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INTRODUCTION
Systematic neo natal screening has been pro gres-sively implemented in industrialized co untries o ver the past 2 decades. Screening pro grams fo r co ngenital hy-po thyro idism (CH) have also been expanding thro ugh-o ut Sugh-o uth America and develugh-o ping cugh-o untries, where se-vere mental deficiency fro m CH has clearly been re-duced.1 The vast majo rity o f pro grams are no w using a
primary thyro xine (T4)-backup thyro tro phin (TSH) o r a primary TSH test.2
In Brazil, co rd blo o d evaluatio n has been reco mmended, particularly because o f the sho rt ho spital stay o f o ur no rmal pregnant wo men.3 Also , TSH
has been reco mmended as the primary screening test because it detects no t o nly permanent spo radic co n-genital hypo thyro idism, who se incidence is abo ut 1 per 3500-4000 births in o ur regio n, but also co mpensated o r transient primary hypo thyro idism, who se incidence can be as high as 1 in 10 neo nates and who se main cause is io dine deficiency.3-6 There is so me evidence that
o ur regio n is deficient in io dine supplementatio n.7,8
Ho wever, T4 primary screening pro grams have still been carried o ut and are widely preferred in many assistance centers in Brazil. Altho ugh there have been so me pre-vio us studies o n the perinatal facto rs influencing TSH and T4 co ncentratio ns in co rd blo o d, particularly in high-risk newbo rns, tho se small fo r gestatio nal age and/o r preterm infants, there is still po o r kno wledge abo ut the po ssible influence o f severe maternal diseases o ver sen-sitive TSH measurement metho ds. The aim o f the present wo rk was to investigate the influence o f no n-thyro idal mo thers’ diseases o n o ur ro utine screening pro gram using primary co rd TSH values.
Original Article
REVISTA PAULISTA DE MEDICIN A
Thyroid stimulating hormone
le ve ls in cord blood are not influe nce d
by non-thyroidal mothe rs’ dise ase s
Department of Medicine, Center for Integrated Assistance in Women’s Health,
Faculdade de Medicina da Universidade Estadual de Campinas, Campinas and
Congenital Hypothyroidism Screening Program, Department of Medicine - Endocrinology,
Universidade Federal de São Paulo / Escola Paulista de Medicina, São Paulo, Brazil
a b s t r a c t
CON TEX T: Screening pro g rams no t o nly o ffer the o ppo rtunity to trace and treat almo st all cases o f co ng enital hypo thyro idism but also mean larg e saving s to the health system. Ho wever, carefully planned strateg ies are necessary to extend their benefits and reduce co sts.
OBJECTIVE: To determine the po ssible influence o f maternal diseases that affect maternal-fetal placenta dynamics o n primary thyro id stimu-lating ho rmo ne (TSH) screening fo r co ng enital hypo thyro idism.
DESIGN : Pro spective no n-rando miz ed clinical trial with at least 3 mo nths o f fo llo w-up.
SETTIN G: A public university referral center [CAISM/ Ho spital das Clínicas, Faculty o f Medicine, University o f Campinas, Campinas, SP].
PARTICIPAN TS: 4 1 5 neo nates divided into 5 g ro ups: eig hty-three infants bo rn fro m cardiac mo thers; 9 8 fro m mo thers that had to x-emia; 5 4 o f the mo thers had diabetes mellitus; 4 0 were HIV po sitive and 1 4 0 had no diseases.
IN TERVEN TION : All newbo rns had co rd blo o d samples co llected o n filter paper at birth.
M AIN M EASUREM EN TS: TSH was measured fro m dried blo o d spo ts using a ho memade immuno fluo rescence assay (sensitivity in dried blo o d spo ts = 0 .1 mU/ L).
RESULTS: There was no sig nificant difference in the mean TSH levels amo ng the 5 g ro ups. Mo reo ver, TSH levels were aro und 5 mU/ L in 4 8 % o f the newbo rns, indicating that o ur reg io n is severely deficient in io dine.
CON CLUSION S: O ur results indicate that primary TSH screening pro g rams using co rd blo o d are no t affected by maternal diseases. W e sug g est that, besides its technical advantag es o ver heel punc-tures with T4 primary appro aches, neo natal screening using primary co rd blo o d TSH may also be used as a mo nito ring to o l fo r evalua-tio n and co ntro l o f io dine deficiency diso rders (IDD).
