Clinical hypothyroidism is associated with subfertility and in those women who conceive, there is an increased risk of miscarriage, stillbirth, preeclampsia, and preterm delivery.1–5 There is also some evidence that subclinical hypothyroidism, defined by an increased serum concentration of thyroid-stimulating hormone (TSH) in the presence of normal levels of free thyroxine, may be associated with an increased risk for miscarriage, stillbirth, and preeclampsia.6,7 A recent review of the literature concluded that both subclinical hypothyroidism and autoimmune thyroid disease in euthyroid women are associated with preterm delivery.8 However, two large screening studies investigating the possible association between thyroid dysfunction and preterm delivery reported contradictory results. Casey et al9 measured serum TSH in 17,298 pregnancies attending for routine antenatal care before 20 weeks and reported that in the 404 women with subclinical hypothyroidism, compared with the euthyroid women, there was a twofold increase in risk of delivery before 34 weeks (4.5% compared with 2.5%). The authors speculated that prematurity may be the link between decreased neurodevelopment in the children of women with subclinical hypothyroidism during pregnancy.10 In contrast, Cleary-Goldman et al11 assessed maternal thyroid function in 10,990 pregnancies at 10–13 weeks and reported that the rate of delivery before 37 weeks in 240 women with subclinical hypothyroidism was not significantly different than in euthyroid pregnancies (5.6% compared with 7.2%).
These contradictory results may be the consequence of differences between the studies in the gestational age defining preterm delivery and the proportion of cases with iatrogenic rather than spontaneous preterm delivery, which was not specified.9,11 An additional factor that may account for contradictory results between studies is the distribution of maternal characteristics in the study populations. We have reported that in establishing reference ranges for maternal thyroid function, it is necessary to take into account certain maternal characteristics, which affect the measured levels of TSH and free thyroxine.12 We have also found that in women with antithyroid antibodies, compared with the antibody negative group, the median TSH was higher and the median free thyroxine was lower and concluded that in establishing normal ranges of thyroid function, it is necessary to exclude antibody-positive patients. We examined 3,592 singleton pregnancies with normal outcome from women with no history of thyroid disease and negative for antithyroid antibodies and demonstrated that serum TSH increases and free thyroxine decreases with gestation within 11–13 weeks, TSH increases and free thyroxine decreases with body mass index, free thyroxine decreases but TSH does not change significantly with maternal age, and both TSH and free thyroxine are lower in women of African racial origin than in whites.12 The aim of this retrospective study is to estimate the possible association between maternal thyroid dysfunction and preterm delivery by comparing antithyroid antibody positivity and serum TSH and free thyroxine levels at 11–13 weeks of gestation after appropriate adjustments for maternal characteristics in pregnancies which subsequently resulted in spontaneous delivery before 34 weeks with normal pregnancies delivering after this gestation.
This study on maternal thyroid function is part of an ongoing screening study for adverse obstetric outcomes in women attending for their routine first hospital visit in pregnancy. In this visit, which is held at 11+0–13+6 weeks of gestation, we record maternal characteristics, including age; racial origin (white, African American, South Asian, East Asian, and mixed); cigarette smoking during pregnancy (yes or no); method of conception (spontaneous or assisted); medical history of chronic hypertension, history of thyroid disease, and medication for hyper- or hypothyroidism; parity (parous or nulliparous if no delivery beyond 23 weeks); weight, height; and body mass index. We then perform an ultrasonographic scan to confirm gestational age from the measurement of the fetal crown–rump length to diagnose any major fetal abnormalities and to measure fetal nuchal translucency thickness. We also measure maternal serum free β-human chorionic gonadotropin and pregnancy- associated placental protein A as part of screening for aneuploidies by a combination of fetal nuchal translucency and serum biochemistry.13,14 Additionally, blood is collected for research and the separated plasma and serum are stored at −80°C for subsequent biochemical analysis. Written informed consent was obtained from the women agreeing to participate in the study, which was approved by King's College Hospital Ethics Committee.
In this study, we retrospectively examined maternal thyroid function and antithyroid antibodies at 11–13 weeks in 102 singleton pregnancies with no history of thyroid disease, resulting in spontaneous preterm delivery before 34 weeks of gestation of phenotypically normal neonates (preterm delivery group). The values were compared with those of 4,318 singleton pregnancies with no history of thyroid disease, resulting in live birth after 34 weeks of phenotypically normal neonates (normal outcome group).12 This study group included all eligible patients recruited from the first-trimester screening study between March 2006 and December 2006. Pregnancies complicated by preeclampsia were excluded from both the preterm delivery and normal outcome groups.
