Hypothyroxinemia is most commonly seen in women during pregnancy and not only has adverse effects on maternal and fetal neurological development, but also causes damage to the fetus. Treatment with active intervention may improve pregnancy outcome and fetal neurological development and reduce the occurrence of related diseases.
Hypothyroxinemia generally refers to a state of abnormal thyroid function in which thyroid stimulating hormone (TSH) levels are normal and free T4 is below normal. Simple hypothyroxinemia is characterized by negative thyroid autoantibodies, but T4 levels below the reference range. In clinical practice, this type of disorder is most often seen in women during pregnancy. Because of the possible adverse effects on pregnancy outcome and the fetus, this disease is gradually attracting the attention of endocrinologists and obstetricians and gynecologists.
1. Diagnosis of hypothyroxinemia
At present, there is no unified standard for the diagnosis of hypothyroxinemia, and the following four methods are mostly used for evaluation.
(1) Free T4 is below the 10th percentile of the normal reference range for the general population. This is currently the most commonly used method internationally. It is also the standard recommended by the 2011 American Thyroid Association guidelines on the diagnosis and management of thyroid disease during pregnancy and postpartum and the 2012 Chinese guidelines on the diagnosis and management of thyroid disease during pregnancy and postpartum.
(2) Total T4 is below 1.5 times the lower limit of the normal population reference range.
(3) TSH between the 2.5th and 97.5th percentile and free T4 below the 2.5th percentile.
(4) Below the lower limit of gestational month-specific total T4 or free T4. To date, the normal reference ranges of pregnancy-specific total T4 and free T4 recommended by countries vary.
2. Effects of hypothyroxemia on pregnancy outcome
(1) Changes in thyroid function during pregnancy
The synthesis of thyroid hormone-binding globulin (TBG) increases during pregnancy due to estrogen stimulation, and the level of TBG gradually increases from the 6th to the 8th week of gestation, reaching a peak around the 20th week of gestation and continuing thereafter until delivery. In general, TBG increases approximately two to three times from basal status, and the increase in TBG leads to an increase in total T4 levels. Therefore, total T4 during pregnancy does not reflect the exact level of circulating thyroid hormones in the mother.
On the other hand, placental secretion of human chorionic gonadotropin increases in early pregnancy. Since only its subunits are identical to TSH, human chorionic gonadotropin has the effect of stimulating thyroid hormone secretion, and the increase of thyroid hormone suppresses TSH secretion and reduces serum TSH level by 20% to 30%. In view of this, changes in thyroid hormone metabolism during pregnancy inevitably bring about changes in the reference range of serum thyroid function indicators. Therefore, there is a need to establish pregnancy-specific reference values for serum thyroid function indicators. 2011 American Thyroid Association guidelines firstly proposed reference values for TSH specific to the three stages of pregnancy: 0.1-2.5 mIU/L in T1, 0.2-3.0 mlU/L in T2, and 0.3-3.0 mlU/L in T3. Chen Yanyan et al. found that the normal range of pregnancy-specific thyroid function as and the normal range of thyroid function in the non-pregnant population to screen for the prevalence of hypothyroidism, respectively. The prevalence of hypothyroidism in women at 4, 8, 12, 16, and 20 weeks of gestation diagnosed with gestation-specific normal thyroid function ranges was 3.69% 1.1%, 2.92%, 1.29%, and 2.29%, respectively. If the diagnostic criteria for the non-pregnant population were used, the prevalence of hypothyroxinemia was 3.45%, 0.66%, 2.34%, 1.29%, and 1.83%, respectively, of missed diagnoses. The investigators concluded that the use of pregnancy-specific thyroid function reference range as an evaluation index can reduce the underdiagnosis rate of subclinical hypothyroidism and hypothyroxinemia in the first half of pregnancy.
(2) Effect of hypothyroxinemia on maternal pregnancy outcome
A woman’s requirement for thyroid hormones is much higher after pregnancy than in the absence of pregnancy and continues throughout pregnancy into the perinatal and lactation periods. In pregnant women with good iodine nutrition, the degree of decline in serum thyroid hormone levels tends to be maintained at borderline levels. In the presence of moderate or significant iodine deficiency, a decrease in serum free T4 levels can occur, leading to hypothyroxinemia. Thus, iodine deficiency is one of the main causes of hypothyroxinemia in pregnant women. Studies have shown that any degree of hypothyroidism during pregnancy, including hypothyroidism, subclinical hypothyroidism and hypothyroxinemia, can lead to a significantly increased incidence of miscarriage, preeclampsia, preterm delivery, breech delivery and fetal death.
