Obstetrics & Gynecology:
Thyroperoxidase and Thyroglobulin Antibodies in Early Pregnancy and Placental Abruption
Haddow, James E. MD; McClain, Monica R. PhD; Palomaki, Glenn E. BS; Neveux, Louis M. BA; Lambert-Messerlian, Geralyn PhD; Canick, Jacob A. PhD; Malone, Fergal D. MD; Porter, T. Flint MD; Nyberg, David A. MD; Bernstein, Peter S. MD; D'Alton, Mary E. MD; for the First and Second Trimester Risk of Aneuploidy (FaSTER) Research Consortium
From the Women and Infants Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; Savjani Institute for Health Research, Standish, Maine; Columbia University College of Physicians and Surgeons, New York, New York; Royal College of Surgeons in Ireland, Dublin, UK; the University of Utah and Intermountain HealthCare, Salt Lake City, Utah; Swedish Medical Center, Seattle, Washington; and Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
See related article on page 293.
Partially supported by Grant Number RO1 HD 38652 from the National Institutes of Health and the National Institute of Child Health and Human Development.
Corresponding author: James E. Haddow, MD, Co-Director, Division of Medical Screening & Special Testing, Women & Infants Hospital, Alpert Medical School of Brown University, 70 Elm Street, 2nd Floor, Providence, RI 02903; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the relationship between thyroid antibodies and placental abruption.
METHODS: This cohort study assesses thyroperoxidase and thyroglobulin antibodies in relation to placental abruption among 10,062 women with singleton viable pregnancies (from the First and Second Trimester Risk of Aneuploidy [FaSTER] trial). A thyroperoxidase antibody cutoff of 50 international units/mL is used for comparison with published data from another cohort.
RESULTS: Women with elevated thyroperoxidase antibody levels in the first and second trimesters have a higher rate of placental abruption than antibody-negative women. This relationship is less strong in the first trimester (1.51% compared with 0.83%; odds ratio [OR], 1.83; 95% confidence interval [CI], 0.99–3.37) than in the second trimester (1.78% compared with 0.82%; OR, 2.20; 95% CI, 1.21–3.99). A similar, but weaker, relationship is present for thyroglobulin antibodies. Sixty-four of 782 thyroperoxidase antibody-positive pregnancies without abruption become negative by the second trimester; one pregnancy with abruption becomes antibody-positive. Odds ratios for pregnancies with both thyroperoxidase and thyroglobulin antibody elevations are also higher (first trimester: OR, 2.10; 95% CI, 0.91–4.86; second trimester: OR, 2.73; 95% CI, 1.17–6.33).
CONCLUSION: The present data confirm an association between thyroid antibody elevations and placental abruption described in a recent report. These findings, however, do not provide support for recommending routine testing for thyroid antibodies during pregnancy.
LEVEL OF EVIDENCE: II
Abbassi-Ghanavati et al recently reported a threefold increase in pregnancies with placental abruption among women with thyroid peroxidase antibodies (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7–6.7).1 This prompted us to reexamine that relationship in a cohort of pregnancies with thyroid-related measurements that were enrolled secondarily in conjunction with a multicenter observational study (the First and Second Trimester Risk of Aneuploidy [FaSTER] trial).2–4 Although the primary purpose of the FaSTER trial was to study newer screening strategies for Down syndrome,5 the collection of serum samples at two intervals during early pregnancy, coupled with outcome data, allowed a broader range of investigation. The present analysis focuses on thyroid peroxidase antibody for comparison with the recent study, but thyroglobulin antibody measurements are also available and are examined. The objective of this study was to estimate the relationship between thyroid antibodies and placental abruption.
