Epidemiological Study On Thyroid Diseases During Pregnancy

ObjectivesThe role of thyroid hormones is essential for the development of fetal brain. Thyroid hormones deficiency can cause the delayed neuropsychological development, even cause cretinism.Brain development can be divided into three phases based on the initiation and completion of specific developmental events.The first phase(the former twenty gestational weeks)of brain development consists of neuronal histogenesis and migration.Most of thyroid hormones derived from the mother because fetal thyroid function can not mature until twenty gestational weeks.After these processes are completed the developing neurons begin the maturation process.The maturing neuron establishes intercellular connections via the growth of dendrites,subsequent formation of synapses and myelination of the neuronal axon.Recently,growing concern has been expressed by specialists that more attention should be paid to the impact of thyroid insufficiency in early pregnancy on fetal neuropsychological development of phase 1. The main etiology of thyroid insufficiency is hypothyroidism,especially subclinical hypothyroidism.Results of a large-scale prospective study performed by our group showed that the prevalence of subclinical hypothyroidism was 3.4%.Some investigator reported the prevalence of subclinical hypothyroidism during pregnancy was 2%to 3%. These indicate that the effect of maternal thyroid insufficiency on fetal brain development is common.Clinical trials have showed that mild thyroid insufficiency such as subclinical hypothyroidism and hypothyroxinemia during pregnancy can affect fetal neuropsychological development.All of these results highlighted the research on the impact of maternal thyroid dysfunction in early pregnancy on the brain development of the offspring.But many problems have not been resolved,such as no consensus has been reached on the gestational age-specific reference intervals for thyrotropin(TSH)and thyroid hormones,no data from prospective study on levothyroxine treatment for subclinical hypothyroidism during pregnancy.The objective of this epidemiological study is to establish gestational age-specific reference intervals for serum TSH,total thyroxine(TT₄),free thyroxine(FT₄);to acquire the prevalence of hypothyroidism in the first half of pregnancy;to evaluate the effects of levothyroxine on the thyroid function of women with subclinical hypothyroidism diagnosed in early pregnancy prospectively,and to assess the efficacy and safety of levothyroxine treatment.Methods1.SubjectsEpidemiological investigation was performed in ten hospitals in the Shenyang city from May 2005 to December 2007.We recruited 5290 pregnant women among which 4102 pregnant women had gestational age fewer than 8 weeks.108 pregnant women with subclinical hypothyroidism accepted the follow-up regularly,in which 53 were treated with levothyroxine and 55 were not treated.66 normal pregnant women served as controls.2.Methods of observation and interventionSerum TSH,thyroid peroxidase antibody(TPOAb),FT₄(and TT₄)and urine iodine were detected in the screening population.Patients with abnormal lab results were tested twice.The pregnant women enrolled in the cohort accepted the follow-up at 12(G12),16(G16),20(G20),24(G24),28(G28),32(G32)and/or 36(G36)week gestation.Serum TSH,total triiodothyronine(TT₃),TT₄,free triiodothyronine(FT₃), FT₄,TPOAb,thyroglobulin antibody(TgAb)and urine iodine excretion were detected at each follow-up.All the serum parameters were measured by super-sensitive chemiluminescence immunoassay(IMMULITE,Diagnostic Products Corporation,Los Angeles,CA,USA).Urine iodine was detected by the colorimetric ceric ion arsenious acid ash method based on the Sandell-Kolthoff reaction.In the pregnant women with subclinical hypothyroidism,levothyroxine doses were selected based on baseline serum TSH levels.Patients in groupâ… -A(baseline TSH level＞2.5 to 5.0mIU/L)received 50μg/d levothyroxine;patients in groupâ… -B(baseline TSH level＞5.0 to 8.0mIU/L)received 75μg/d levothyroxine;patients in groupâ… -C(baseline TSH level＞8.0 to 17.2mIU/L)received 100μg/d levothyroxine.The levothyroxine doses were adjusted to maintain the serum TSH levels of pregnant women under control—0.3 to 2.5mIU/L for the first trimester;0.3 to 3.0mIU/L for the second trimester and the third trimester.Thyroid function parameters were evaluated every four weeks and the levothyroxine doses were adjusted based on the lab results.3.Statistical analysisSPSS 11.5 was used to analyze the data.Normal distribution data are presented as (?)