KEY W O RDS: C o ng e nita l hypo thyro idism. Sc re e ning pro g ra m. Maternal diseases.
• Laura Sterian W ard • Ilda Shiz ue Kunii • Rui Mo nteiro de Barro s Maciel
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METHODS
The pro cedures that fo llo w were in acco rdance with the ethical standards o f the co mmittee respo n-sible fo r human experimentatio n and with the Helsinki declaratio n o f 1975, as revised in 1983.
Setting
A public university referral center, the Center fo r Integrated Assistance in Wo men’s Health at the Uni-versity o f Campinas - Centro de Assistência Integrada à Saúde da Mulher/Ho spital das Clínicas da Faculdade de Medicina da Universidade de Campinas, Campinas.
Design
Pro spective no n-rando mized clinical trial with at least 3 mo nths fo llo w-up.
Participants
We examined and enro lled a minimum o f 415 new-bo rns fro m the Maternity Department o f the University o f Campinas (CAISM/UNICAMP). In acco rdance with their mo thers’ pro files, they were divided into 5 gro ups:
Group A. Co mpo sed o f 83 infants o f mo thers with co ngestive cardiac diseases, including Chagas’ dis-ease, hypertensive cardiac disdis-ease, and valve disease. They were divided into Functio nal Type II (n = 23 pa-tients), Functio nal Type III (n = 39) and Functio nal Type IV (n = 21), acco rding to the criteria co mmittee o f the New Yo rk Heart Asso ciatio n.9
Group B. Co mpo sed o f 98 infants fro m mo thers with toxemic pregnancies classified as moderate (diastolic blood pressure < 10 mmHg; n = 72 patients) o r severe (diasto lic blo o d pressure > 10 mmHg; n = 26 patients).
Group C. Co mpo sed o f 54 infants fro m diabetic
mo thers, classified into type A (n = 30), type B (n = 13) and type C (n = 11), acco rding to the Priscilla White classificatio n.10
Group D. Co mpo sed o f 40 infants fro m mo thers
Table 1. Thyroid stimulating hormone (TSH) le ve ls in mU/L, e xpre sse d as me an and standard de viation, of infants of group A: cardiac dise ase mothe rs (n = 83); group B: toxe mic mothe rs (n = 98); group C: diabe tic mothe rs (n = 54); group D: HIV positive mothe rs; group
E: control he althy mothe rs (n = 140). Group C is sub-divide d into Priscilla White classe s A (n = 30), B (n = 13) and C (n = 11). Statistical comparison re ve ale d no diffe re nce among groups (P > 0.05)
Groups Thyroid stimula ting hormone M ea n SD
A 6 .5 1 3 .5 8
B 6 .1 3 4 .8 5
C 6 .0 8 4 .7 6
Class A 6 .4 3 4 .5 8
Class B 6 .9 4 3 .9 8
Class C 6 .0 4 4 .1 5
D 6 .4 2 4 .1 0
E 6 .4 2 4 .1 0
Figure 1. Percentile distribution of TSH levels for the 5 different groups of infants born from: group A: toxemic mothers (N = 98); group B: diabetic mothers N = 54); group C: cardiac disease mothers (N = 83) ; group D: HIV positive mothers and group E: control healthy mothers (N = 140). P > 0.05.
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infected by the human immuno deficiency virus (HIV po sitive) but with no active disease.
Group E. A co ntro l gro up o f 140 no rmal preg-nant wo men.
Diagnostic test
Co rd blo o d samples were co llected by labo r-ro o m perso nnel. TSH co ncentratio ns were measured in 2-3 o ut o f 5 co rd blo o d spo ts co llected o n filter paper, using a ho memade immuno fluo rescence assay described else-where.11 The detectio n limit o f the assay in dried blo o d
spo ts is 0.1 mU/L and in plasma is 0.05 mU/L, with inter and intra-assay co efficients o f variatio n o f 5 and 10%, re-spectively. T4 was also measured with a fluo ro metric as-say with a sensitivity o f 1.6 mg/dL, with inter and intra-assay co efficients o f variatio n o f 5 and 10%, respectively.
