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The functioning of the thyroid gland is significantly altered by pregnancy. The production of thyroxine (T4) and triiodothyronine (T3), increase almost one and half times in pregnancy. In healthy women, these changes take place seamlessly as a part of the normal physiology of pregnancy but many women with borderline thyroid status develop abnormalities in the functioning of the thyroid gland during pregnancy. Thyroid dysfunction during pregnancy is widely prevalent. That is why thyroid function is assessed commonly during pregnancy. Clinical features The symptoms of hypothyroidism during pregnancy and in the nonpregnant state are similar. The manifestations can range from fatigue, hair fall, dry skin, intolerance to cold, gain in weight and constipation. Many of these symptoms occur commonly in pregnancy and identification of hypothyroidism on the basis of symptoms can be misleading. Pregnant women with hypothyroidism often do not manifest any symptoms. Subclinical hypothyroidism (SCH) is usually asymptomatic and detected only on laboratory testing. Laboratory findings To meet the metabolic demands during pregnancy, the thyroid physiology is altered that are manifested in changes in thyroid function tests. The changes include elevated T4-binding globulin (TBG), that raise the total T4 and T3 levels by 1.5 times higher than in nonpregnant state. Besides, high serum human chorionic gonadotropin (hCG) levels, particularly in early pregnancy, resulting in a reduction in serum thyroid stimulating hormone (TSH) levels in the first trimester. If population and trimester-specific reference range for TSH are not available, an upper reference cut off of approximately 4 mU/L can be used. Trimester-specific reference values for free T4 (FT4) should be provided with the assay kits.
High levels of bound T4 in pregnancy can make an assessment of FT4 challenging. Assays based on methods of separation like equilibrium dialysis or ultrafiltration are laborious, time-consuming, expensive, and not widely available. FT4 measurement is performed by indirect analog immunoassays by the majority of clinical laboratories, largely because of its ability to be quickly performed on automated platforms. Measurement of total T4 may be superior to immunoassay measurement of FT4 in pregnant women. However, reference ranges should take into account the 50% increase in TBG occurring in pregnancy. Thyroid peroxidase (TPO) antibodies are elevated in 30-60% of pregnant women with an elevated TSH. The risk of complications is higher in women with SCH and positive TPO antibodies compared to those with negative TPO antibodies. If the serum TSH is >2.5 mU/L, estimation of TPO antibodies should be done. TPO antibody positivity can tilt the decision to start T4 treatment in pregnant women with TSH between 2.5 to 4.0 mU/L and can also help to predict the risk of postpartum thyroid dysfunction. Diagnosis The diagnosis of primary hypothyroidism during pregnancy is based upon the finding of an elevated serum TSH level, calculated using population and trimester-specific TSH ranges for women with pregnancy. Any women with symptoms suggestive of hypothyroidism should undergo a TSH estimation. There is inadequate evidence to recommend for or against routine screening for thyroid dysfunction of asymptomatic pregnant women but estimation of TSH is commonly done in the first trimester of pregnancy in clinical practice. As per the recommendation of the American Thyroid Association (ATA) 2017 guidelines the following trimester-specific ranges and cutoffs can be considered when local assessments are not available. In the first trimester, the lower reference value of TSH can be decreased by 0.4 mg/L, while the upper reference range is reduced by 0.5mU/L. This usually corresponds to a TSH upper reference limit of 4.0mU/L. Women with central hypothyroidism from pituitary or hypothalamic disease will not have elevated TSH concentrations during pregnancy. For women in the first trimester of pregnancy with a TSH above 4.0 mU/L, FT4 or total T4 value should be estimated to differentiate between SCH and overt hypothyroidism.
Pregnancy Complications Hypothyroidism can have adverse effects on pregnancy outcomes, depending upon the severity of the biochemical abnormalities:
Overt hypothyroidism — Uncorrected overt hypothyroidism in pregnancy is unusual (0.3-0.5% of screened women).
