Congenital hypothyroidism and newborn screening

• Congenital hypothyroidism (CHT) is thyroid hormone deficiency present from birth; in most cases it is permanent, and in screened countries it is found days after birth rather than months later.
• It is the commonest preventable cause of intellectual disability where screening exists, because thyroid hormone is needed for normal brain and bone development in early life.
• Most programmes screen a dried blood spot taken from a heel prick, usually measuring thyroid-stimulating hormone (TSH), with thyroxine (T4) added where resources allow.
• A baby with CHT is treated with daily oral levothyroxine; doses of 10 to 15 micrograms per kilogram per day are used in severe disease, with the aim of normalising TSH within two to three weeks.
• Treatment started within the first two weeks of life gives an excellent neurodevelopmental outcome; delay risks irreversible brain damage. ^[1]

By the end of this page you should be able to:

1. Explain why congenital hypothyroidism matters in the first weeks of life.
2. Describe the aetiology and the difference between primary and central congenital hypothyroidism.
3. Plan newborn screening: what the heel prick measures, when it is taken, and which babies need a second sample.
4. Interpret a screening and confirmatory result and know the thresholds that trigger treatment.
5. Prescribe and monitor levothyroxine in a newborn, including dose by severity.
6. Recognise the complications of untreated disease and the long-term outlook on adequate treatment.
7. Tailor practice for preterm, low birth weight, sick, twin and Down syndrome babies, and in low-resource settings.

It is convenient to think in two levels. Primary congenital hypothyroidism is a defect of the thyroid gland itself, so TSH is high and free T4 is low. Central congenital hypothyroidism is a defect of the hypothalamus or pituitary, so TSH is low, normal or only slightly raised while free T4 is low. Primary disease is far more common; central disease is detected in roughly 1 in 30,000 to 1 in 16,000 screened newborns. ^[1]

Primary congenital hypothyroidism has two main groups. Thyroid dysgenesis is a problem of development: an absent, ectopic or hypoplastic gland; it causes most cases and is usually sporadic. Dyshormonogenesis is a problem of synthesis: an enzyme defect in making or organising thyroid hormone, such as a sodium-iodide symporter defect, thyroid peroxidase defect or thyroglobulin defect; these are often inherited in an autosomal recessive pattern and can run in families. Rarer causes include central hypothyroidism (isolated or as part of congenital hypopituitarism) and impaired thyroid hormone action. ^[1]

The most common cause of congenital hypothyroidism overall is a poorly developed or absent thyroid gland, and in newborn blood spot programmes thyroid dysgenesis underlies about one quarter to one half or more of permanent cases depending on local ethnicity and iodine status. ^[1][3]

The incidence depends on the screening strategy and on iodine status. A systematic European panel found roughly 1 in 3,000 to 1 in 2,000 newborns have primary congenital hypothyroidism; central disease is rarer, at about 1 in 30,000 down to 1 in 16,000. ^[1] An earlier estimate of about 1 in 7,000 was revised to about 1 in 4,000 within a few years of screening starting in the United Kingdom, partly because milder cases became detectable as TSH cut-offs fell. ^[1]

In the United Kingdom one newborn in about 2,000 has congenital hypothyroidism, while in screening programmes roughly 1 in 3,000 to 1 in 2,000 infants are detected overall. ^[1][2] The condition is more common in girls, in several ethnic groups, in consanguineous families for the synthetic defects, and in babies conceived by assisted reproduction, although local factors dominate. Rates are driven by iodine deficiency in many parts of the world, which places 70 percent of infants (those born where there is no screening) at a higher risk of thyroid hormone deficiency. ^[1]

Down syndrome carries a 14- to 21-fold higher than expected incidence of congenital hypothyroidism, and thyroid dysgenesis on chromosome 21 effects is the probable explanation. ^[1]