However, a study of 17,298 women during pregnancy found that the number of women with hypothyroxemia alone was 233 (1.3%), but no women with hypothyroxemia were found to have adverse perinatal pregnancy outcomes such as gestational hypertension, placental abruption, preterm delivery, or neonatal asphyxia, among other conditions. For this reason, the investigators pointed out that hypothyroxinemia should be a physiological alteration during pregnancy. In addition, Harem et al. observed the relationship between early pregnancy hypothyroxemia and pregnancy outcome by small for gestational age, birth weight Z value, preterm birth, and neonatal Apgar score, and also found that hypothyroxemia alone did not have any adverse effect on pregnancy outcome or fetal growth. However, Cleary-Goldman et al. evaluated pregnancy outcome by testing TSH, free T4, thyroid peroxidase antibodies, and thyroglobulin antibodies in 10,990 women in early and mid-pregnancy. The results found that the incidence of hypothyroxemia in early and mid-pregnancy was 2.1% and 2.3%, respectively. Moreover, hypothyroxinemia was associated with preterm delivery and macrosomia in early pregnancy; and with gestational diabetes in midtrimester. In addition, the risk of premature rupture of membranes is significantly increased when two thyroid autoantibodies (thyroid peroxidase antibody, thyroglobulin antibody) are positive in any trimester.
(3) Effect of hypothyroxinemia on the offspring
A Spanish cohort study enrolling a total of 1761 children and their mothers found that maternal low free T4 levels were associated with reduced offspring psychological and psychomotor development scores without a significant association with TSH levels, suggesting that low free T4 levels may be associated with delayed neurological development in the offspring. The Dutch Generation RStudy, a non-randomized prospective study, found that pregnant women with simple hypothyroxinemia adversely affected the offspring’s ability to communicate at age 3 years, increasing their risk by 1.5 to 2 times. Another study also found that women with subclinical hypothyroidism, hypothyroxemia and elevated thyroid peroxidase antibody titers between 16 and 20 weeks of gestation had offspring with lower mean IQ scores and motor scores than controls at 25 to 30 months of age. This suggests that maternal thyroid function status during pregnancy can affect the level of motor and intellectual development of children, especially cognitive and memory abilities.
The presence of hypothyroxinemia in early gestation has been reported to have a particularly pronounced effect on the fetus. Early gestation is a period of rapid fetal brain development, when fetal thyroid function is not yet established, and therefore the thyroxine needed for brain development comes mainly from the mother. Kooistra et al. also suggested that free T4 levels in early gestation, but not TSH levels or free T4 levels in late gestation, are the main influence on fetal neurodevelopment. A study by Finken et al. on the responsiveness of 1765 children suggested that mothers with reduced free T4 levels during early gestation had offspring with slower motor responses, reduced responsiveness, and diminished visuomotor abilities. Therefore, maternal hypothyroxinemia in early gestation is a risk factor for delayed early cognitive development in children, which can lead not only to delayed expressive language cognitive function, but also, a higher risk of delayed nonverbal cognitive function and even autism.
3. Intervention of hypothyroxinemia during pregnancy
Authoritative domestic and foreign guidelines agree that to date, there are no randomized controlled studies on the effect of hypothyroxemia alone on pregnancy outcomes, so there is a lack of evidence-based medicine for the treatment of hypothyroxemia alone during pregnancy. Although there are many studies on the increase of adverse pregnancy outcomes and neurointellectual developmental impairment in the offspring in hypothyroxemia alone, the conclusions are not uniform and, therefore, levothyroxine T4 treatment for hypothyroxemia is not routinely recommended. However, some investigators still emphasize that hypothyroxinemia alone should be treated aggressively, which may be beneficial for pregnancy outcome and fetal neuropsychiatric development.
(1) Iodine supplementation
Hypothyroxinemia in pregnant women is usually the result of iodine deficiency, even in iodine-sufficient areas. For hypothyroxinemia caused by iodine deficiency, if iodine supplementation is used, it is recommended to start early in pregnancy, preferably 6 to 12 weeks before gestation. The World Health Organization and the International Council for the Control of Iodine Deficiency Disorders recommend an iodine intake of at least 250 μg/d for women during pregnancy and lactation.
Timely iodine supplementation has been shown to have a positive effect on the neurodevelopment of their offspring compared to mothers who are not iodized. For this reason, it is recommended to increase iodine intake before and during early pregnancy. In particular, iodine supplementation early in pregnancy is of great importance since pregnant women with mild hypothyroxinemia in the first trimester may result in delayed neurobehavioral development of their offspring.
(2) Thyroxine supplementation
In the state of pregnancy, T4 from the mother enters the fetus and is converted into T3 through the action of type II deiodinase, which then exerts its physiological effects. Therefore, the preferred replacement drug for patients with hypothyroidism during pregnancy is levothyroxine T4. For women with hypothyroidism before pregnancy, the thyroxine dose needs to be adjusted promptly to maintain maternal serum TSH and free T4 at normal levels during pregnancy.
In a study by Kasatkina et al, timely thyroxine supplementation before 5-9 weeks of gestation in hypothyroidism reduced the risk of newborns with low IQ scores in the first year of life, and their offspring had the same level of IQ as the offspring of normal pregnant women. In conclusion, hypothyroxinemia not only has adverse effects on maternal and fetal neurological development, but also causes damage to the fetus, and treatment by active intervention may improve pregnancy outcome and fetal neurological development and reduce the occurrence of related diseases. However, more large multicenter, randomized, controlled studies are needed in the future to further clarify the harms and management principles of hypothyroxinemia.