from the fetal circulation than maternal stimulating antibodies.Maternal euthyroidism is particularly important inthe later stages of pregnancy, as poorly controlledhyperthyroidism can lead to suppression of the fetalpituitary thyroid axis resulting from placental transferof thyroxine. A case-control study noted a low thyrotrophin concentration, a blunted result (that is,suppressedcomparedwiththenormalresponse)witha thyrotrophin releasing hormone test, and low serumthyroxine concentration in a group of neonates whosemothershadhadpoorlycontrolledhyperthyroidisminthe third trimester of pregnancy. The condition maylast up to six months, as described in two case series.
Subclinical hyperthyroidism has no known associatedadverse pregnancy outcomes.
How does pregnancy affect hyperthyroidism?
A deterioration in previously diagnosed thyroiddisease is not uncommon during the first trimester of pregnancyandmaybeduetoanincreaseinthetitreof TRAb concentrations or high levels of human chor-ionic gonadotrophin acting as a thyroid stimulator.Relapsemayalsobecausedbyimpairedabsorptionof antithyroid medication secondary to vomiting that isassociatedwithpregnancyorbyreluctancetocontinuemedication in the first trimester.
Human immune regulation involves homoeostasisbetweenThelper1(Th1)andThelper2(Th2)activity,with Th1cells drivingcellular immunityandTh2 cellshumoralimmunity.Theimmunestatusofpregnancyisa Th2 state, which allows tolerance of the fetus during pregnancy,andthisisthoughttobethereasonwhytheseverity of Graves
hyperthyroidism (and otherautoimmune diseases) usually lessens after the first trimester.
Hyperthyroidism before pregnancy may remit during pregnancy but will recur in the postpartumperiod as the immune status reverts to a Th1 state.On rare occasions, labour, caesarean section, andinfections may aggravate hyperthyroidism to theextent that cases of thyroid storm (a life threatening form of hyperthyroidism) have been observed.
How is hyperthyroidism treated in pregnancy?
Prepregnancy planning and counselling
Ideally,awomanwhoknowsshehashyperthyroidismshould seek prepregnancy advice, although no evi-dence exists yet for the benefit of this.
Patients already treated for hyperthyroidism caused byGraves
Although patients who have already been treated forhyperthyroidismmayhavereceivedantithyroiddrugs,had surgery, or had radioiodine therapy and beeuthyroid (whether receiving thyroxine or not),neonatal hyperthyroidism may still occur. TRAbconcentration should be measured early in pregnancyin a euthyroid pregnant women who has previouslyhadsurgeryor radioiodine therapy.
If the concentra-tion is high at this time, the fetus should be evaluatedcarefullyduringgestation(withserialultrasonography)and the antibodies measured again in the thirdtrimester. If the TRAb concentration is high at 36 weeks, the neonate needs to be checked forhyperthyroidism after delivery.
Treatment of hyperthyroidism in pregnancy
Box 3 outlines the main elements in managing hyperthyroidism in a pregnant woman. At all stagesof pregnancy antithyroid drugs are the preferredtreatment (table).
Radioiodine is contraindicated(box 4) and surgery requires pretreatment with anti-thyroid drugs to render the patient euthyroid.The thionamides carbimazole, methimazole (themetabolite of carbimazole), and propylthiouracil areall effective in inhibiting thyroidal biosynthesis of thyroxine during pregnancy. Propylthiouracil is thepreferred drug in pregnancy as carbimazole andmethimazole are (albeit rarely) associated with terato-genic effects.An early study also reported less placental transferof propylthiouracil than of methimazole, but results of a more recent study measuring propylthiouraciland methimazole concentrations and examining placental perfusion in vitro have not shown anyadvantage for propylthiouracil in relation to placentaltransport.Furthermore,thetwodrugsseemtohavenodifference in effect on fetal and neonatal thyroidfunction.This use of propylthiouracil as the initial preferreddrug for maternal hyperthyroidism is an expert consensus recommendation of the EndocrineSociety.
In countries where propylthiouracil isnot available, carbimazole and methimazole are
Mostpregnantwomenwithhyperthyroidismareknowntohavehadthyroiddiseasebeforethe onsetof gestation and will alreadybe receiving treatment. Anewdiagnosisof hyperthyroidismisuncommoninearlypregnancy,asuntreateddiseaseisassociatedwithreducedfertility.However,inaseriesof14970firsttrimesterbloodsamples,undiagnosedGraves
Featuressuch astachycardia,palpitations, systolicmurmur,bowel disturbance, emotional upset, and heatintolerancemaybe seen in normal pregnancybut shouldalertthe clinician tothe possibilityof hyperthyroidism,particularlyifa goitreormorespecificfeatureof thyroid disease(weightloss, eye signs,tremor or pre-tibialmyxoedema)isobserved. Newlydiagnosedhyperthyroidismshould be aggressivelytreated.
Drug Mode of action Dose Adverse effects
Propylthiouracil Inhibitsthyroxinesynthesis;inhibitsperipheralconversion ofthyroxine totriiodothyronineStarting: 300-450 mg/day;maintenance: 50-100 mg/dayRash, fever, agranulocytosisCarbimazole Inhibitsthyroxinesynthesis Starting: 15-40mg/day;maintenance: 5-15 mg/dayAsabove, plusaplasiacutisand methimazoleembryopathyPropranolol Reduces adrenergicsymptoms10-40 mg,3-4 times/day(short termuse only)Bronchospasm, intrauterinegrowthrestriction, neonatalhypoglycaemia
22 MARCH 2008
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