There is no single modifiable risk factor for sporadic thyroid dysgenesis; the evidence points to polygenic and possibly epigenetic influences on thyroid development early in embryogenesis. Dyshormonogenesis is usually recessive, and families should be counselled that a subsequent child has roughly a 25 percent recurrence risk for the same synthetic defect. ^[1]

Iodine is the essential substrate for thyroid hormone, so both deficiency and excess matter. Avoid iodine-containing antiseptics around birth because they can induce transient hypothyroidism, particularly in preterm babies whose Wolff-Chaikoff protective mechanism is not yet mature. ^[1]

Other causes of transient neonatal hypothyroidism include maternal antithyroid drugs, maternal blocking antibodies, severe non-thyroidal illness and extreme prematurity. These babies may pass screening or have a delayed TSH rise, so clinical suspicion should override a normal result where appropriate. ^[1]

Postnatal factors can also produce transient hypothyroidism: maternal antithyroid medication, blocking antibodies, severe illness and premature birth can all suppress the developing axis. These babies may fail screening initially; the cure is clinical suspicion, repeated testing and, where safe, avoidance of iodine-rich antiseptics in neonatal intensive care. ^[1]

Thyroid hormone is required for neuronal migration, myelination and the development of the auditory system in utero and after birth, and for normal endochondral ossification and thermogenesis in the newborn. A fetus with congenital hypothyroidism is partly protected during pregnancy by maternal thyroid hormone crossing the placenta, which is why these babies look normal at birth and why their blood spot result, rather than their appearance, makes the diagnosis. The protection runs out over the first weeks of life: without replacement there is severe and largely irreversible neurodevelopmental damage, classically described as cretinism, with severe mental retardation, short stature, deafness and neurological deficits. ^[1]

The earliest detectable changes are biochemical long before they are clinical. A high TSH and low free T4 produce prolonged jaundice (conjugated and unconjugated hyperbilirubinaemia), a large posterior fontanelle, macroglossia, a wide-open sutures feel, umbilical hernia, hypotonia, feeding difficulty, cold mottled skin and constipation. None is specific, which is why screening is so important and why every infant with unexplained prolonged jaundice should have thyroid function tested. ^[1]

Neurodevelopmental follow-up should include screening for attention and memory problems, hearing impairment and behaviour difficulties; some children need speech and occupational therapy and classroom support. Their adult outcomes are otherwise very good when treatment is started early and maintained consistently. ^[1]

Most affected newborns are asymptomatic at birth. When signs are present they are subtle and progress over two to six weeks.

History (as reported by parents or staff):

• prolonged jaundice beyond two weeks (often the first clue)
• poor feeding, lethargy and somnolence
• constipation with infrequent meconium
• cold intolerance, dry skin and prolonged acrocyanosis
• hoarse cry and poor weight gain

Examination:

• large posterior fontanelle and wide cranial sutures
• macroglossia
• nasal stuffiness and a thyroid goitre if synthesis is the defect
• umbilical hernia and distended abdomen
• hypotonia, delayed reflexes, large tongue and myxoedematous facies in older untreated infants
• short stature and delayed bone age (a knee X-ray may document severity in a confirmed case) ^[1]

These features are non-specific; dysmorphic features should prompt a careful search for syndromic congenital hypothyroidism and associated congenital malformations, especially cardiac malformations. ^[1]

The first distinction is primary versus central disease, made on TSH and free T4. The main mimics are:

Screening is done on a dried blood spot obtained from a heel prick. Programmes vary, but the usual approaches are primary TSH with reflex free T4, primary free T4 with reflex TSH, or combined TSH and free T4. The most sensitive test for detecting primary congenital hypothyroidism is TSH, and where resources allow free T4 is added so that central disease can also be found. ^[1]