Statistical Methods
Co mputer statistical pro grams, EPIINFO and STATGRAG, Micro so ft 5.0, were used fo r analyzing data.
Duncan, Ryan-Eino t-Gabriel Welsh, chi-square (
χ
2),Kruskal-Wallis (H) and ANOVA (F) tests were used to verify differences between gro ups and subgro ups. Re-sults were expressed as the mean ± standard deviatio n (SD). The level o f significance was taken as P < 0.05.
RESULTS
The infant’s sex, duratio n o f labo r, mo de o f deliv-ery and use o f utero genic agents were similar in all gro ups (
χ
2 = NS). Table 1 represents TSH mean levels, expressedas the mean and standard deviatio n, in patients o f the 5 gro ups. In Figure 1, these data are expressed as their percentile distributio n in each o f the 5 gro ups.
Co mpariso n o f these results sho ws no statistical difference amo ng gro ups o r subgro ups (H = 0.4963; P = 0.29; F = 0.609, P = 0.65). All values were belo w o ur cut-o ff value fo r co ngenital hypo thyro idism (20 mU/L). No child demo nstrated any feature that co uld be suspected as co n-genital hypo thyro idism during a fo llo w-up o f, at least, 3 mo nths (mean 5 mo nths, SD 2). Fo rty-eight percent o f the newbo rns presented a TSH co rd blo o d level abo ve 5 mU/L. There was no statistical difference in the distribu-tio n o f TSH > 5 mU/L cases in the different gro ups.
DISCUSSION
Clinical diagno sis o f co ngenital hypo thyro idism is difficult at birth and measurements o f TSH are essen-tial fo r this diagno sis. A screening pro gram no t o nly o f-fers the o ppo rtunity to trace and treat almo st all cases but also means large savings to the co untry.12 Ho wever,
to extend the benefits o f screening pro grams and reduce co sts, carefully planned strategies are necessary. The Brazilian Endo crine So ciety reco mmends a primary TSH, T4 back-up pro gram o n co rd blo o d samples. Ho wever, T4 has still been defended as the ideal metho d by many services that also use heel puncture perfo rmed at the 3rd to 5th day o f life. We have previo usly demo nstrated that, altho ugh bo th strategies are able to detect all cases o f hypo thyro idism, umbilical co rd blo o d is technically superio r to heel puncture and primary TSH clearly re-duces the recall index fo r co nfirmatio n o f the results.13
Infants bo rn prio r to term have lo wer co rd serum T4 co ncentratio ns that co rrelate with gestatio nal age o r birth weight.14
Previo us repo rts have sho wn that o ther facto rs, like maternal diseases affecting placental dynam-ics, may influence T4 values and thus the screening pro -grams that use primary T4.15,16 Ho wever, data o n the po
s-sible influence o f these facto rs o n co rd blo o d TSH are scarce. Franklin, et al. analyzed the effects o f maternal diabetes mellitus, to xemia, fetal distress and o ther fac-to rs and co ncluded that they did no t affect co rd serum TSH co ncentratio ns.15 Only the delivery metho d
influ-enced co rd serum T4. Ano ther early repo rt fro m Fuse, et al. also suggested that TSH values in co rd blo o d co uld be less influenced by perinatal facto rs than T4 values.16
We investigated newbo rns fro m mo thers affected by se-vere no thyro idal diseases, including HIV. Our data co n-firm that even severe maternal diseases do no t affect a screening pro gram using primary TSH fro m co rd blo o d. The Wo rld Health Organizatio n (WHO), United Natio ns Inte rnatio nal Childre n’s Em e rge ncy Fund (UNICEF), and the Internatio nal Co uncil fo r Co ntro l o f Io dine Deficiency Diso rders (ICCIDD) have included neo natal TSH as o ne o f the indicato rs fo r assessing io -dine deficiency diso rders (IDD) and their co ntro l.6 In
the absence o f io dine deficiency, the frequency o f neo -natal TSH abo ve 5 mU/L who le blo o d (o r 10 mU/L se-rum) is less than 3%. A frequency o f 3-19.9% indicates mild IDD. Frequencies o f 20-39.9% and abo ve 40% indi-cate mo derate and severe IDD, respectively. We fo und a 48% prevalence o f TSH cases abo ve 5 mU/L indicat-ing that o ur regio n is severely deficient in io dine. Re-cently Haddo w et al suggested that maternal thyro id dysfunctio n during pregnancy may impair the subse-quent neuro psycho lo gical develo pment in children, raising o ur co ncerns abo ut io dine supplementatio n.8,17
We suggest that, besides its technical advan-tages o ver heel punctures with T4 primary appro aches, neo natal screening using primary co rd blo o d TSH may also be used as a mo nito ring to o l fo r IDD evaluatio n and co ntro l in Brazil.
