin antibody was a better predictor of pregnancy loss than IgG anti-ß2-glycoprotein or IgG antiphosphatidylserine. Adjusted for other risk factors, the risk of pregnancy loss was eight times greater in subjects with elevated levels of IgG anticardiolipin antibody than in subjects with lower levels. The multivariate logistic regression analysis (full model containing all three antibodies) suggested collinearity between IgG anticardiolipin antibody and IgG antiphosphatidylserine for the outcome, yet IgG anticardiolipin antibody was the only antiphospholipid antibody statistically significantly associated with pregnancy loss.

Although anticardiolipin antibodies were previously correlated with anti-ß2-glycoprotein 1 in sera from subjects with the antiphospholipid antibody syndrome,13 we found low correlation between levels of IgG anticardiolipin antibody and IgG anti-ß2-glycoprotein 1 (Spearman correlation coefficient = 0.18, P = .001). This result might be due to differences in selection of subjects (ie, subjects with complex autoimmune disease in other studies versus healthy pregnant women in ours). We also found the overall clinical usefulness of these assays in our low-risk pregnant cohort to be limited because of low sensitivity and low positive predictive value (Table 3Go). The sensitivity (54%) and specificity (75%) improved in subjects who had any one test positive, but the positive predictive value remained low at 15% (Table 3Go).

There were no subjects with pregnancy loss who had levels of IgG anti-ß2-glycoprotein 1 greater than the 95th percentile. Sample size limited our ability to study the effect of higher levels of antibodies to ß2-glycoprotein 1 in low-risk pregnancy. We also evaluated the unadjusted (Table 2Go) and adjusted relative risks (data not shown) of IgG anticardiolipin and IgG antiphosphatidylserine at levels greater than the 75th percentile and found this cutoff level not as predictive for pregnancy loss. Another limitation of this study was our inability to control for the effect of long-term freezing and freeze-thawing of samples. However, because of our methods, all samples underwent the same duration of freezing and the same freeze-thaw cycles, minimizing differences between groups. The handling was the same for all antibody testing.

Pregnancy-induced hypertension was not associated with any of the antiphospholipid antibodies in this study. Other authors showed associations between antiphospholipid antibodies and hypertensive disorders of pregnancy.14,15 Few cases of pregnancy-induced hypertension were diagnosed in this low-risk cohort (reducing the power of the study). A previous study15 concentrated on high-risk cases with later timing of blood samples closer to onset of preeclampsia.

There is little reason to screen low-risk pregnant women for antiphospholipid antibodies because the positive predictive value of elevated levels of these autoantibodies is quite low.1 The limited data in this field clearly indicates the need for more longitudinal, prospective studies with larger sample sizes to further evaluate antiphospholipid antibodies and adverse outcomes, change in antiphospholipid antibodies levels during pregnancy (especially between the embryonic and fetal periods), and influence of other risk factors associated with pregnancy loss.


   Footnotes
 
Funding was provided by the Rocky Mountain Chapter of the Arthritis Foundation.

PII S0029-7844(98)00388-3

Received May 11, 1998. Received in revised form July 29, 1998. Accepted August 13, 1998.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Lynch A, Silver R, Emlen W. Antiphospholipid antibodies in healthy pregnant women. Rheum Dis Clin N Am 1997;23:55–69.[Medline]

2. Galli M, Comfurius P, Maassen C, Hemker H, De Baets M, Van Breda-Vriesman P, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335:1544–7.[Medline]

3. Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990;336:177–8.[Medline]

4. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation.ß2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990;87:4120–4.[Abstract/Free Full Text]

5. Lynch A, Marlar R, Murphy J, Davilla G, Santos M, Rutledge J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome. Ann Intern Med 1994;120:470–5.[Abstract/Free Full Text]

6. Harris EN. The second international anti-cardiolipin standardization workshop/the Kingston anti-phospholipid antibody study (KAPS) group. Am J Clin Pathol 1990;94:476–84.[Medline]

7. Roubey RAS, Eisenberg RA, Harper MF, Winfield JB. "Anticardiolipin" autoantibodies recognize ß2-glycoprotein 1 in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995;154:954–60.[Abstract]

8. National High Blood Pressure Educational Program Working Group report on high blood pressure in pregnancy. Am J Obstet Gynecol 1990;163:1691–712.[Medline]

9. Goldstein SR. Embryonic death in early pregnancy: A new look at the first trimester. Obstet Gynecol 1994;84:294–7.[Abstract/Free Full Text]

10. Branch DW. Thoughts on the mechanism of pregnancy loss associated with the antiphospholipid syndrome. Lupus 1994;3: 275–80.[Free Full Text]

11. Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. Antiphospholipid antibodies and fetal death. Obstet Gynecol 1996;87:489–93.[Abstract]

12. Moore KL. The developing human. 3rd ed. Philadelphia: WB Saunders, 1982.

13. Sanmarco M, Soler C, Christides C, Raoult D, Weiller PJ, Gerolami V, et al. Prevalence and clinical significance of IgG isotype anti-ß2-glycoprotein 1 antibodies in antiphospholipid syndrome: A comparative study with anticardiolipin antibodies. J Lab Clin Med 1997;129:499–506.[Medline]

14. Branch DW, Andres R, Digre KB, Rote NS, Scott JR. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989;73:541–5.[Abstract/Free Full Text]

15. Yamamoto T, Yoshimura S, Geshi Y, Sasamori S, Okinaga T, Kobayashi T, et al. Measurement of antiphospholipid antibody by ELISA using purified ß2-glycoprotein 1 in preeclampsia. Clin Exp Immunol 1993;94:196–200.[Medline]




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