Timing matters. Samples taken before about 48 hours of age can miss a rising TSH, and many programmes take the spot at around day 5, the heel prick performed by a midwife or health visitor at home. ^[1][2] Babies who are sick, preterm, of low birth weight, or are twins need special attention because they can have a falsely normal or delayed TSH rise. Preterm babies should be considered for a postscreening sample at about 10 to 14 days, Down syndrome babies should have TSH measured at the end of the neonatal period, and same-sex twins should have a second screen. ^[1]

Confirmatory tests in any baby with an abnormal screen are serum free T4 and TSH. The baby should be referred to an expert centre promptly. Imaging with radioisotope scintigraphy, ultrasound or both can be used once treatment has started, since it does not change the need to treat; a knee X-ray may assess severity of intra-uterine hypothyroidism. ^[1]

Diagnostic thresholds. Treatment is started immediately when serum free T4 is below and TSH is clearly above the age-specific reference interval. If serum TSH is above 20 milliunits per litre at confirmatory testing (around the second week), treatment is started even when free T4 is normal. If TSH is between 6 and 20 milliunits per litre beyond 21 days in an otherwise healthy baby with free T4 in the reference interval, clinicians either start treatment and retest off-treatment later, or retest in one to two weeks. A filter-paper TSH above 40 milliunits per litre is treated without waiting for serum results in settings where laboratory testing is not readily available. A low free T4 with a low, normal or slightly raised TSH is a clue to central disease. ^[1]

Treatment is indicated if the serum free T4 is below the age-specific reference interval, or if TSH is clearly high. Severe, moderate and mild forms can be graded by the serum free T4 concentration: very low (below 5 picomoles per litre), 5 to 10 picomoles per litre, and 10 to 15 picomoles per litre respectively. ^[1] This is a guide to initial dose and to prognosis, not a reason to delay treatment. In healthy newborns with TSH between 6 and 20 milliunits per litre and a normal free T4, the decision is less certain; either treat and retest later off treatment, or retest in 1 to 2 weeks.

Imaging has a diagnostic but not a therapeutic role: suspicion must be treated first and imaging done afterwards. Scintigraphy, with or without a perchlorate discharge test, shows whether the gland is absent, ectopic or eutopic and can reveal organification defects; ultrasound measures size and position and is useful for follow-up of dyshormonogenesis, where a goitre develops. A short, poorly ossified bone (shown on a knee X-ray) reflects long-standing severe intra-uterine hypothyroidism. ^[1] Imaging also reassures families by showing the cause and informs genetic counselling.

Genetics is approached narrowly. Counselling should explain thyroid dysgenesis versus dyshormonogenesis, and genetic testing should be considered when the family history, imaging or a known syndrome points to it, using modern sequencing where available. Familial recurrence is about 25% in dyshormonogenesis but much lower in dysgenesis; syndromic central disease may also warrant testing of parents and siblings. ^[1]

• All infants with a high TSH should be examined for dysmorphic features and congenital malformations, particularly cardiac. ^[1]
• When central disease is suspected, exclude adrenal insufficiency before starting thyroxine; if it cannot be excluded, give glucocorticoid first to avoid an adrenal crisis. ^[1]

Start levothyroxine as early as possible and no later than two weeks after birth (or immediately after confirmatory sampling if the baby is identified by a later screen). Levothyroxine alone is the drug of choice; it is given orally once a day. ^[1]

• Severe disease (free T4 below 5 picomoles per litre with a raised TSH): 10 to 15 micrograms per kilogram per day.
• Mild disease (free T4 above 10 picomoles per litre with a raised TSH): about 10 micrograms per kilogram per day. ^[1]
• Borderline (free T4 in the age-specific reference interval): consider 5 to 10 micrograms per kilogram per day.
• Central disease: in severe cases 10 to 15 micrograms per kilogram per day; in milder cases 5 to 10 micrograms per kilogram per day, with the aim of keeping free T4 above the mean value for age. ^[1]

These neonatal dosing ranges are consistent with the replacement doses used in older hypothyroid patients and with the high-dose regimens of 10 to 15 micrograms per kilogram per day reported to normalise levels within two to three weeks. ^[1][4]

