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Department of Endocrinology (R.N., G.F.), Azienda Ospedaliera LE/1, 73100 Lecce, Italy; Department of Obstetrics and Gynecology (T.M.), Casa di Cura "Salus", 72100 Brindisi, Italy; Department of Internal Medicine (A.P., D.D.), Azienda Ospedaliera PR, "Di Vaio" Hospital, 43036 Fidenza, Italy; and Endocrine Unit (H.H.), Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan, Brunei Darussalam BA 1000
Address all correspondence and requests for reprints to: Roberto Negro, Department of Endocrinology, Azienda Ospedaliera LE/1, P.O. "V. Fazzi", Piazza F. Muratore, 73100 Lecce, Italy. E-mail: robnegro{at}tiscali.it.
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Abstract |
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Objective: We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT4) treatment exerts beneficial effects.
Design: This was a prospective study.
Setting: The study was conducted in the Department of Obstetrics and Gynecology.
Patients: A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb+).
Intervention: TPOAb+ patients were divided into two groups: group A (n = 57) was treated with LT4, and group B (n = 58) was not treated. The 869 TPOAb– patients (group C) served as a normal population control group.
Main Outcome Measures: Rates of obstetrical complications in treated and untreated groups were measured.
Results: At baseline, TPOAb+ had higher TSH compared with TPOAb–; TSH remained higher in group B compared with groups A and C throughout gestation. Free T4 values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13–2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59–9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18–2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93–18.7).
Conclusions: Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT4 is able to lower the chance of miscarriage and premature delivery.
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Introduction |
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Another matter of concern is the relationship between thyroid function and obstetrical complications. Several studies confirmed that not only is overt hypothyroidism associated with maternal and fetal adverse consequences, but also subclinical hypothyroidism or euthyroidism in patients affected by TAI may adversely affect the mother or fetus (4, 5, 6, 7, 8). Additionally, unfavorable obstetric events appear to be more frequent when hypothyroidism is diagnosed too late and/or when the levothyroxine (LT4) replacement is not adequate to ensure euthyroidism during pregnancy (7). The dual aims of the present study are to assess whether euthyroid women positive for thyroid peroxidase antibodies (TPOAb+) are affected by a higher rate of obstetrical complications and to explore the hypothesis that LT4 treatment may improve the outcome of affected patients.
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Subjects and Methods |
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LT4 administration was started on the first endocrinological visit, which occurred 3–7 d after the first gynecological visit. A computer program was used to randomly assign the TPOAb+ patients to either group A or group B. A sealed opaque envelope was assigned to each patient; only the doctor treating the patient, who did not participate in any subsequent phase of the study, knew which group the patient was in. Medical doctors participated in different phases of the protocol, so that each was unaware of which group the patients belonged to. If hyperthyroidism was observed, the patient was excluded from the study protocol.
Obstetrical complications were classified as follows. Gestational hypertension was defined as an intrapartum systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg. Severe preeclampsia was diagnosed in women with hypertension who had at least one of the following: blood pressure higher than 160/110 mm Hg, serum creatinine greater than 1.0 mg/dl, a platelet count less than 100,000/µl, serum aspartate aminotransferase level at least twice the normal value, persistent headache or scotomata, 2+ or greater proteinuria, or more than 2 g protein excreted in 24 h. A birth before 37 wk gestation was considered to be a preterm birth.
Serum TSH and FT4 were measured using a third-generation electrochemiluminescence immunoassay (Roche, Basel, Switzerland). The reference values were 0.27–4.2 mIU/liter for TSH and 9.3–18.0 ng/liter (12–33.5 pmol/liter) for FT4. Intra- and interassay coefficients of variation were 2.4 and 9.5% for TSH and 4.7 and 6.9% for FT4. TPOAb titers were determined using a RIA kit (Brahms Diagnostica, Berlin, Germany). The reference range was 0–100 kIU/liter. TPOAb titers of more than 100 kIU/liter were considered positive.