±s while skewed distribution data are expressed as median.Comparison between two groups was made using t test or Mann-Whitney test.Multiple group comparisons were made using a two-way ANOVA or Kruskal-Wallis test.A 'P' value of less than 0.05 was considered to be statistically significant.Results1.Gestation age-specific reference intervals for thyroid hormonesSerum TSH lowered gradually in the first trimester and dropped to the lowest level at G12 which was 35.0%lower than that of non-pregnant controls.And then it rose gradually and remained stable in the third trimester when the level was 29.17%higher than that of non-pregnant controls.Serum TT₄ level rose quickly in the first trimester and decreased slightly in the second trimester,and stayed the high level in the third trimester.The median TT₄ level in the first,the second and the third trimester was 1.44, 1.62 and 1.49 times higher than that of non-pregnant controls,respectively.Serum FT₄ level increased slightly in the first trimester,then decreased slightly in the second trimester,and remained stable in the third trimester.The median FT₄ level at G4 and G8 was 12.96%and 11.73%higher than that of non-pregnant controls.The FT₄ level decreased slightly between G12 to G20 and remained stable in the third trimester when the level was 16.67%lower than that of non-pregnant controls.2.Epidemiological investigation of hypothyroidism in the first half of pregnancyThe total prevalence of raised serum TSH level was 5.94%in the first half of pregnancy.The prevalence at G4,G8,G12,G16 and G20 was between 4.68%and 6.52%,and no differences were found among them.The total prevalence of decreased serum TSH level was 4.77%.The prevalence was 7.57%at G4 which was the highest. The total rate of positive TPOAb was 9.17%,fluctuating between 9.06%and 9.65% from G4 to G16,and it decreased significantly at G20.Based on the non-pregnant reference intervals,the prevalence of overt hypothyroidism at G4,G8,G16 and the whole population,that of subclinical hypothyroidism and hypothyroxinemia in all groups was lower than that based on the gestation age-specific reference intervals.The rate of missed diagnosis of overt hypothyroidism was 0.83%,0.20%,0.32%and 0.45% at G4,G8,G16 and the whole population,respectively.At G4,G8,G12,G16,G20 and the whole population,the missed diagnosis of subclinical hypothyroidism was 0.18%, 2.85%,4.10%,3.24%,3.21%and 1.83%,respectively,and that of hypothyroxinemia was 3.45%,0.66%,2.34%,1.29%,1.80%and 1.80%,respectively.In G4,G8 and the whole population,the rate of positive TPOAb in pregnant women with overt hypothyroidism was higher than that of controls and the prevalence of overt hypothyroidism in the pregnant women with positive thyroid peroxidase antibody was higher than that in the pregnant women with negative ones.In G4,G8,G12,G16 and the whole population,the rate of positive TPOAb in pregnant women with subclinical hypothyroidism was higher than that of controls and the prevalence of subclinical hypothyroidism in the pregnant women with positive thyroid peroxidase antibody was higher than that in the pregnant women with negative ones in these groups.The rate of positive TPOAb in hypothyroxinemia pregnant women was similar to that of controls and the prevalence of hypothyroxinemia in the pregnant women with positive thyroid peroxidase antibody was similar to that in the pregnant women with negative ones.The serum TSH level was higher in pregnant women with positive TPOAb than that in those with negative ones.The results of Logistic regression showed that positive TPOAb was independent risk factor for the elevated TSH level in the first half of pregnancy(OR=5.586).3.Study on the efficacy and safety of levothyroxine replacement therapy for pregnant women with subclinical hypothyroidism throughout pregnancyPregnant women with subclinical hypothyroidism received levothyroxine treatment before G8(Groupâ… ).The serum TSH level dropped from 5.20mIU/L to 1.11mIU/L at G12.Then it stayed between 1.04 and 1.39mIU/L before delivery.The fluctuation range is similar to that of groupâ…¢(0.87 to 1.39mIU/L).The serum TT₄ level increased to 157.66nmol/L at G12.Then it stayed between 140.28 and 158.94nmol/L until delivery.The TT₄ level in groupâ… was higher than in healthy controls(groupâ…¢)(126.77 to 143.50nmol/L).The serum FT₄ level rose to 19.55pmol/L at G12.Then it decreased to 14.40pmol/L at G24.It stayed at this level until delivery.The serum FT₄ level in groupâ… was higher than in groupâ…¢(12.95 to 16.90pmol/L).The serum TT₃ level kept increasing until G28.Then it decreased a little before delivery.The serum FT₃ level kept increasing until G16.Then it remained stable during G16 to G28 and dropped a little before delivery.No differences were found in serum TT₃ and FT₃ concentration between groupâ… and groupâ…¢.The serum TSH levels from the women