Pregnancy changes in thyroid function tests. The changes

Pregnancy causes significant alteration on functioning ofthyroid gland. Synthesis of thyroid hormones, thyroxine (T4), andtriiodothyronine (T3), increase almost one and half times along with a 50% increasein the daily requirement of iodine. In healthy women these changes take placenormally as a part of normal physiology of pregnancy. But many women withborderline thyroid dysfunction manifest clinically relevant thyroidabnormalities during pregnancy.

Thyroid dysfunction during pregnancy is widelyprevalent. That is why thyroid function is assessed commonly during pregnancy. Correctassessment of maternal thyroid status in setting of pregnancy remains challenging,and interpretation of thyroid assays is different from the nonpregnant state. Althoughthe management of overt hypothyroidism in pregnancy is standardized, contradictoryopinion exists regarding management of subclinical hypothyroidism (SCH) inpregnancy.  Clinicalmanifestations The symptoms of hypothyroidism during pregnancy and innonpregnant state are similar. The manifestations can range from fatigue, hairfall, dry skin, intolerance to cold, gain in weight and constipation. Many ofthese symptoms occur commonly in pregnancy and identification of hypothyroidismon the basis of symptoms can be misleading. Many pregnant women withhypothyroidism often do not manifest any symptoms.

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SCH in usually asymptomaticand detected only on laboratory testing.   Laboratoryfindings To meet the metabolic demands during pregnancy, there arechanges in thyroid physiology that are manifested in changes in thyroidfunction tests. The changes include elevated T4-binding globulin (TBG), thatraise the total T4 and T3 levels by 1.5 times higher than in nonpregnant state.Besides, high serum human chorionic gonadotropin (hCG) levels, particularly inearly pregnancy, result in a reduction in serum thyroid stimulating hormone(TSH) levels in first trimester.

If population and trimester-specific reference ranges for TSHare not available, an upper reference cut off of approximately 4 mU/L can beused. Trimester specific reference values for free T4 (FT4) should be providedwith the assay kits. High levels of bound T4 in pregnancy can make assessmentof FT4 challenging. Assays based on methods of separation like equilibriumdialysis or ultrafiltration are laborious, time-consuming, expensive, and notwidely available. FT4 measurement is performed by indirect analog immunoassaysby the majority of clinical laboratories, largely because of its ability to bequickly performed on automated platforms.

 Measurement of total T4 may be superior to immunoassaymeasurement of FT4 in pregnant women. However, reference ranges should take intoaccount the 50% increase in TBG occurring in pregnancy into. 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 TPOantibodies compared to those with negative TPO antibodies.  If the serum TSH is >2.5 mU/L, estimationof TPO antibodies should be done. TPO antibody positivity can tilt the decisionto start T4 treatment in pregnant women with TSH between 2.5 to 4.

0 mU/L alsoto predict the risk of postpartum thyroid dysfunction.  Diagnosis The diagnosis of primary hypothyroidism during pregnancy isbased upon the finding of an elevated serum TSH level, calculated usingpopulation and trimester-specific TSH ranges for women with pregnancy. Anywomen with symptoms suggestive of hypothyroidism should undergo a TSHestimation. There is inadequate evidence to recommend for or against routine screeningfor thyroid dysfunction of asymptomatic pregnant women but estimation of TSH iscommonly done in first trimester of pregnancy in clinical practice. As per the recommendation of the American Thyroid Association(ATA) 2017 guidelines 2017 the following trimester-specific ranges and cutoffs canbe considered when local assessments are not available. In the first trimester,the lower reference value of TSH can be decreased by 0.4 mU/L, while the upperreference range is reduced by 0.5mU/L.

This usually corresponds to a TSH upperreference limit of 4.0mU/L. Women with central hypothyroidism from pituitary orhypothalamic disease will not have elevated TSH concentrations duringpregnancy. For women in the first trimester of pregnancy with a TSH above 4.

0mU/L, FT4 or total T4 value should be estimated to differentiate between SCHand overt hypothyroidism.   PregnancyComplications Hypothyroidism can have adverse effects on pregnancyoutcomes, depending upon the severity of the biochemical abnormalities: ?Overt hypothyroidism?Subclinical hypothyroidism?Maternal hypothyroxinemia (isolated low maternal FT4) Overthypothyroidism — Uncorrected overt hypothyroidism in pregnancy is unusual(0.3-0.5% of screened women).

Anovulation in hypothyroid women and increasedrate of first trimester spontaneous abortion (often undetected) are responsiblefor this finding. In continuing pregnancies, hypothyroidism has beenassociated with an increased risk of several complications, including:?Preeclampsia and gestational hypertension?Placental abruption?Nonreassuring fetal heart rate tracing?Preterm delivery, including very preterm delivery (before32 weeks)?Low birth weight ?Increased cesarean section rate?Postpartum hemorrhage?Perinatal morbidity and mortality?Neuropsychological and cognitive impairment in the child  Subclinicalhypothyroidism — SCH is more common than overt hypothyroidism. In areaswith iodine sufficiency, 2.0 to 2.5% of screened women have SCH. Women with SCHhave a lower chance to develop complication than those with overt disease. In some but not all studies, women with SCH were reported tobe at increased risk for severe preeclampsia, preterm delivery, placentalabruption, and/or pregnancy loss compared with euthyroid women.