Statistical analysis was performed using an SPSS (SPSS, Inc., Chicago, IL) program, by means of Fisher’s exact test. Correlations between variables were assessed using Spearman’s test, and differences between mean values were determined by the Mann-Whitney U test. A multivariate approach was used, starting with a univariate model for each individual variable. Mean TSH values were calculated after log transformation. All statistical tests were considered statistically significant whenever P < 0.05.
This study was conducted in accordance with guidelines in the Declaration of Helsinki. The Institutional Review Board approved the study protocol, and all the participants gave a written informed consent.
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Results |
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). Ninety-two percent of the women consulted the endocrinologist before the 20th wk of gestation (Fig. 1, top). The LT4 administered in group A was 49.7 ± 14 µg/d; eight patients received 0.5 µg/kg·d (30.6 ± 4.9 µg/d), 35 received 0.75 µg/kg·d (47.7 ± 6.0 µg/d), and 14 received 1 µg/kg·d (64.7 ± 8.7 µg/d). When the LT4 treatment was started, the gestational ages were similar in the three subgroups submitted to the three different dosages (9.6 ± 5, 10.1 ± 3.7, and 10.9 ± 3.8 wk, respectively). In group A, 23 of 45 patients (40%) started LT4 treatment by the 8th week and 45 (79%) by the 12th week (Fig. 1, bottom).
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Whether they had extremely or moderately elevated TPOAb titers, women in groups A and B showed a 62% decrease in TPOAb titers at delivery compared with the initial values.
Initially, the mean TSH values were significantly higher in groups A and B compared with group C (1.6 ± 0.5 and 1.7 ± 0.4, respectively, vs. 1.1 ± 0.4 mIU/liter; P < 0.05 and P < 0.05, respectively). In group A, TSH baseline values were significantly different between the three subgroups given 0.5, 0.75, and 1.0 µg/kg·d dosages of LT4 (0.7 ± 0.2, 1.4 ± 0.3, and 2.6 ± 0.7 mIU/liter; P < 0.01). However, at 20 and 30 wk gestation and after parturition, TSH values were similar in the three subgroups (Fig. 2). The TSH values of group B remained significantly higher than those of groups A and C during the entire gestation period, with a sharp increase at parturition (3.5 ± 0.7 mIU/liter; P < 0.01). At delivery, 19% of group B showed a TSH value higher than the normal range (Fig. 3, top).
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, bottom). The differentiated LT4 dosages assigned on the basis of the TSH starting values thus allowed us to obtain, in the intervention group (group A), TSH and FT4 values that were not significantly different from the normal control group (group C).
Obstetrical complications
Group A and group C had a similar miscarriage rate (3.5 and 2.4%, respectively), whereas group B was characterized by a higher percentage of pregnancy loss (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13–2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59–9.48, respectively] (Fig. 4, top). The difference in miscarriage rates was a result of patients who miscarried within the first trimester of pregnancy; in fact, in groups A and B, all the miscarriages occurred within the first trimester, and in group C, 19 of 21 miscarriages occurred during the first trimester. Consequently, we conclude that LT4 treatment could not significantly influence the miscarriage rate, if given after 12 wk. The two pregnancy losses observed in group A occurred at 7 and 10 wk gestation (both pregnant women were on LT4). One of the eight pregnancy losses observed in group B occurred at 6 wk, two at 7 wk, three at 8 wk, and one each at 10 and 11 wk gestation. In group C, two of 21 pregnancy losses occurred at 6 wk, five at 7 wk, eight at 8 wk, two at 10 wk, and one each at 11, 12, 16, and 21 wk gestation. Group B presented a higher number of premature deliveries (22.4%) compared with group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18–2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93–18.7) (Fig. 4, bottom). Thus, the LT4 treatment appeared to be effective in reducing miscarriages whether given before or after the first trimester of pregnancy. Other obstetrical complications (i.e. hypertension, preeclampsia, and placental abruption) (Table 2) and the clinical characteristics of newborns (weight, height, cranial perimeter, and APGAR score) did not vary between groups.
