Abstract
Background:
Studies have shown that altered thyroid function in early pregnancy may affect normal placental development and hence fetal growth. Our hypothesis is that maternal thyroid function in the first trimester is altered in pregnancies that subsequently deliver small for gestational age (SGA) neonates.
Methods:
Maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were measured at 11+0 to 13+6 weeks' gestation in 212 singleton pregnancies with no history of thyroid disease that subsequently delivered SGA neonates and the values were compared with the results of 3598 normal pregnancies delivering neonates with birth weight above the 5th percentile for gestation.
Results:
There were no significant differences between the normal and SGA groups in median multiple of the median (MoM) TSH (1.07 vs. 1.061 MoM), FT4 (0.992 vs. 1.010 MoM), and FT3 (0.991 vs. 0.990 MoM).
Conclusion:
In women with no history of thyroid disease delivering SGA neonates, thyroid function during the first trimester of pregnancy is not significantly different from women delivering non-SGA neonates.
Introduction
The mechanism underlying trophoblast proliferation and invasion is largely unknown, but there is some evidence implicating thyroid hormones in this process. In vitro studies reported that thyroid hormone receptors are expressed in extravillous human trophoblast and thyroid hormones upregulate proliferation and the invasive potential of this trophoblast (7,8). Addition of thyroid hormones to an organ culture system of human placental tissue from early pregnancy stimulated the production of several placental hormones, including progesterone, human chorionic gonadotrophin, and estradiol (9). There is also contradictory evidence that clinical and subclinical hypothyroidism is associated with increased risk for both PE and the birth of SGA neonates in the absence of PE (10 –15). In a previous study, we reported that, in pregnancies that develop PE, maternal serum thyroid-stimulating hormone (TSH) at 11–13 weeks of gestation was higher and free thyroxine (FT4) was lower than in normotensive controls (16).
The aim of this study was to investigate further whether the prevalence of maternal thyroid hypofunction at 11–13 weeks of gestation is higher in pregnancies that subsequently delivered SGA neonates in the absence of PE.
Materials and Methods
This was a prospective screening study for adverse obstetric outcomes in women attending for their routine first hospital visit in pregnancy between March 2006 and December 2006. In this visit, which was held at 11+0 to 13+6 weeks of gestation, we recorded maternal characteristics, including age, ancestral origin (Caucasian, African, South Asian, East Asian, and mixed), cigarette smoking during pregnancy (yes or no), method of conception (spontaneous or assisted), medical history of chronic hypertension, parity (parous or nulliparous if no delivery beyond 23 weeks), weight, height, and body mass index (BMI). We then performed an ultrasound 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 measured maternal serum-free β-hCG and PAPP-A (DELFIA EXPRESS analyzer; PerkinElmer, Waltham, MA) as part of screening for aneuploidies by a combination of fetal nuchal translucency thickness and serum biochemistry (17). Additionally, blood was collected for research and the separated plasma and serum were 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 measured the maternal serum concentrations of TSH, FT3, and FT4 at 11–13 weeks in 212 singleton pregnancies with no history of thyroid disease, which did not develop PE and resulted in live birth of phenotypically normal neonates with birth weight below the 5th percentile for gestational age (SGA group) (18). At presentation, none of the women had overt hypothyroidism or hyperthyroidism. The values were compared with the results of our previous study in 3592 singleton pregnancies with no history of thyroid disease, which did not develop PE and resulted in live birth after 34 weeks of phenotypically normal neonates with birth weight above the 5th percentile (16).
Sample analysis
The maternal serum concentrations of FT3, FT4, and TSH were measured by immunoassay using direct chemiluminometric technology (Siemens Advia Centaur assays; Siemens Healthcare Diagnostics Ltd., Surrey, United Kingdom). The minimum detectable concentrations of FT3, FT4, and TSH were 0.3 pmol/L, 1.3 pmol/L, and 0.003 mIU/L, respectively. The intra-assay coefficients of variation were 3.08%, 2.35%, and 2.47% at FT3 concentrations of 2.9, 6.6, and 14.2 pmol/L, respectively; 4.69%, 2.31%, and 2.22% at FT4 concentrations of 6.1, 13.9, and 39.9 pmol/L, respectively; and 2,48%, 2.44%, and 2.41% at TSH concentrations of 0.74, 5.65, and 18.98 mIU/L, respectively.
Statistical analysis
The characteristics of the SGA group and the unaffected group were compared by Mann–Whitney test for continuous variables and Fisher's exact test or chi-square test for categorical variables. The measured concentrations of FT3, FT4, and TSH were converted with multiples of the expected normal median (multiple of the median [MoM]) corrected for gestational age, maternal age, ancestral origin, and BMI (19). We have previously reported that serum TSH increases but FT3 and FT4 decrease with gestational age, and all three are lower in women of African ancestral origin than those of Caucasian ancestral origin. Serum FT3 and FT4 decrease but TSH does not change significantly with maternal age, and serum TSH and FT3 increase but FT4 decreases with BMI (19). The SGA and unaffected groups were compared for median TSH MoM, FT3 MoM, and FT4 MoM using the Mann–Whitney test and for the proportion of cases with serum TSH above the 97.5th percentile and serum FT3 and FT4 below the 2.5th percentile by the chi-square test. Regression analysis was also used to determine the significance of the interrelations between TSH MoM, FT3 MoM, and FT4 MoM.