Levothyroxine can be given with a feed in infants (avoiding soy protein and fibre), at the same time each day; families should be told this is a daily medicine for life unless retesting shows a transient cause. ^[1]

The first goal is to raise circulating thyroid hormone quickly, bringing TSH back into the age-specific reference interval. Free T4 above the reference interval can be accepted while TSH is normal. ^[1]

Follow-up frequency is:

• first clinical and biochemical check at 1 to 2 weeks (sooner, within one week, if a high dose such as 50 micrograms a day is used); ^[1]
• every two weeks until TSH is fully normalised;
• every 1 to 3 months until 12 months; ^[1]
• every 2 to 4 months until 3 years; ^[1]
• every 3 to 6 months until growth is complete. ^[1]

Any dose change is checked 4 to 6 weeks later, and serum should be drawn before or at least four hours after the daily dose. ^[1][4]

If a definitive diagnosis was not made in the first months, re-evaluate the hypothalamic-pituitary-thyroid axis after 2 to 3 years, with a withdrawal of levothyroxine over 4 to 6 weeks and full testing. Primary hypothyroidism is confirmed with a TSH of 10 milliunits per litre or higher. If the baby required less than 3 micrograms per kilogram per day at 6 months, re-evaluation can be brought forward. In countries or regions without ready access to laboratory testing, a filter-paper TSH above 40 milliunits per litre is enough to start treatment. ^[1]

Optimise maternal levothyroxine before and during pregnancy, with monitoring of TSH and free T4 every 4 to 6 weeks during gestation, and counselling about the need to avoid iodine deficiency and excess in affected families. ^[1]

In infants levothyroxine can be given with a feed, which maximises adherence and produces reasonably stable absorption; soy protein and excess fibre should be avoided, and the daily dose should be given at the same time in relation to feeds. Tablets can be crushed into a small amount of milk or water. Because infants grow rapidly, doses need frequent recalculation and parents should know the dose in micrograms and millilitres. ^[1]

Long-term adherence is the dominant predictor of outcome. Educate parents from the time of diagnosis, in child-friendly language later on, and again at transition to adult care. Adolescents often stop treatment after a childhood of good compliance; a structured handover and a named adult clinician prevent this. Women with congenital hypothyroidism need planning before pregnancy because levothyroxine requirements rise. ^[1]

Growth, weight, head circumference and development should be plotted carefully at every visit, alongside periodic vision and hearing checks; speech delay, attention or behaviour problems warrant closer developmental assessment. ^[1]

Untreated or late-treated disease can produce:

• irreversible neurodevelopmental delay, with impaired cognition, attention, memory and speech
• growth failure and short stature
• sensorineural hearing loss
• gross motor delay and ataxia
• in severe untreated infantile disease, the classic features of untreated infant hypothyroidism (cretinism) ^[1]

During treatment complications are usually iatrogenic: undertreatment (ongoing slow growth, delayed dentition, persistently raised TSH) or overtreatment (behavioural change, tachycardia, bone age advancement). Avoid long-term under- or overtreatment during childhood. ^[1]

Structural disease: children with primary hypothyroidism due to dyshormonogenesis may develop goitre and nodules with time, so TSH is kept in the lower part of the normal range and ultrasound is checked periodically; thyroid cancer has been reported rarely and nodules need fine-needle aspiration when suspicious. ^[1]

Central disease plus panhypopituitarism may also present with hypoglycaemia, micropenis and undescended testes, and needs full endocrine assessment. ^[1]

Children detected by screening and treated promptly, ideally within the first two weeks, have an excellent outcome. Adequately treated children with non-syndromic disease have normal growth and puberty, fertility comparable with unaffected people, and normal bone, metabolic and cardiovascular health. ^[1] Psychomotor development and school progression should still be checked periodically, and hearing tests should be repeated before school age. ^[1]