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Discussion |
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The prevalence of TAI in our population was 11.7%, a percentage that is in agreement with the data found in other studies (1, 8, 9). Furthermore, the average age of women affected by TAI was slightly, but significantly, older than the unaffected group; this finding indirectly confirms that the presence of thyroid antibodies is associated with reduced fertility. One proposed hypothesis to explain the association of TAI with an increase in miscarriages is that TAI represents a risk factor for subfertility, delaying pregnancy in women with TAI; thus, when women with TAI do become pregnant, they are older and face a higher risk of pregnancy loss (10, 11).
At the beginning of their pregnancy, women with TAI showed a higher TSH level compared with those who were TPOAb–, although the mean TSH level was still within the normal range. As previously demonstrated, these subjects are prone to developing subclinical or overt hypothyroidism during pregnancy (8). In these cases, the thyroid fails to adapt its function to the increased hormone requirement (12). Although it is not currently recommended to start LT4 treatment in TAI, pregnancy may represent a difficult challenge for the thyroid. We noted that after parturition, about half of the patients in this study had FT4 values below the minimal limit. Therefore, this study confirms that a thyroid with a reduced functional reserve does not compensate for the increased hormone requirement caused by high thyroid-binding globulin concentrations, increased volume distribution of thyroid hormones, and increased placental T4 transport and degradation (13). In the TPOAb– group (group C), TSH values increased from 1.1 mIU/liter at 10 wk gestation to 2.1 mIU/liter at term. The spontaneous increment in serum TSH was, however, quantitatively and significantly less than the one observed in group B (untreated TPOAb+ group). Concerning the adaptation of thyroid function during pregnancy, it has to be taken into account that this study was conducted in Italy, a country that is still characterized by iodine deficiency, because iodized salt is not compulsory by law. On the basis of the results of this study, we speculate that the tendency of hypothyroxinemia in healthy pregnant women presents a strong stimulus for the pituitary to compensate, with a subsequent rise in TSH values.
The development of hypothyroidism can generally be predicted at the beginning of pregnancy on the basis of the TSH value and TPOAb titers, so that patients displaying TSH more than 2.0 mIU/liter and/or high TPOAb (>2000 kIU/liter) are more likely to develop overt thyroid dysfunction (8). A secondary endpoint of the present study was to fine tune the LT4 replacement dose and develop, if possible, practical suggestions on how to treat patients at risk of developing hypothyroidism. In fact, the subgroups given three different dosages of LT4 showed a significant difference initially in baseline TSH values that was abolished during gestation. From the data, we can say that the assigned LT4 dose made it possible to maintain the TPOAb+ women in a euthyroid state, with TSH and FT4 values that were similar to the ones showed by the TPOAb– group.
The development of thyroid dysfunction during pregnancy can cause complications. It has been already demonstrated that both overt and subclinical hypothyroidism are associated with obstetrical repercussions. Maternal complications include anemia, postpartum hemorrhage, cardiac dysfunction, preeclampsia, and placental abruption; fetal complications include fetal distress, premature birth, and/or low birth weight, congenital malformations, and fetal/perinatal death (4, 5, 6, 7, 8, 14). In our study population sample, treatment with LT4 had a positive effect on reducing the rates of miscarriages and premature delivery. In fact, this group of patients had a significantly reduced risk of miscarriage compared with the TPOAb+ patients who were not treated with LT4, and LT4 treatment reduced the miscarriage rate to a value comparable to that of the TPOAb– patients. Comparing premature delivery rates, the beneficial intervention with LT4 reduced preterm births in TPOAb+ women to a percentage similar to that of the control population. Timing of treatment initiation appears to be of critical importance. In fact, the LT4 treatment turned out to be extremely effective in reducing the number of miscarriages when given during the early stages of pregnancy, because miscarriages generally occurred within the first trimester. On the other hand, the rate of premature deliveries was also significantly reduced in women whose LT4 treatment was started after the first trimester. This allows us to speculate that euthyroxinemia is primarily important in early pregnancy to avoid miscarriages and to maintain normal placental development and function throughout gestation to avoid preterm deliveries.