The statistical software package SPSS 15.0 (SPSS, Inc., Chicago, IL) was used for data analyses.
Results
The patient characteristics of the SGA and unaffected groups are compared in Table 1. In the SGA group, the maternal age and BMI were lower and the prevalence of African and South Asian women, cigarette smokers, and those with chronic hypertension was higher.
Comparison between the two groups was by chi-square or Fisher's exact test for categorical variables and Mann–Whitney U test for continuous variables.
p < 0.05.
p < 0.0001.
IQR, interquartile range.
In the SGA group, compared with the unaffected group, the median TSH MoM, FT3 MoM, and FT4 MoM were not significantly different (Table 2), and there was no significant association between the gestational age at delivery and TSH MoM (p = 0.662), FT3 MoM (p = 0.538), and FT4 MoM (p = 0.543).
Comparison between the the two groups was by chi-square or Fisher's exact test for categorical variables and Mann–Whitney U test for continuous variables. There was no significant difference between the two groups in any of the variables.
TSH, thyroid-stimulating hormone; FT4, free thyroxine; FT3, free triiodothyronine; MoM, multiple of the median.
The significance of the associations between TSH, FT3, and FT4 in the unaffected and SGA groups is shown in Table 3.
Discussion
The findings of this study indicate that in pregnancies delivering SGA neonates, maternal thyroid function at 11–13 weeks of gestation is not significantly different from those delivering appropriately grown neonates, and there is no evidence that in the SGA group the prevalence of impaired thyroid function is increased.
A previous screening study in which maternal thyroid function was assessed at 15–18 weeks of gestation reported that there was no significant difference in mean birth weight between euthyroid pregnancies and those with subclinical hypothyroidism (15). In contrast, a case–control study reported that the mean birth weight in pregnancies with subclinical hypothyroidism was significantly lower than in euthyroid controls (13). Another screening study before 20 weeks reported that the prevalence of neonates with birth weight below 2.5 kg was not significantly different between euthyroid pregnancies and those with subclinical hypothyroidism (14). However, use of mean birth weight or a cutoff in birth weight without appropriate adjustments for gestational age is not appropriate for the investigation of thyroid function and fetal growth.
The strengths of our study are, first, examination of a large number of appropriately documented cases of SGA and normal controls; second, comparison of the SGA and non-SGA groups after adjustment of the results of thyroid function test for those factors found in a previous study to affect measurements, including gestational age, maternal age, ancestral origin, and BMI (19); and third, assessment of thyroid function in the first-trimester of pregnancy providing the option for therapeutic interventions in future studies to determine whether the prevalence of SGA can be reduced. The weakness of the study was its cross-sectional nature, which did not allow longitudinal assessment of thyroid function from early pregnancy to the development of SGA.
The findings that, first, SGA is not associated with maternal thyroid hypofunction and, second, there is no correlation between gestational age at delivery and TSH, FT3, or FT4 values suggest that the results of in vitro studies concerning the role of thyroid hormones in trophoblast proliferation and invasion (7,8) may not be clinically relevant. Histological studies reported that impaired placentation is observed in all cases of PE with or without SGA and in about half of pregnancies with SGA in the absence of PE (20). However, Doppler studies of the uterine arteries documented that the prevalence of high impedance to flow in pregnancies with PE depends on the gestational age at the onset of the disease. The uterine artery pulsatility index (PI) was above the 95th percentile in 82% of those that developed PE requiring delivery before 34 weeks (early PE) and in 40% of those delivering at or after 34 weeks (late PE) (21). Similarly, in SGA without PE, high pulsatility index was observed in 44% of those that delivered before 34 weeks and in 10% of those delivering at or after 34 weeks. Although the basis of the possible association between hypothyroidism, PE, and SGA was the suggested role of thyroid hormones in promoting placentation and trophoblastic invasion, we have previously found that thyroid hypofunction is observed in pregnancies developing late—rather than early—PE (16). We therefore suggested that the association is unlikely to be mediated by impaired trophoblastic invasion but rather by a metabolic derangement with increased insulin resistance, which is thought to underlie late PE (22 –26).
In conclusion, in pregnancies delivering SGA neonates, maternal thyroid function at 11–13 weeks of gestation is not impaired. Consequently, irrespective of the possible effect of thyroid hormones on placentation, in women with no history of thyroid disease, thyroid function does not have a significant contribution to the prevalence of SGA neonates.
Footnotes
Acknowledgments
This study was supported by a grant from The Fetal Medicine Foundation (UK Charity No. 1037116). The assays were performed by Ms. Tracy Dew at the Department of Clinical Biochemistry at King's College Hospital, London, United Kingdom. The assays were sponsored by PerkinElmer, Inc. (Wallac Oy, Turku, Finland).
Disclosure Statement
The authors declare that no competing financial interests exist.
