Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.
The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.
NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.
Congenital hypothyroidism (CH) is an inborn condition in which thyroid hormone (TH) levels are insufficient for the normal development and function of body tissues. CH is one of the most common preventable causes of intellectual disability worldwide.
Background
In the majority of infants with CH, the disorder is permanent and results from abnormal thyroid gland development or a defect in TH synthesis.1 Less commonly, CH may result from abnormal pituitary or hypothalamic control of thyroid function. In some infants with CH, thyroid dysfunction is transient.2–6 Transient CH can be caused by transplacental passage of maternal antithyroid drugs (carbimazole, methimazole, or propylthiouracil) or thyroid-stimulating hormone (TSH) receptor-blocking antibodies (TRBAb), iodine deficiency or excess, or certain genetic forms of dyshormonogenesis (see section on Assessment of Permanence in the accompanying technical report1 ). Newborn screening (NBS) for CH (and other disorders) is performed at 24 to 72 hours of life. In addition, CH also may be detected on a second newborn screen performed at 2 to 4 weeks of age.7 Clinical and laboratory follow-up of children with CH is essential for appropriate management.7–9
Iodine is a critical component of TH production, and iodine deficiency also remains one of the most common preventable causes of intellectual disability worldwide. Although North America is overall an iodine-sufficient region, recent data indicate that more than one-half of pregnant women in the United States may have mild iodine deficiency.10,11 A prenatal vitamin containing 150 mcg of iodine daily should be taken by all women before and during pregnancy and lactation.12,13
NBS for CH followed by prompt initiation of levothyroxine (L-T4) therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth2,7–9,14–16 and has been adopted in many countries throughout the world.2,7–9,17,18 The incidence of CH ranges from ∼1 in 2000 to 1 in 4000 newborn infants in countries from which NBS data are available.18 This incidence is significantly higher than that reported in the early years of NBS (∼1 in 4000), primarily because of changes in screening strategies that have led to increased detection of milder cases of CH.18–21
Some NBS programs report results in whole blood units, and other programs report results in serum units. Based on the assumption that the average newborn hematocrit is ∼55%, results expressed in serum units are ∼2.2-fold higher than those expressed in whole blood units; for example, a screening TSH of 15 mIU/L in whole blood is roughly equivalent to a TSH of 33 mIU/L in serum.22 Clinicians should identify whether NBS results in their region are expressed in whole blood or in serum units. Most NBS programs in the United States and some in Canada express results in serum units, but many in Canada and the rest of the world express results in whole blood units. Throughout this report, results are expressed in serum units.
Recommendations
I. Newborn Screening
NBS for CH should be performed on all infants in conjunction with state or provincial public health laboratories (see section on NBS Specimen in the accompanying technical report1 ).7–9
Obtain a dried blood spot for NBS by heel stick on approved filter paper card specimens.
For the normal newborn infant, obtain the NBS specimen after 24 hours of life (preferably between 48 to 72 hours) and before hospital discharge or 1 week of life, whichever is sooner.
If the newborn is discharged before 24 hours of life, obtain the NBS specimen before hospital discharge. NBS before 24 hours of life has an increased risk of false-positive results. Perform the initial NBS before blood transfusion, if required before 48 hours of age.
Any of 3 NBS strategies may be used to screen for CH (see section on NBS Test Strategies in the accompanying technical report1 ):
- primary TSH, reflex thyroxine (T4) measurement;
- primary T4, reflex TSH measurement; or
- combined T4 and TSH measurement.
If a newborn infant is transferred to another hospital, the transferring hospital should indicate whether the NBS specimen has been obtained. If the NBS specimen has not been obtained, the receiving hospital should obtain an NBS specimen after transfer.
If any NBS result for CH is abnormal, serum TSH and free thyroxine (FT4) should be measured.
If the first NBS is normal, perform a second NBS at 2 to 4 weeks of age in newborns who:
- are acutely ill (admitted to a NICU);
- are preterm (<32 weeks gestation);
- have very low birth weight (<1500 g);
- received a transfusion before obtaining the NBS;
- have a monozygotic twin (or a same-sex twin, if zygosity is not known) or multiple birth; or
- have trisomy 21 (see section on NBS in Special Populations in the accompanying technical report1 ).
Repeat NBS testing is recommended rather than measurement of serum TSH and FT4 because of the much lower cost of NBS (see section on Special Populations, Preterm/Low Birth Weight Infants in the accompanying technical report1 ).