The maternal serum concentrations of free thyroxine, TSH, antithyroperoxidase, and antithyroglobulin antibodies were measured by immunoassay using direct, chemiluminometric technology. The minimum detectable concentrations of free triiodothyronine, free thyroxine, TSH, antithyroperoxidase, and antithyroglobulin were 0.3 pmol/L, 1.3 pmol/L, 0.003 mIU/L, 15 U/mL, and 30 U/mL, respectively. The intraassay coefficients of variation were 4.69%, 2.31%, and 2.22% at free thyroxine concentrations of 6.1 pmol/L, 13.9 pmol/L, and 39.9 pmol/L, respectively; 2,48%, 2.44%, and 2.41% at TSH concentrations of 0.74 mIU/L, 5.65 mIU/L, and 18.98 mIU/L, respectively; 7.93%, 4.54%, and 6.26% at antithyroperoxidase concentrations of 1.70 U/mL, 10.01 U/mL, and 14.95 U/mL, respectively; and 5.5% and 2.9% at antithyroglobulin concentrations of 62 U/mL and 333 U/mL, respectively. If the serum concentration of antithyroperoxidase and antithyroglobulin was less than 60 U/mL, which was the manufacturer's reference limit, the patients were considered to be antibody-negative.
Comparison between the preterm delivery and normal outcome groups12 was by chi square test or Fisher's exact test for categorical variables and by Wilcoxon rank-sum test for continuous variables. In the antithyroid antibody-negative pregnancies (antithyroperoxidase and antithyroglobulin level of less than 60 U/mL), the measured concentrations of free thyroxine and TSH were logarithmically transformed. However, log10 TSH remained negatively skewed; therefore, square root transformation was applied. Histograms and probability plots showed that the distributions of square root TSH and log free thyroxine were normal. The values were then expressed as multiples of the expected normal median corrected for gestational age and maternal age, racial origin, and body mass index.12 The preterm delivery and normal outcome groups were compared for median TSH multiple of the median and free thyroxine multiple of the median and prevalence of antithyroid antibodies. Pearson correlation was used to determine the significance of the interrelations between square root TSH multiple of the median and log10 free thyroxine multiple of the median. Nonparametric Spearman's correlation coefficient was used to estimate the association between square root TSH multiple of the median and log10 free thyroxine multiple of the median with gestational age at delivery in the preterm delivery group.
The statistical software package PASW statistics 18.0 was used for the data analyses.
The patient characteristics of the preterm delivery and normal outcome groups are compared in Table 1. In the preterm delivery group, there was a higher prevalence of women of African racial origin and those conceiving after ovulation induction.
In the preterm delivery group, compared with the normal outcome group, there was no significant difference in antithyroid antibody positivity (Table 2). In the antithyroid antibody-negative pregnancies in the preterm delivery group, compared with the normal outcome pregnancies, the median free thyroxine multiple of the median was reduced (P<.001) but the median TSH multiple of the median was not significantly different (P=.331; Fig. 1; Table 3). In the preterm delivery group, serum TSH was above the 95th centile of the normal range in one (1.2%) case and serum free thyroxine was below the fifth centile in eight (9.4%) cases and they were not significantly different from the normal outcome group (P=.128 and P=.077, respectively).
There were significant associations between square root TSH multiple of the median and log10 free thyroxine multiple of the median in both the preterm delivery (r=−0.329, P=.002) and normal outcome (r=−0.245, P<.001) groups. In the preterm delivery group, there was no significant association between gestation at delivery and square root TSH multiple of the median (r=−0.053, P=.629) or log10 free thyroxine multiple of the median (r=0.061, P=.579).
The findings of this study demonstrate that in pregnancies resulting in spontaneous early preterm delivery, there is no evidence of increased prevalence of antithyroid antibody positivity or maternal thyroid dysfunction at 11–13 weeks.