with subclinical hypothyroidism without levothyroxine treatment (groupâ…¡)remained a high level throughout pregnancy.The dynamic changes of the levels of serum TT₄,FT₄,TT₃ and FT₃ in groupâ…¡are similar to the changes in group â…¢.To keep the serum TSH levels of pregnant women under control--0.3 to 2.5mIU/L for the first trimester and 0.3 to 3.0mIU/L for the second trimester and the third trimester.Patients in groupâ… -A(baseline TSH level＞2.5 to 5.0mIU/L)received 50μg/d levothyroxine and 91.6%of tests achieved the goal.Patients in the groupâ… -B(baseline TSH level＞5.0 to 8.0mIU/L)received 75μg/d levothyroxine and 86.4%of tests achieved the goal.Patients in groupâ… -C(baseline TSH level＞8.0 to 17.2mIU/L) received 100μg/d levothyroxine and 78.0%of tests achieved the goal.No iatrogenic hyperthyroidism occurred though 17.1%of tests in groupâ… -C exceeded the levels of normal pregnancy.The titers of serum TPOAb and TgAb decreased gradually during pregnancy.Among the pregnant women with high TPOAb levels at baseline,the titer of TPOAb was 80.13%lower at G20 than at G8 in those with levothyroxine treatment and it was 52.24%lower in those without levothyroxine treatment.And among the pregnant women with high TgAb levels at baseline,the titer of TgAb was 89.12%lower at G20 than at G8 in those with levothyroxine treatment and it was 62.76%lower in those without levothyroxine treatment.No differences were found in the pregnancy outcomes and the newborns evaluation among the three groups.Conclusion1.We have established the gestational month-specific and the trimester-specific reference intervals for serum TSH,TT₄ and FT₄ in China for the first time.2.During pregnancy,serum TSH level decreased in the first trimester and dropped to the lowest at 12 weeks.It rose gradually during the second and the third trimester. Serum TT₄ level rose quickly in the first trimester and decreased slightly in the second trimester,and remained the high level in the third trimester.The median TT₄ levels in the first,the second and the third trimester were 1.44,1.62 and 1.49 times higher than that of the non-pregnant controls.Serum FT₄ levels increased slightly in the first trimester,then decreased slightly in the second trimester,and remained stable in the third trimester.3.Thyroid function indexes fluctuated profoundly during pregnancy and it is essential to establish gestation-age specific reference intervals for appropriate diagnosis of subclinical hypothyroidism and hypothyroxinemia during pregnancy.4.This study is the first systematic epidemiological study on thyroid diseases during pregnancy.5.In this study,we have acquired the prevalence of overt hypothyroidism, subclinical hypothyroidism and hypothyroxinemia according to the gestation age-specific reference intervals for thyroid hormones in the first half of pregnancy for the first time in China.6.To evaluate thyroid function based on gestation age-specific reference intervals will reduce the rate of missed diagnosis of hypothyroidism,especially that of subclinical hypothyroidism before 16 week and that of hypothyroxinemia before 8 week gestation.7.Positive TPOAb is the independent risk factor for the occurrence of subclinical hypothyroidism in the first half of pregnancy which indicates that thyroid function should be monitored closely in the pregnant women with positive TPOAb.8.This study is the first systematic study on levothyroxine replacement therapy for pregnant women with subclinical hypothyroidism in the world.9.It is effective and safe to treat pregnant women with subclinical hypothyroidism using levothyroxine properly.10.During the period of levothyroxine treatment for pregnant women with subclinical hypothyroidism,serum TSH and FT₄ are sensitive and can be used to monitor the efficacy.11.In pregnant women with subclinical hypothyroidism,levothyroxine treatment with the following doses can maintain the serum TSH level within the ideal range without iatrogenic hyperthyroidism.(1)Baseline serum TSH level from＞2.5 to 5.0mIU/L,levothyroxine 50μg/d;(2)Baseline serum TSH level from＞5.0 to 8.0mIU/L,levothyroxine 75μg/d;(3)Baseline serum TSH level from＞8.0 to 17.2mIU/L,levothyroxine 100μg/d seems to be a little higher,so the doses should be adjusted based on the thyroid tests.12.During pregnancy immune system is inhibited in mother and the inhibitory effect is more obvious in the first half of pregnancy.So the titers of thyroid antoantibodies in the latter half of pregnancy can not indicate the immune status of thyroid correctly.13.Levothyroxine treatment can promot the decrement of thyroid autoantibodies levels and can improve the impaired thyroid immune status.14.Levothyroxine treatment is safe for pregnancy outcomes and newborns.