If a second NBS performed before 36 weeks’ corrected gestational age is normal, repeat NBS testing is recommended 4 weeks later (6–8 weeks of life) or at 36 weeks’ corrected gestational age, whichever is earlier.23
When NBS is performed after 1 week of life, use age-specific reference ranges to interpret results. NBS programs should provide age-specific reference ranges for interpretation.
The NBS program should communicate abnormal results directly to the primary care provider (PCP) in a timely fashion to facilitate appropriate follow-up care.
- The screening program should communicate NBS results promptly both to the birthing location/hospital (where they should be entered in the electronic health record, if possible) and to the PCP (if known), along with an interpretation of the screening test results and recommendations for follow-up testing, if appropriate.24 PCPs are responsible for reviewing NBS test results for newborn infants in their care, as they would for any test result for their patients.
If a PCP receives NBS results for a patient for whom he or she is not caring or whom he or she cannot locate, the PCP should notify the NBS program immediately.
- It is suggested that NBS programs work toward creating a system in which NBS test results are automatically entered in the patient’s electronic health record and are available to both the birthing hospital and the PCP. Electronic health records could build some clinical decision support consistent with the guidance in this document.
II. Management of Abnormal NBS (see Fig 1 and section on Interpretation and Management of Confirmatory Serum Testing Results in the accompanying technical report1 )
When the PCP receives an abnormal NBS result for CH, a confirmatory measurement of TSH and FT4 in a serum sample should be obtained as soon as possible (within 24 hours, when possible).
Consultation with a pediatric endocrinologist is indicated, if possible, to assist in diagnosis and management.
Immediate follow-up actions are based on the TSH level of the NBS:
If the NBS TSH is >40 mIU/L, L-T4 treatment should be initiated after drawing the confirmatory serum sample, without waiting for the results.
If the NBS TSH is ≤40 mIU/L, await the results of the confirmatory serum sample (preferably with a 24-hour turnaround time), and hold off on starting L-T4 treatment.
The infant should be evaluated by a physician (PCP or pediatric endocrinologist) without delay, optimally within 24 hours or on the next office day after the NBS results are received. The physician should:
Obtain a complete history that includes prenatal maternal thyroid status, maternal medications, and family history.
Perform a complete physical examination.
Assess the risk of TRBAb-mediated hypothyroidism and consider measuring TRBAb in the infant and/or mother if there is a history of a maternal autoimmune thyroid disorder or a previous infant affected by maternal TRBAb. If TRBAb are present, no specific additional treatment is needed besides management of the hypothyroidism, and a transient course may be anticipated.
Consider obtaining imaging to establish the etiology of CH but only if the results will influence clinical management (see section on Imaging in the accompanying technical report1 ).
Subsequent actions are based on the results of the confirmatory serum sample:
- If serum TSH is elevated and serum FT4 is low, initiate (or continue) L-T4 treatment.
- If serum TSH is >20 mIU/L and serum FT4 is normal, initiate (or continue) L-T4 treatment.
- If serum TSH is elevated but ≤20 mIU/L and serum FT4 is normal, L-T4 treatment may be initiated, or serum TSH and FT4 may be monitored closely every 1 to 2 weeks without treatment. If FT4 becomes low, or if TSH elevation >10 mIU/L persists beyond 4 weeks of age, L-T4 treatment is recommended.
- In infants with serum TSH elevation >5 mIU/L but ≤10 mIU/L that persists beyond 4 weeks of age, there is insufficient evidence to recommend treatment versus observation. In such cases, consultation with a pediatric endocrinologist (if it has not already occurred) is recommended to formulate a management plan specific to the patient.
- If serum TSH is normal or low and serum FT4 is low, evaluate for possible central hypothyroidism with further testing as clinically indicated. Obtain confirmatory serum testing, including TSH with FT4. Measuring a thyroxine-binding globulin concentration when T4 is low but FT4 is normal may assist in distinguishing central hypothyroidism from thyroxine-binding globulin deficiency.25 Infants with central CH should be evaluated, in consultation with a pediatric endocrinologist, for additional hypothalamic-pituitary dysfunction. Consideration should be given to the timing of this evaluation before starting L-T4 treatment, because such treatment may lower cortisol levels.
III. Imaging
Thyroid imaging is optional in the evaluation of infants with CH and may be performed if the results will influence clinical management. The decision to undertake imaging may be assisted by consultation with a pediatric endocrinologist.
Attempts to perform imaging should never delay the treatment of CH.
- Imaging with thyroid ultrasonography or scintigraphy may assist in establishing the etiology of CH.26 However, in many cases, imaging does not alter the clinical management of the patient before age 3 years (see section on Imaging in the accompanying technical report1 ). Accurate scintigraphy can only be performed when the TSH is elevated; it may be performed before initiating L-T4 treatment or within the first 2 to 3 days after initiating treatment. Scintigraphy can also be performed after 3 years of age during a trial off L-T4 therapy.