From the data we observed, we cannot definitively exclude the possibility that the increased miscarriage rate found in TPOAb+ women may be partly because of their older age. The age difference between TPOAb+ and TPOAb– patients was just 2 yr; therefore, we cannot state that, also with a greater age difference, LT4 is able to, as such, reduce pregnancy loss. Another question is whether TAI is an indicator of an unfavorable autoimmune environment. In a recent study carried out in infertile women undergoing assisted reproduction technologies, a lower delivery rate was found in TPOAb+ compared with TPOAb–. However, in that study, LT4 treatment was not found to be beneficial (15). Taking this into consideration, we can speculate that the difference between women undergoing assisted reproduction technologies and the patients examined in this paper is that the populations had differences in fertility. In other words, autoimmunity in infertile women, (with not only TPOAb, but also antiphospholipid and antinuclear antibodies, for example) may play a major role in fertilization, implantation, and placental development, so that LT4 treatment alone is not effective. Conversely, in fertile women, as in this study, TAI alone may play a lesser role, and the advantageous effects of LT4 become more evident. Then, although we cannot exclude the influence of age and autoimmunity on obstetrical complications, on the other hand we can confirm that euthyroid pregnant women affected by autoimmune thyroid disease are inclined to develop thyroid dysfunction during gestation.
The TPOAb+ women not treated with LT4 had, as a group, lower FT4 values compared with the other two groups. Considering the fact that basal TSH concentrations in the upper reference range are often associated with subnormal thyroid function, the TPOAb+ women in this study displayed relatively reduced thyroid hormone values (16). There are two undesirable consequences to having low or low-normal FT4 values, the risk of obstetrical complications and the risk of altered fetal brain development. Up to midgestation, when the fetal thyroid begins to work, early fetal brain development depends exclusively on the availability of FT4 in embryonic and fetal tissues; thus, during early gestation, maternal euthyroxinemia appears to be critical for normal fetal brain development (17). Every effort must be made to detect and prevent early maternal hypothyroxinemia to prevent neurodevelopmental defects, which may include an increased chance of lower IQ and a higher risk of cerebral palsy, (18, 19). Furthermore, reports of poor development in many babies faced with premature interruption of the maternal supply of thyroid hormone, occurring when the thyroid is still immature, also indicate that the fetal brain needs thyroid hormones throughout the whole gestation period and that an adequate supply of maternal T4 has an important protective role after midgestation (20). Therefore, as a final thought about thyroid function, in this context, not only TSH but also FT4 needs to be monitored and promptly adjusted throughout the entire gestation period. Impaired thyroid function is associated with an increased risk of miscarriage and premature deliveries; a substitutive treatment with LT4 is able to compensate for the reduced thyroid function reserve, lowering the chance of miscarriage and premature deliveries.
To our knowledge, this is the first study that clearly shows the benefits of LT4 administration, not only to correct maternal thyroid function but also to decrease the rate of undesired obstetrical events and bring their prevalence down to those of the control population. Our results lead us to agree with Poppe and Glinoer (21), who recommend screening women early in pregnancy for TPOAb and for thyroid function. We also agree with their recommendation of administering LT4, at least, to women who have a TSH value greater than 2.0 mIU/liter and/or a high titer of thyroid antibodies.
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Footnotes |
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Abbreviations: CI, Confidence interval; FT4, free T4; LT4, levothyroxine; RR, relative risk; TAI, thyroid autoimmunity; TPOAb, thyroid peroxidase antibodies.
Received August 11, 2005.
Accepted April 11, 2006.
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, P < 0.05.