MATERIALS AND METHODS
As previously described, participants in the multicenter FaSTER trial were enrolled between October 1, 1999, and December 31, 2002.5 Enrollment was restricted to women with singleton pregnancies. Institutional Review Board approval was obtained at all of the recruitment centers. At five of these centers, supplementary consent was sought from participants beginning partway through the study to allow their residual serum samples to be used for additional research studies. Samples from the 10,990 women who consented at those centers (Montefiore Medical Center, Bronx, NY; Swedish Medical Center, Seattle, WA; LDS Hospital, Salt Lake City, UT; Utah Valley Regional Medical Center, Provo, UT; and McKay Dee Hospital, Ogden, UT) were eligible for inclusion in the present study. Women who did not consent and those whose pregnancies were affected by Down syndrome were excluded.
Inclusion criteria also required that thyroid-related measurements be available at both 11–13 weeks of gestation and 15–18 weeks of gestation, that gestational ages be established by ultrasonography, and that pregnancies be viable at the time when the second serum sample was obtained in the second trimester. From the 10,329 women who met those inclusion criteria, 267 were excluded because the question about whether the woman had hypothyroidism was not answered; 10,062 women remained for analysis, 392 of whom reported having an existing diagnosis of hypothyroidism. These self-reports were not individually confirmed, but the rate of antibody positivity and distribution of thyroid-stimulating hormone measurements for the group as a whole offered indirect evidence that this classification was generally reliable.4 Detailed demographic characteristics of the study population at each of the five enrollment sites are shown in an earlier publication.6 The present analyses focus on the 9670 women without hypothyroidism (10,062-392), but the relationship between antibodies and placental abruption among the 392 hypothyroid women is briefly described as well.
Postdelivery follow-up was performed by medical record review by the research coordinator at each site or by telephone interview with the patient. A single perinatologist and a pediatric geneticist reviewed detailed maternal and pediatric medical records for the following patient subsets: abnormal first, second, or both trimester screening; adverse obstetric or pediatric outcomes; and 10% of normal subjects randomly selected at each site from the trial database. Further details of collection of follow-up data are published elsewhere.2
Thyroid-related measurements in this cohort were available from previous studies coupled with outcome data relating to pregnancy and delivery.2–4,6,7 This offered the opportunity to compare the relationship between thyroperoxidase antibody status and placental abruption with findings from a recent report.1 In that study, thyroid peroxidase antibody levels were above 50 international units/mL in approximately 6% of 17,219 study subjects, and 10 of the 58 cases of abruption occurred in those women. Among the 9670 women in our cohort, 86 cases of placental abruption were identified. Assuming similar rates of antibody positivity and segregation of placental abruption, our study size would be sufficient to confirm the previous results (OR, 3.37; 95% CI, 1.92–5.92).
Samples were stored at −80°C and tested for thyroid antibodies between July 2004 and May 2005 (storage was for 3–6 years). Levels of thyroperoxidase and thyroglobulin antibodies were measured using the Immulite 2000 methodology. Normative data involving these analytes have been published separately for this cohort along with details of assay performance.8 Samples were thawed overnight before assay, and first and second trimester samples from each woman were assayed within 24 hours of each other. In the present analysis, women's antibody measurements are considered positive if thyroperoxidase antibody concentrations are greater than 50 international units/mL or if thyroglobulin antibody concentrations are greater than 40 international units/mL. The concentration of 50 international units/mL for thyroperoxidase antibodies is used here to allow comparison with the recent study.1
Odds ratios and tests of significance for 2×2 tables were computed using Epistat. Two-group comparisons were calculated using the Student's t test. Significance was two-tailed at the .05 level. All other data analyses were performed using SAS 9.1. Stepwise logistic regression was used to adjust the observed ORs for possible covariates of the outcomes of interest (eg, preterm delivery). The baseline model included maternal age, body mass index, gravidity (primipara, multipara), and race (white, nonwhite).2 Stepwise regression was then used to identify the following four variables that also entered one (or more) of the models: smoking (yes, no), gestational diabetes, educational level (less than 12, 12, more than 12 years), and recruitment site. The final fixed models used for adjusting the ORs consisted of all eight variables.