Where treatment is delayed beyond the first weeks, the outlook for intellect and stature worsens; the degree depends on severity and duration. This is the main argument for worldwide screening, given that about 70 percent of infants are born where it is not available. ^[1]

Newborn screening has almost eliminated the severe consequences of untreated congenital hypothyroidism wherever it is established. It should be introduced worldwide. The UK National Screening Committee recommends screening for congenital hypothyroidism; testing has been offered as part of the newborn blood spot programme since 1981, and the 2015 review found no evidence to change this. ^[1][3]

What the heel prick screens for. In the UK newborn blood spot programme the list includes congenital hypothyroidism (incidence about 1 in 2,000 births), sickle cell disease (1 in 2,800), cystic fibrosis (1 in 2,500), and seven inherited metabolic diseases (phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1, homocystinuria and tyrosinaemia type 1). In some areas screening for severe combined immunodeficiency and spinal muscular atrophy is being evaluated. Phenylketonuria or medium-chain acyl-CoA dehydrogenase deficiency occurs in about 1 in 10,000 births, rarer ones in 1 in 100,000 to 1 in 300,000. ^[2]

Timing and handling matter as much as the test itself. In the UK the blood spot is taken at day 5 with a heel prick; screening is offered up to 12 months for most conditions (up to 8 weeks for cystic fibrosis), but earlier is better so treatment can start. ^[2]

• preterm, low-birth-weight and sick babies: may have a false-negative or delayed rise in TSH; obtain a second sample at 10 to 14 days and avoid iodine antiseptics. ^[1]
• twins: an affected twin may screen normal because of fetal blood mixing; repeat or a low threshold for retesting is advised, and the non-affected sibling should be followed for later TSH rise. ^[1]
• Down syndrome: measure TSH at the end of the neonatal period; high incidence and non-thyroidal illness can mask detection. ^[1]
• family history of thyroid disease or a known genetic defect: test free T4 and TSH even if screening was normal. ^[1]
• clinical suspicion despite a normal result should override it, particularly where the family history suggests central disease. ^[1]

Every pregnant woman should ingest about 250 micrograms of iodine per day; in iodine-deficient regions fortified salt or targeted supplementation lowers the incidence of transient hypothyroidism. ^[1]

Pregnancy. Women with congenital hypothyroidism planning pregnancy should have levothyroxine optimised beforehand, with TSH and free T4 monitoring every 4 to 6 weeks in pregnancy and dose changes as needed; after delivery the dose is reduced to the preconception dose and thyroid function is rechecked at about 6 weeks. ^{[1] [4]}

Children with syndromic disease such as iodine organification defects may grow goitres and need ongoing ultrasound; thyroid cancer has been reported rarely and suspicious nodules need aspiration. ^[1]

Adherence is the dominant variable over time; preparation of the child and family from diagnosis, and again at transition to adult care, sustains treatment. ^[1]

• A single dried-spot TSH with a cut-off of 40 milliunits per litre is enough to start treatment where serum testing is unavailable. ^[1]
• Where no laboratory is available, clinical vigilance (prolonged jaundice, large posterior fontanelle, umbilical hernia, constipation, hypotonia) should prompt referral; a normal screen must not be allowed to reassure when signs are present. ^[1]
• Levothyroxine and laboratory reagents may need to be imported; keep a steady supply for every diagnosed child, because interruption is the commonest cause of poor outcome.
• Universal salt iodisation and maternal iodine supplementation are the prevention measures that matter most at population level. ^[1]

• The Endocrinology hypothyroidism topic covers acquired hypothyroidism, Hashimoto disease, the interpretation of TSH and free T4 in older children and adults, and levothyroxine replacement principles.
• Anticipatory guidance and screening topics cover newborn screening in general.
• Antihyperglycaemic drugs and insulin is not related but illustrates other endocrine replacement therapy.