IV. Genetic Testing (see section on Genetic Testing in the accompanying technical report1 )
For children with isolated primary CH, genetic testing is an option when a genetic diagnosis would alter clinical management.
For central CH or CH associated with clinical features of a recognizable syndrome or an underlying genetic condition, consultation with a geneticist is recommended. The decision to undertake genetic testing may be assisted by consultation with a pediatric endocrinologist or geneticist.
Infants with trisomy 21 who do not have CH are at risk for developing primary hypothyroidism during the first year of life. Therefore, in infants with trisomy 21:
- A second NBS should be performed at 2 to 4 weeks of life.
- Serum TSH should be measured at 6 and 12 months of life.
V. Treatment (Table 1)
CH should be treated with enteral L-T4 at a starting dose of 10 to 15 mcg/kg/day administered once daily (see section on Treatment in the accompanying technical report1 ).8–10,27
Treatment should be initiated as soon as possible after the diagnosis is confirmed (optimally by 2 weeks of age if identified on the first NBS).
Downward adjustment of the dose after laboratory evaluation at 2 weeks of age may be needed to avoid overtreatment.28
Enteral administration of L-T4 tablets is the treatment of choice. L-T4 tablets can be crushed and suspended by the parent or guardian in 2 to 5 mL (∼1 tsp) of human milk, nonsoy-containing formula, or water. A commercial oral solution of L-T4 is approved by the US Food and Drug Administration for use in children; however, limited experience with its use showed that dosing may differ slightly from dosing with tablet formulations.29,30 L-T4 suspensions prepared by compounding pharmacies may lead to unreliable dosing.31,32
L-T4 can be administered at any time of day in infants and toddlers (morning or evening, with or without feeds), as long as the timing and manner of administration are consistent. Coadministration with soy, fiber, iron, or calcium can impair L-T4 absorption. Breastfeeding may continue without interruption.33 If enteral administration is not possible, L-T4 can be administered intravenously at 75% of the enteral dose.34
The endocrinologist and/or PCP should provide critical parental education regarding (1) the etiology of CH, (2) the benefit of early diagnosis and treatment in preventing intellectual disability, (3) the appropriate method for administering L-T4, (4) substances that can interfere with L-T4 absorption (eg, soy, iron, calcium, and/or fiber), and (5) the importance of adherence to the treatment plan, including regular follow-up care. Written instructions provided to caregivers may enable adherence and avoid administration errors.
Educational resources can be obtained from the American Thyroid Association (www.thyroid.org/congenital- hypothyroidism/), the Pediatric Endocrine Society (https://pedsendo.org/patient-resource/congenital-hypothyroidism/), the Endocrine Society (education.endocrine.org/content/congenital- hypothyroidism-pim-diagnosis- and-management), NIH (ghr.nlm.nih.gov/condition/congenital- hypothyroidism), the Magic Foundation (www.magicfoundation.org/Misc/ViewContent.aspx?Content ID=856ac9d3-dec2-4f96-81be- b36e257afb88), and others.
The goal of L-T4 treatment is to support normal neurocognitive development and growth. Achieving optimal outcome depends on early initiation of adequate L-T4 treatment (optimally by 2 weeks of age when detected on the first NBS), particularly in severe cases of CH.27,35 Rapid normalization of serum FT4 and TSH levels (optimally within 2 to 4 weeks of treatment initiation) leads to improved neurocognitive outcomes (see section on Developmental Outcomes in the accompanying technical report1 ).36–40 Delayed initiation of treatment and longer time to normalization of thyroid function are associated with poorer outcomes.41,42
After initial normalization, serum TSH should be maintained in the age-specific reference range; serum FT4 levels should be maintained in the upper half of the age-specific reference range unless achieving a serum FT4 level in this range would result in a TSH level less than the reference range.
Ideally, the same L-T4 formulation should be maintained consistently until 3 years of age to achieve consistent euthyroidism and minimize the need for additional laboratory monitoring. If feasible, the use of a brand name L-T4 formulation to provide a consistent formulation may be superior for children with severe CH.43 If generic L-T4 is prescribed, it is preferable to use L-T4 from a consistent manufacturer.
Treatment with liothyronine generally is not indicated. The use of liothyronine in patients with persistent severe resistance to thyroid hormone (elevated TSH despite elevated FT4), in whom adequate control cannot be established with L-T4 alone has not been demonstrated to improve outcomes and should be considered only in consultation with a pediatric endocrinologist.44,45
VI. Monitoring (Table 1)
During the first 3 years of life, clinical evaluation should be conducted regularly (as specified below), including assessment of developmental progress and growth (see section on Monitoring in the accompanying technical report1 ).