Table 1 shows demographic characteristics of study subjects according to thyroperoxidase antibody status at 15–18 weeks of gestation. Women with elevated antibody levels are older, on average, and fewer are primigravid. Comparisons of these characteristics are similar for thyroperoxidase antibody status in the first trimester as well as among women with and without thyroglobulin antibodies. The table also shows that the frequency of placental abruption is significantly higher among thyroperoxidase antibody-positive women (P=.05). Although not shown in the table, this relationship is directionally similar in the first trimester but not significant.
Table 2 shows that there is a 0.68% higher absolute rate of placental abruption (from 0.83% to 1.51%; OR, 1.83) among women with elevated levels of thyroperoxidase antibodies in the first trimester. In the second trimester, the absolute rate is 0.96% higher (from 0.82% to 1.78%; OR, 2.20), and the OR is only slightly lower after adjustment. The higher OR in the second trimester results from 64 of 782 thyroperoxidase antibody-positive women in the first trimester without placental abruption being reclassified as antibody-negative in the second trimester, whereas one antibody-negative woman in the first trimester with placental abruption becomes reclassified as antibody-positive.
Table 2 also shows that there is a 0.40% higher absolute rate of placental abruption (from 0.86% to 1.26%; OR, 1.47) among women with elevated levels of thyroglobulin antibodies in the first trimester. In the second trimester, the absolute rate is 0.61% higher (from 0.85% to 1.46%; OR, 1.73). The higher OR in the second trimester results from 98 of 706 antibody-positive women in the first trimester without abruption being reclassified as antibody-negative in the second trimester; none are reclassified as antibody-positive. Although thyroglobulin ORs in both trimesters are in the same direction as for thyroperoxidase antibodies, neither reaches statistical significance. Not shown in the table is a separate subgroup of hypothyroid women, 49% with elevated thyroperoxidase antibodies and 31% with elevated thyroglobulin antibodies. Among these women, the overall rate of placental abruption is 0.76% (three in 392). This is not different from the overall 0.89% rate among women without hypothyroidism. The three cases of placental abruption contained within this group are too few for meaningful conclusions to be drawn about antibody-based differences.
Table 3 shows antibody relationships with placental abruption according to whether only thyroperoxidase, only thyroglobulin, or both are elevated during early pregnancy. The absolute rate of placental abruption shows the greatest increase among women with elevated levels of both antibodies (by 0.90% in the first trimester and 1.38% in the second trimester; OR, 2.10 and 2.73, respectively). Once again, however, statistical significance is reached only in the second trimester. Between the first and second trimesters, 72 of 346 women without placental abruption are removed from the double antibody-positive category as opposed to none of the six with abruption. Women with elevated levels of only one of the two antibodies also have higher ORs for abruption in both trimesters, but these associations are less strong than when levels of both antibodies are elevated.
The OR reported by Abbassi-Ghanavati et al1 for placental abruption among women with elevated thyroperoxidase antibody levels (OR, 3.4; 95% CI, 1.7–6.7) is higher than either first- or second-trimester ORs among women in the present study. The overall conclusion for the two studies is, however, consistent, although the absolute overall occurrence rates differ considerably (3.4 per 1,000 for Abbassi-Ghanavati et al and 8.9 per 1,000 for the present cohort). The ranges of thyroperoxidase antibody concentrations among women with elevated levels are 53 to 392 international units/mL for the earlier study compared with 83–2,150 international units/mL (first trimester) and 52–1,500 international units/mL (second trimester) in the present cohort. Table 4 shows the effect of placental abruption on selected pregnancy outcomes. The cases with and without placental abruption are shown separately according to thyroperoxidase antibody status in the second trimester. Among women with thyroperoxidase antibody levels at or below 50 international units/mL, placental abruption is associated with significantly lower median birth weight, median gestational age at birth, percent of preterm births, and percent of deliveries complicated by preterm premature rupture of membranes. Similar differences are apparent in the presence of placental abruption among women with thyroperoxidase antibody levels above 50 international units/mL, but numbers are too small to show statistical significance (the statistical significance shown for preterm premature rupture of fetal membranes is explained by no occurrences among the 13 women with abruption). Thyroperoxidase antibody status does not appear to influence the effect of placental abruption on the parameters shown (range of P values for comparisons of “yes” groups=.34 to .95, except for preterm premature rupture of fetal membranes).