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1. Vela M, Gambo a S, Lo era-Luna A, Aguirre BE, Perez-Palacio s G, Velazquez A. Neo natal screening fo r co ngenital hypo thyro idism in Mexico : experience, o bstacles, and strategies. J Med Screen 1999;6:77-9.
2. LaFranchi S. Co ngenital hypo thyro idism: etio lo gies, diagno sis, and management. Thyro id 1999;9:735-40.
3. Kuba VM, Co eli CM, Meirelles RMR, Bo tler J, Faria R, Petruci CM. Avaliação de custo-efetividade dos testes de rastreamento de hipotiroidismo congênito em Campo s, Rio de Janeiro . Arq Bras Endo crino l Metabo l 1997;41:1-5.
4. Franco DB, Maciel RMB, Matsumura LK, Faria AM, Vieira JGH. Implantação do pro grama de rastreamento do hipo tiro idismo co ngênito na Fundação Ho spitalar do Distrito Federal: meto do lo gia, resultado s, dificuldades e pro po stas. Estudo co mparativo co m recém-nato s de o utro s estado s. Arq Bras Endo crino l Metabo l 1997;41:6-13.
5. Meirelles RMR, Maciel RMB, Machado FA, Castro AS. Subsídio s para a regulamentação das leis que estabelecem a o brigato riedade do diagnó stico do hipo tiro idismo co ngênito e fenilceto núria. Arq Bras Endo crino l Metabo l 1991;35:12-4.
6. Delange F. Screening fo r co ngenital hypo thyro idism used as an indicato r o f the degree o f io dine deficiency and o f its co ntro l. Thyro id 1998;8:1185-92 .
7. Esteves RZ. Determinação da excreção urinária de io do em esco lares brasileiro s. São Paulo , 1997. Universidade Federal de São Paulo / Esco la Paulista de Medicina; 1997. Do cto ral Thesis.
8. Medeiros-Neto G. Programa de correção da carência crônica de iodo no Brasil através da adição de io do ao sal: do sucesso inicial à incerteza atual. Arq Bras Endo crino l Metabo l 1998;42:235-7.
REFERENCES
9. Diseases o f the heart and blo o d vessels. No menclature and criteria fo r diagno sis. The criteria co mmittee o f the New Yo rk Heart Asso ciatio n. 6th editio n. Bo sto n: USA; 1964.
10. White P. In: Joslin’s Diabetes Mellitus. 11th edition. Philadelphia: Lea & Fabiger; 1971.
11. Vieira JGH, Kunii IS, Nishida SK, Matsumura LK, Russo EMK, Maciel RMB. Desenvo lvimento e aplicação de um méto do imuno fluo rimétrico para a do sagem de tiro tro fina humana (TSH) no so ro e em sangue to tal co lhido em papel de filtro . Arq Bras Endo crino l Metabo l 1992;36:7-12.
12. Ward LS, Zanella MT, Menabó E, et al. Estimativa da relação custo -benefício de um pro grama para detecção preco ce do hipo tiro idismo co ngênito . Rev Ass Med Bras 1988;34:276-82.
13. Ward LS, Maciel RMB, Magalhães RF, et al. Comparação entre duas estratégias para a detecção preco ce do hipo tiro idismo co ngênito . Rev Ass Med Brasil 1998;44:81-6.
14. La Franchi S. Thyro id functio n in the preterm infant. Thyro id 1999;9:71-8.
15. Franklin RC, Carpenter LM, O’Grady CM. Neonatal thyroid function: influence o f perinatal facto rs. Arch Dis Child 1985;60:141-4.