Because of the increased risk of hearing deficits in individuals with CH, formal hearing evaluation should be considered whenever there is clinical concern for a hearing deficit or abnormal language development.14,46
Serum TSH and FT4 should be measured10,47,48 (www.aap.org/en-us/Documents/periodicity_schedule.pdf):
One to 2 weeks after the initiation of L-T4 treatment and every 2 weeks until serum TSH level is normal;
Every 1 to 2 months during the first 6 months of life (monthly in infants with severe CH [initial serum TSH >100 mIU/L or FT4 <0.4 ng/dL]);
Every 2 to 3 months during the second 6 months of life; and
Every 3 to 4 months between 1 and 3 years of age.
Ideally, blood samples for laboratory tests should be obtained at least 4 hours after the administration of L-T4 to avoid spurious elevation of FT4 level.
VII. Long-Term Follow-Up
After 3 years of age, measurement of TSH is recommended:
Every 6 to 12 months until growth is complete;
Four to six weeks after any change in LT-4 dose or formulation; and
At more frequent intervals in children with severe CH, problems with adherence to the L-T4 treatment plan, or TSH levels outside the age-specific reference range.
After 3 years of age, monitoring of TSH is sufficient. FT4 may be measured if medication adherence or suboptimal control is a concern.
After the first 3 years of life, clinical evaluation and assessment of growth and development should be performed every 6 to 12 months.
Pediatric endocrinologists should establish protocols for tracking children with CH in their practice to optimize management and prevent loss to follow-up (see section on Long-Term Follow-up in the accompanying technical report1 ). Currently, many patients in whom CH is diagnosed are lost to follow-up.49–52 Because inadequate treatment of CH may have negative consequences for development, the endocrinologist can establish protocols to help prevent children with CH from being lost to follow-up. Examples may include the monitoring of appointments/scheduling and prescription refills and telephone outreach. The PCP also has an important role in ensuring that affected children remain on L-T4 therapy for CH.53
VIII. Assessment of the Permanence of Hypothyroidism
CH is confirmed to be permanent in cases of thyroid dysgenesis or if the serum TSH increases >10 mIU/L after the first year of life (see section on Assessment of Permanence in the accompanying technical report1 ).
Patients with permanent CH should remain on lifelong L-T4 therapy.
If a diagnosis of permanent CH has not been confirmed, a trial off L-T4 therapy should be strongly considered at 3 years of age, particularly if the patient is adequately treated with a low dose of L-T4 (<2 mcg/kg/day). A trial off L-T4 may be conducted as follows:
Discontinue L-T4 for 4 weeks, then measure serum TSH and FT4 levels.54
If TSH and FT4 levels remain in the age-specific reference range, transient CH is confirmed.
If the TSH is >10 mIU/L and/or FT4 is low, permanent CH is confirmed and LT-4 therapy should be reinstituted.
If the TSH is mildly elevated (greater than the age-specific reference range, but ≤10 mIU/L) and FT4 is normal, repeat serum TSH and FT4 levels in another 4 to 8 weeks to determine if there is (1) normal thyroid function (indicating transient CH), (2) permanent CH (TSH >10 mIU/L or low FT4), or (3) persistent hyperthyrotropinemia (TSH persistently elevated but ≤10 mIU/L, with normal FT4). There is insufficient evidence to determine if the treatment of persistent hyperthyrotropinemia is of clinical benefit, but many practitioners elect to treat it out of caution.
It is critical that patients not be lost to follow-up while trialing off L-T4 therapy.
Developmental Outcome
NBS has substantially improved neurodevelopmental outcomes in patients with CH, and severe intellectual impairment typically does not occur in patients who receive the diagnosis and are treated early and adequately (see section on Developmental Outcome in the accompanying technical report1 ). Adequate L-T4 treatment of CH (early initiation of L-T4 10 to 15 mcg/kg/day, with normalization of thyroid function within 2 weeks) results in grossly normal neurocognitive function in adulthood.27 However, detailed studies reveal neuropsychologic deficits in some children with CH, including impaired visuospatial processing and deficits in memory and sensorimotor function. If a child is adequately treated for CH but developmental progress and/or growth is abnormal, evaluation for potential intercurrent illness, hearing deficit,46 or other hormone deficiency is warranted.