Among several pregnancy outcomes examined in relation to thyroid antibodies in a previous report from the FaSTER study,2 only a higher rate of preterm premature rupture of the membranes was significant. In those analyses, the cutoff used for thyroperoxidase antibody positivity was 35 international units/mL. Although not mentioned specifically, placental abruption was among the outcomes evaluated. The present analysis, undertaken in response to the recent report by Abbassi-Ghanavati et al,1 analyzes the relationship between thyroperoxidase antibody and placental abruption using their higher 50-international units/mL cutoff. Both studies used chemiluminescent assays on an automated platform (Immulite 2000 Analyzer) to measure thyroperoxidase antibodies. In the present study, raising the cutoff to 50 international units/mL lowers the antibody-positive rate substantially (from 9.5% to 7.6%) while removing only one case of placental abruption from the antibody-positive classification. Also, the percent of women with elevated antibody levels becomes lower in the second trimester among those without placental abruption, resulting in a slight increase in the OR. A limitation of the present (and other) studies is lack of data on thyroperoxidase antibody status in the third trimester and how it might further affect ORs. Collecting third-trimester data (closer to the event) might be a reasonable next step. It has long been recognized that titers of thyroid antibodies decrease as pregnancy progresses with approximately 25% of women who are antibody-positive in the first trimester becoming antibody-negative in the third trimester.9
The present report also finds that placental abruption may occur more often in the presence of thyroglobulin antibody elevation. This association is not as great as for thyroperoxidase antibody in either trimester as indicated by the ORs and 95% CIs. Furthermore, only nine of the 86 placental abruption cases segregate with elevated thyroglobulin antibodies in the two trimesters as opposed to 12 and 13 cases, respectively, with elevated thyroperoxidase levels. The largest OR (2.73) occurs during the second trimester among women with elevated levels of both antibodies. Only six of the 86 placental abruption cases are identified by this combined approach, however. In the report by Abbassi-Ghanavati et al, 10 of 58 cases of placental abruption (17.2%) were associated with elevated levels of thyroperoxidase antibodies as opposed to 13 of 86 (15.1%) during the second trimester in the present study.
Placental abruption is estimated to occur at the rate of approximately one in 100 pregnancies.8,10,11 The 0.89% rate of placental abruption in the present study is consistent with this estimate but considerably higher than the 0.34% rate found by Abbassi-Ghanavati et al. A portion of this discrepancy might be explained by demographic differences (eg, age). A study of 30,378,902 live births and stillbirths (1995–2002) in 2006, using data from the National Center for Health Statistics, found a placental abruption rate of 0.6%. In that study, Ananth et al found associations with both acute inflammatory processes and chronic clinical processes (which included either vascular dysfunction or chronic inflammation),12 thereby offering a possible causal explanation for a proportion of the cases. They suggested thinking of placental abruption in terms of “causative heterogeneity.” The association between thyroperoxidase antibodies and placental abruption is consistent with that study's findings, although Ananth et al did not examine antibody-induced thyroiditis as a specific example of chronic inflammation. Abbassi-Ghanavati et al independently postulated that inflammation might play a role in at least some cases of placental abruption, either directly or through compromising thyroid function. Documentation of associations between various inflammatory processes and placental abruption offers insights into causality but does not offer guidance as to possible strategies for avoidance of this important source of morbidity and mortality in pregnancy.
There is currently not an effective method for predicting placental abruption or for avoiding its occurrence. If a preventive treatment were to be developed, the current data indicate that thyroperoxidase antibody screening would detect 15% of all placental abruption cases at a false-positive rate of 7.6% and an odds of being affected of 1:55. Using this approach to select candidates for intervention would require that 56 antibody-positive women be treated to avoid one event (assuming 100% effectiveness). At present, routine testing of thyroperoxidase antibodies during pregnancy cannot be justified for this purpose.
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Figure. No caption available.
© 2011 by The American College of Obstetricians and Gynecologists.
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