Anovulation in hypothyroid women and increased rate of first-trimester spontaneous abortion (often undetected) are responsible for this finding. In continuing pregnancies, hypothyroidism has been associated with an increased risk of several complications, including:
Subclinical hypothyroidism — SCH is more common than overt hypothyroidism. In areas with iodine sufficiency, 2.0 to 2.5% of screened women have SCH. Women with SCH have a lower chance to develop complication than those with overt disease. In some but not all studies, women with SCH were reported to be at increased risk for severe preeclampsia, preterm delivery, placental abruption, and/or pregnancy loss compared with euthyroid women. It is uncertain if the children of women with SCH are at risk for neuropsychological impairment.
Observational studies suggest a possible association between SCH in pregnancy and impaired cognitive development in children. Women with SCH and positive TPO antibodies have a tendency towards higher risk of adverse pregnancy outcomes. The risk of complications increases in TPO positive women with TSH >2.5 mU/L but was not consistently demonstrated in TPO negative women until TSH values exceeded 5 to 10 mU/L. Pregnancy outcome for women undergoing in vitro fertilization may be worse among those with preconception TSH values higher than 2.5 mU/L. Low maternal free T4 — Isolated maternal hypothyroxinemia is defined as a maternal FT4 level in the lower 2.5 to 5 percentile of the reference range along with a TSH concentration in the normal range. Isolated maternal hypothyroxinemia has not been clearly demonstrated to be associated with worsening of the perinatal and neonatal outcome. In a multicenter trial, women with isolated maternal hypothyroxinemia, T4 supplementation did not show significant differences in neurodevelopmental or behavioral outcomes in the children at five years of age. In addition, there were no significant differences in the frequencies of preterm delivery, preeclampsia, gestational hypertension, miscarriage rate, or other maternal or fetal outcomes. Treatment Indications for treatment over Hypothyroidism – All pregnant women with newly diagnosed, overt hypothyroidism (elevated TSH >4 mU/L, with low T4) should be treated with T4.
Subclinical Hypothyroidism – Most authorities suggest treatment of pregnant women with SCH (elevated TSH > 4 mU/L with normal T4), irrespective of TPO antibody status. TSH 2.6 to 4 mU/L – T4 therapy may be considered for women with TPO antibody positive women with TSH concentrations >2.5 mg/L and below 4 mU/L. T4 therapy is not recommended for TPO antibody negative women with a normal TSH (TSH <4.0 mU/L). In women with TSH between 2.6 and 4 mU/L who are not treated with thyroid hormone, TSH should be reassessed later during pregnancy. Euthyroidism (TSH 4 mU/L with low free T4: Close to full replacement dose (around 1.6 mcg/kg body weight per day)
Monitoring and dose adjustments — After initiation of T4 therapy, the patient should be reevaluated and serum TSH measured in four weeks. The goal is to maintain TSH in the lower half of the trimester-specific reference range or below 2.5 mU/L. If the TSH remains above the target range, the dose of T4 can be increased by 12 to 25 mcg/day. TSH measurement should be done every 4 weeks in the first half of pregnancy because dose adjustments are often required. TSH can be monitored less often (at least once each trimester) in the latter half of pregnancy, as long as the dose is unchanged. Preexisting hypothyroidismGoal preconception TSH — Women with prior hypothyroidism who are planning to conceive should optimize their thyroid hormone replacement. The target preconception serum TSH level is between the lower reference limit and 2.5 mU/L. Early dose adjustments — T4 dose requirements may increase during pregnancy in women with preexisting hypothyroidism. Hypothyroid women after detection of pregnancy should preemptively increase their T4 dosage by around 30 percent and notify their clinician as soon as possible. Subsequent adjustment in dosage are made upon the basis of serum TSH estimates done every 4 weeks until TSH normalizes.
Although untreated (or incompletely treated) hypothyroidism can adversely affect pregnancy, no data suggest that women with adequately treated subclinical or overt hypothyroidism have an increased risk of any obstetrical complication. There is no indication for any additional obstetric monitoring in pregnancies of women with either SCH or overt disease who are being monitored and treated correctly.
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