Preterm birth is the leading cause of perinatal death and handicap in children and the vast majority of mortality and morbidity relates to early delivery before 34 weeks.15,16 Delivery before 34 weeks occurs in approximately 2% of singleton pregnancies and in two-thirds of the cases this is the result of spontaneous onset of labor or preterm prelabor rupture of membranes and in the other one-third, it is iatrogenic, mainly resulting from preeclampsia.17 Consequently, in investigating the possible association maternal thyroid dysfunction and preterm delivery, we first excluded cases of iatrogenic preterm delivery and second selected those delivering before 34 weeks than 37 weeks because they have a worse pregnancy outcome. A previous study of 28 pregnancies delivering before 32 weeks reported that at 15 weeks of gestation, the maternal serum TSH was above the 97.5th centile in a significantly higher proportion of cases than in 124 pregnancies delivering at term (14% compared with 6%).18 However, in this study, 64% of the cases with early preterm delivery had hypertensive disorders of pregnancy and it is therefore uncertain whether it is spontaneous preterm delivery or hypertensive disease that is associated with thyroid dysfunction.
In women of African racial origin, the rate of spontaneous early preterm delivery was higher than in whites. This is compatible with the results of previous studies. National statistics in the United States demonstrate that the risk of preterm delivery in women of African racial origin is 1.6 times higher than in whites.19 Similarly, a population-based study of 585,291 singleton pregnancies from North London, UK, reported that after correcting for other confounders, the risk of spontaneous delivery before 37 weeks was higher by 1.6 times for women of African racial origin compared with whites.20 As for the association between preterm delivery and the use of ovulation induction drugs, some studies suggest a method-related cause and others that infertility rather than its treatment is the cause because infertile women who are older are more likely to have chronic medical conditions.21–23
The prevalence of antithyroid antibody positivity in women with spontaneous early preterm delivery was not higher than in those with normal pregnancy outcome. This finding is in agreement with the results of a screening study for antithyroid antibodies in early pregnancy, which found that the rate of preterm delivery was not significantly different between the antibody-positive and -negative pregnancies.24 In contrast, some studies reported that the rate of preterm delivery in euthyroid women with antithyroglobulin, antithyroperoxidase, or both antibodies was two to three times higher than in women with no antithyroid antibodies.25,26 Additionally, a study of euthyroid women positive for antithyroperoxidase antibodies reported that the administration of levothyroxine during pregnancy, compared with no treatment, was associated with significant reduction in the rate of preterm delivery (7% compared with 22%).27
Serum TSH was not higher in the preterm delivery group than in the normal outcome group. This finding is compatible with the results of a screening study in 9,404 pregnancies at 15–18 weeks, which reported that there was no significant difference in mean gestation at delivery between those with TSH at or above 6 mU/L and those with TSH below 6 mU/L.28 The results are also compatible with the findings of the first-trimester screening study of Cleary-Goldman et al11 in which the rate of delivery before 37 weeks in women with subclinical hypothyroidism was not significantly different than in euthyroid pregnancies. In contrast, the screening study of Casey et al9 in which thyroid function was assessed before 20 weeks of gestation reported that in women with subclinical hypothyroidism, there was a doubling in the rate of delivery before 34 weeks.
In the spontaneous early preterm delivery group, the median serum free thyroxine concentration was reduced but the incidence of free thyroxine below the fifth centile was not significantly different from the incidence in the normal outcome group. In both the studies of Cleary-Goldman et al and Casey et al, isolated maternal hypothyroxinemia, defined by TSH between the 2.5th and 97.5th centiles and free thyroxine below the 2.5th percentile, was not associated with increased risk of preterm delivery.11,29
The strengths of our study are first, distinction between spontaneous and iatrogenic preterm delivery; second, adjustment of measured concentrations of serum TSH and free thyroxine for the maternal factors known to affect these measurements; and third, examination of a large number of spontaneous early preterm deliveries. We found that there is no significant difference between the preterm delivery and normal outcome groups in the prevalence of antithyroid antibody positivity, subclinical hypothyroidism, or isolated hypothyroxinemia. It is therefore unlikely that maternal thyroid dysfunction at 11–13 weeks has an important contribution to the overall prevalence of spontaneous early preterm delivery. However, the design of our study does not allow conclusions to be drawn as to whether antithyroid antibody positivity, subclinical hypothyroidism, or isolated hypothyroxinemia in early pregnancy increases the risk for subsequent spontaneous early preterm delivery.
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