Conclusions
Despite the evident success of NBS, physicians need to consider hypothyroidism when clinical symptoms are present that suggest this diagnosis, despite previous normal NBS thyroid test results. Failure of normal neurodevelopment can result from hypothyroidism in infants who had normal NBS results when hypothyroidism manifests or is acquired after NBS, or when errors occur in NBS screening. Hypothyroidism may be present in infants in whom NBS screening was not performed (eg, some home deliveries) or results were not communicated to the infant’s PCP.55 Therefore, when clinical symptoms or signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum TSH and FT4 is indicated, regardless of NBS results.
Treatment and Monitoring of Congenital Hypothyroidism
Treatment with levothyroxine |
Administer daily at a consistent time and in a consistent manner |
Preferred: enteral route |
Preferred: tablets, crush and suspend in 2–5 mL of human milk, non-soy-containing formula, or water |
Alternative: commercial branded oral solution |
Administer with or without food |
Alternative route: intravenous route |
75% of enteral dosing |
Laboratory monitoring |
Preferred: TSH and FT4 |
Alternative: TSH and Total T4 |
Therapeutic targets: |
TSH:a age-specific reference range (generally 0.5–5 mIU/L after 3 mo of life) |
FT4 (or total T4): upper half of age-specific reference range |
Treatment with levothyroxine |
Administer daily at a consistent time and in a consistent manner |
Preferred: enteral route |
Preferred: tablets, crush and suspend in 2–5 mL of human milk, non-soy-containing formula, or water |
Alternative: commercial branded oral solution |
Administer with or without food |
Alternative route: intravenous route |
75% of enteral dosing |
Laboratory monitoring |
Preferred: TSH and FT4 |
Alternative: TSH and Total T4 |
Therapeutic targets: |
TSH:a age-specific reference range (generally 0.5–5 mIU/L after 3 mo of life) |
FT4 (or total T4): upper half of age-specific reference range |
For central hypothyroidism, measure only FT4 (or total T4).
Algorithm for action after newborn screening for congenital hypothyroidism.
Lead Authors
Susan R. Rose, MD, FAAP
Ari J. Wassner, MD, American Thyroid Association Representative
Kupper A. Wintergerst, MD, FAAP
Nana-Hawa Yayah Jones, MD
Robert J. Hopkin, MD, FAAP
Janet Chuang, MD
Jessica R. Smith, MD, Pediatric Endocrine Society Representative
Katherine Abell, MD
Stephen H. LaFranchi, MD, FAAP
Section on Endocrinology Executive Committee, 2020–2021
Kupper A. Wintergerst, MD, FAAP
Kathleen E. Bethin, MD, FAAP
Brittany Bruggeman, MD, FAAP (Fellowship Trainee)
Jill L. Brodsky, MD, FAAP
David H. Jelley, MD, FAAP
Bess A. Marshall, MD, FAAP
Lucy D. Mastrandrea, MD, PhD, FAAP
Jane L. Lynch, MD, FAAP (Immediate Past Chairperson)
Council on Genetics Executive Committee, 2020–2021
Leah W. Burke, MD, MA, FAAP
Timothy A. Geleske, MD, FAAP
Ingrid A. Holm, MD, FAAP
Wendy J. Introne, MD, FAAP
Kelly Jones, MD, FAAP
Michael J. Lyons, MD, FAAP
Danielle C. Monteil, MD, FAAP
Amanda B. Pritchard, MD, FAAP
Pamela Lyn Smith Trapane, MD, FAAP
Samantha A. Vergano, MD, FAAP
Kathryn Weaver, MD, FAAP
Liaisons
Aimee A. Alexander, MS, CGC, Centers for Disease Control and Prevention
Christopher Cunniff, MD, FAAP, American College of Medical Genetics
Mary E. Null, MD, Section on Pediatric Trainees
Melissa A. Parisi, MD, PhD, FAAP, National Institute of Child Health and Human Development
Steven J. Ralson, MD, American College of Obstetricians and Gynecologists
Joan Scott, MS, CGC, Health Resources and Services Administration
Staff
Paul Spire
Drs Rose, Wassner, Wintergerst, Yayah-Jones, Hopkin, Chuang, Smith, Abell, and LaFranchi were equally responsible for conceptualizing, writing, and revising the manuscript and considering input from all reviewers and the board of directors; and all authors approved the final manuscript as published and agree to be accountable for all aspects of the work.
Clinical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
COMPANION PAPER: A companion to this article can be found online at http://www.pediatrics.org/cgi/doi/10.1542/peds.2022-060420.
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr LaFranchi reported a financial relationship with UpToDate as an author on the topic of congenital hypothyroidism and a financial relationship with IBSA Pharma as an advisory board member. Dr Hopkin reported a consultant relationship with Sanofi and received honoraria.
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