Maternal Thyroid Function at Eleven to Thirteen Weeks of Gestation and Subsequent Delivery of Small for Gestational Age Neonates

Introduction

S mall for gestational age (SGA) neonates, with birth weight below the 5th percentile, are at increased risk of perinatal death and handicap. The condition is heterogeneous and constitutionally includes small neonates and growth-restricted ones because of impaired placentation, genetic disease, or environmental damage. In normal pregnancy, the spiral arteries in the placental bed are invaded by trophoblast, which becomes incorporated into the vessel wall and replaces the endothelium, muscular layer, and neural tissue. These physiological changes convert the spiral arteries from narrow muscular vessels to wide nonmuscular channels independent of maternal vasomotor control. Impaired trophoblastic invasion and placentation are thought to be the underlying mechanisms for many cases of preeclampsia (PE) and of impaired fetal growth in the absence of PE (1 –4). Abnormal placentation is reflected in increased impedance to flow in the uterine arteries at 11–13 weeks of gestation both in pregnancies that subsequently develop PE and, to a lesser extent, in those delivering SGA neonates in the absence of PE (5,6).

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).

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.

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).

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.