16. Fuse Y, Wakae E, Nemo to Y, et al. Influence o f perinatal facto rs and sampling methods on TSH and thyroid hormone levels in cord blood. Endocrinol Japon 1991;38:297-302.
17. Haddow JE, Palomaki GE, Williams JR et al. Maternal thyroid deficiency during pregnancy and subsequent neuro psycho lo gical develo pment o f the child. NEJM 1999;341:549-55.
r e s u m o
CON TEX TO: O s pro g ramas de detecção preco ce traz em eco no mias ao sistema de saúde e o ferecem a o po rtunidade de rastrear e tratar preco cemente caso s de hipo tiro idismo co ng ênito .
OBJETIVO: Determinar influências de doenças que afetam a dinâmica ma-terno-fetal-placentária sobre programas de detecção precoce de hipotiroi-dismo congênito que se baseiam na dosagem do hormônio tirotrófico (TSH).
TIPO DE ESTUDO: Ensaio clínico pro spectivo não -rando mizado co m, ao meno s, três meses de seg uimento .
LOCAL: Centro Universitário Público de Referência - Centro de Atendimento Integrado a Saúde da Mulher (CAISM).
PARTICIPAN TES: 4 1 5 recém-nascido s de 5 g rupo s de parturientes: 8 3 crianças eram filhas de mães cardio patas; 9 8 de mães co m to xemia g ravídica; 5 4 de mães diabéticas; 4 0 de mães po rtado ras de imuno deficiência adquirida (HIV); e 1 4 0 de mães híg idas.
PROCEDIM EN TOS: To do s o s recém-nascido s tiveram amo stras de sangue de co rdão umbilical co letadas em papel de filtro ao nascimento .
VARIÁVEIS ESTUDADAS: Do sag em de TSH em sang ue co letado em papel de filtro usando um ensaio imuno fluo ro métrico pró prio (sensibilidade em manchas de sang ue seco = 0 .1 mU/ L).
RESULTADOS: Não encontramos diferença na média de TSH dos 5 grupos. Além disso, os níveis de TSH estavam acima de 5 mU/ L em 48% dos bebês, sugerindo que nossa região é severamente deficiente em iodo.
CON CLUSÕES: N o sso s resultado s demo nstram que pro g ramas de detecção precoce de hipotiroidismo congênito, que utilizam primariamente TSH, não são afetados por doenças maternas não-tiroidianas. Sugerimos que, além das vantagens técnicas sobre a punção de calcanhar com dosagem primária de T4, os programas de detecção precoce que utilizam primariamente TSH de cordão umbilical também podem ser usados como instrumento de avaliação e controle da carências de iodo.
PALAV RAS-CH AV E: Hip o tiro id ismo c o ng ê nito . Ra stre a me nto . Do ença materna.
Laura Ste rian Ward, MD, PhD. Internal Medicine, Department o f Medicine, Faculty o f Medical Sciences, State University o f Campinas (UNICAMP), Campinas, Brazil.
Ilda Shizue Kunii. Bio lo gist, Head o f the Co ngenital Hypo thyro idism Screening Labo rato ry, Divisio n o f Endo crino lo gy, Department o f Medicine, Universidade Federal de São Paulo /Esco la Paulista de Medicina, São Paulo , Brazil.
Rui Monte iro de Barros Macie l, MD, PhD. Pro fesso r, Head o f the Co ngenital Hypo thyro idism Screening Pro gram, Divisio n o f Endo crino lo gy, Department o f Medicine, Universidade Federal de São Paulo / Esco la Paulista de Medicina, São Paulo , Brazil.
Source s of funding: Endo crino lo gy Studies Center o f the Universidade Federal de São Paulo /Esco la Paulista de Medicina (CENEPAM) and CNPQ – pro ject 405494/88.2.
Conflict of inte re st: no ne
Last re ce ive d: 02 May 2000
Acce pte d: 19 May 2000
Addre ss for corre sponde nce :
Laura Sterian Ward
GEMOCA, Clínica Médica. – FCM/UNICAMP Cid. Universitária Zeferino Vaz
Campinas/SP – Brasil – CEP 13081-970 E-mail: ward@ unicamp.br
p u b lis hin g in fo r m a t io n