It is uncertainif the children of women with SCH are at risk for neuropsychologicalimpairment. Observational studies suggest a possible association between SCH inpregnancy and impaired cognitive development in children. Women with SCH and positiveTPO antibodies have a tendency towards higher risk of adverse pregnancyoutcomes.

The risk of complications increases in TPO positive women with TSH>2.5 mU/L but was not consistently demonstrated in TPO negative women untilTSH values exceeded 5 to 10 mU/L.  Pregnancyoutcome for women undergoing in vitro fertilization may be worse among thosewith preconception TSH values higher than 2.

5 mU/L.  Low maternalfree T4 — Isolated maternal hypothyroxinemia is defined as a maternal  FT4 level in the lower 2.5 to 5 percentile ofthe reference range along with a TSH concentration in normal range. Isolatedmaternal hypothyroxinemia has not been clearly demonstrated to be associatedwith worsening of perinatal and neonatal outcome. In a multicenter trial, womenwith isolated maternal hypothyroxinemia, T4 supplementation did not showsignificant differences in neurodevelopmental or behavioral outcomes in thechildren at five years of age. In addition, there were no significantdifferences in the frequencies of preterm delivery, preeclampsia, gestationalhypertension, miscarriage rate, or other maternal or fetal outcomes.      Treatment Indicationsfor treatmentOvert Hypothyroidism – All pregnant women with newly diagnosed,overt hypothyroidism (elevated TSH >4 mU/L, with low T4) should be treated withT4.

 Subclinical Hypothyroidism – Most authorities suggest treatmentof pregnant women with SCH (elevated TSH > 4 mU/L with normal T4), irrespectiveof TPO antibody status.  TSH 2.6 to 4 mU/L – T4 therapy may be considered for womenwith TPO antibody positive women with TSH concentrations >2.

5 mU/L and below4 mU/L.   T4 therapy isnot recommended for TPO antibody negative women with a normal TSH (TSH <4.0mU/L). In women with TSH between 2.6 and 4 mU/L who are not treated withthyroid hormone, TSH should be reassessed later during pregnancy. Euthyroidism(TSH <2.

5 mU/L) with TPO antibody positive and recurrent miscarriage – Someauthorities consider T4 therapy in pregnant euthyroid women with history of recurrentmiscarriage and positive TPO antibody status.Low FT4,Normal TSH – There is no evidence to consider treatment.Dosing RecommendationsThe treatmentof choice for correction of hypothyroidism in pregnancy is the same as innonpregnant patients: synthetic T4. The purpose of T4 replacement in pregnancyis to restore euthyroidism as soon as possible. T4 should be taken on an emptystomach, ideally an hour before breakfast.? TSH >4mU/L with low free T4:  Close to fullreplacement dose (around 1.6 mcg/kg body weight per day)? TSH >4 mU/L,with normal free T4: Intermediate dose (around 1 mcg/kg per day)? TSH 2.6 to4 mU/L: If a decision has been made to treat, low dose (typically 50 mcg daily)Monitoring and dose adjustments — Afterinitiation of T4 therapy, the patient should be reevaluated and serum TSHmeasured in four weeks.

The goal is to maintain TSH in the lower half of thetrimester-specific reference range or  of<2.5 mU/L. If the TSH remains above the target range, the dose of T4 can beincreased by 12 to 25 mcg/day. TSH measurement should be done every 4 weeks inthe first half of pregnancy because dose adjustments are often required. TSHcan be monitored less often (at least once each trimester) in the latter halfof pregnancy, as long as the dose is unchanged.  Preexisting hypothyroidismGoal preconception TSH — Women withprior hypothyroidism who are planning to conceive should optimize their thyroidhormone replacement.

The target preconception serum TSH level is between thelower reference limit and 2.5 mU/L. Early dose adjustments — T4 doserequirements may increase during pregnancy in women with preexistinghypothyroidism.

Hypothyroid women after detection of pregnancy shouldpreemptively increase their T4 dosage by around 30 percent and notify theirclinician as soon as possible. Subsequent adjustment in dosage are made upon  the basis of serum TSH estimates done every 4weeks until TSH normalizes. Althoughuntreated (or incompletely treated) hypothyroidism can adversely affectpregnancy, no data suggest that women with adequately treated subclinical orovert hypothyroidism have an increased risk of any obstetrical complication. Tthereis no indication for any additional obstetric monitoring in pregnancies of womenwith either SCH or overt disease who are being monitored and treated correctly.