Tilburg University
Should all pregnant women be screened for hypothyroidism?
Pop, V.J.M.; van Baar, A.L.; Vulsma, T.
Published in:
The Lancet: A Journal of British and Foreign Medicine, Surgery, Obstetrics, Physiology, Pathology,
Pharmacology, Public Health and News
Publication date:
1999
Document Version
Publisher's PDF, also known as Version of record
Link to publication in Tilburg University Research Portal
Citation for published version (APA):
Pop, V. J. M., van Baar, A. L., & Vulsma, T. (1999). Should all pregnant women be screened for hypothyroidism?
The Lancet: A Journal of British and Foreign Medicine, Surgery, Obstetrics, Physiology, Pathology,
Pharmacology, Public Health and News, (354), 1225-1226.
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4 Kannel W B , D’Agostino RB, Belanger A J. Concept of bri d ging the gap from youth to adulthood. Am J Med Sci 1 9 9 5 ; 310 ( s u p p l ) :S 1 5 – 2 1 . 5 Rao S, Po rter DC, Chen X, Herliczek T, L owe M, K e yo m a rsi K.
L ova s t at i n - m e d i ated G1 arrest is through inhibition of the proteasome, independent of hy d r ox y m e t hyl glutaryl-CoA reductase. Proc Natl A c a d Sci USA 1 9 9 9 ; 9 6 : 7 7 9 7 – 8 0 2 .
6 D owney A M , Greenberg JS, V i r gilio SV, Berenson GS. H e a l t h promotion model for “ H e a rt Smart ” : the medical school, u n i ve rsity and c o m m u n i t y. Health Va l u e s 1 9 8 9 ; 1 3 : 3 1 – 4 6 .
7 Niinikoski H, Lapinleimn H,V i i k a ri J, et al. G r owth until 3 ye a rs of age in a prospective , randomized trial of a diet with reduced sat u r ated fat and cholesterol. Pe d i at ri c s 1 9 9 7 ; 9 9 : 6 8 7 – 9 4 .
8 DISC Collaborat i ve Research Group. E f f i c a cy and safety of lowe ri n g d i e t a ry intake of fat and cholesterol in children with elevated low density lipoprotein cholesterol. JA M A 1 9 9 5 ; 2 7 3 : 1 4 2 9 – 3 5 .
9 Stein EA, I l l i n g wo rth DR, K w i t e r ovich PO, et al. E f f i c a cy and safety of l ova s t atin in adolescent males with heterozygous fa m i l i a l
hy p e r c h o l e s t e r o l e m i a : a randomized controlled tri a l . JAMA 1 9 9 9 ; 2 8 1 : 1 3 7 – 4 4 .
p r e g n a n cy. F u rt h e rm o r e , l ova s t atin can arrest cells in the G-1 phase of the cell cy c l e .5D i e t a ry intervention and the
use of bile-acid sequestrants may not lower cholesterol c o n c e n t r ations sufficiently during pregnancy and may result in micronutrient inadequacy harmful to fetal gr ow t h . D i e t a ry manipulation may require supplementation with vitamins and minerals. All these measures may best be left until after the birt h . Equally important is the population or public-health approach to risk prevention in children and young adults before they themselves become parents.6
D ata from the Bogalusa Heart Study and other p o p u l ations of children in the USA suggest a high p r e valence of obesity and of adve rse serum lipid concentra-tions and blood pressure values among children. T h e presence of a family history of heart disease, more than one risk factor for CHD in childhood, and adve rse behav i o u rs , such as excess dietary intake of calori e s , s at u r ated fat and c h o l e s t e r o l , cigarette smoking, and physical inactivity, a r e h a r b i n g e rs of the development of cardiovascular disease. C a r d i ovascular risk fa c t o rs do not occur as isolated eve n t s. They persist into adulthood, resulting in progr e s s i ve target-organ damage from both atherosclerosis and hy p e rt e n s i o n , e ven in early life. Since unfavourable lifestyles and relat e d t r a i t s , such as raised blood pressure and serum lipids and early at h e r o s c l e r o s i s , are so prevalent among people in i n d u s t rialised countri e s , it is imperat i ve to examine all children and start prevention early in life.
The Finnish experience (STRIP Study) has shown that l owe ring of dietary fat in infa n cy does not harm gr ow t h d u ring the first 3 ye a rs of life.7 Nor did the Dietary
I n t e rvention Study in Children (DISC) show adve rs e effects of lowe ring of dietary fat on gr owth among p r e a d o l e s c e n t s.8 In terms of drug therapy for fa m i l i a l
hy p e r c h o l e s t e r o l a e m i a , a study of the efficacy and safety of l ova s t atin among adolescent boys with familial hy p e r -cholesterolaemia showed no adve rse effects on gr owth and sexual development over the 48-week duration of the tri a l .9
It would be prudent to consider drug therapy for children at ve ry high risk of atherosclerosis after completion of pubert a l gr ow t h , especially for those with LDL cholesterol above 160 mg/dL (4·1 mmol/L) despite ri gid dietary treat m e n t and a positive family history of CHD and hy p e r c h o l e s t e r o -l a e m i a .
Findings from the paediat ric studies cited above , complemented by necropsy dat a ,1 - 3 s h ow clearly that ri s k
fa c t o rs can be identified in childhood, and that dietary m a n i p u l ation to decrease intake of sat u r ated fat and cholesterol without undue restriction of calories has not interfered with gr ow t h . The increasing secular trends in o b e s i t y, the spread of cardiovascular disease wo r l d w i d e ,a n d the increasing prevalence of type 2 diabetes are compelling reasons for attempts to alter the natural course of atherosclerosis to start in childhood.
*Gerald S Bere n s o n ,S a t h a nur R Sriniva s a n
*Tulane Center for Cardiovascular Health,and Department of Epidemiology, Tulane School of Public Health,Tulane University Medical Center, New Orleans, LA 70112, USA
1 McGill HC Jr. Pe rsistent problems in the pathogenesis of at h e r o s c l e r o s i s. A t h e r o s c l e r o s i s 1 9 8 4 ; 4 : 4 4 3 – 5 1 .
2 Berenson GS, Wattigney WA , Tr a cy RE, et al. Atherosclerosis of the aort a and coronary art e ries and cardiovascular risk fa c t o rs in persons aged 6 to 30 ye a rs and studied at necropsy (the Bogalusa Heart Study). Am J C a r d i o l 1 9 9 2 ; 7 0 : 8 5 1 – 5 8 .
3 R e l ationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking: a preliminary report from the Pat h o b i o l o gical Determinants of Atherosclerosis in Youth (PDAY ) Research Group. JAMA 1 9 9 0 ; 2 6 4 : 3 0 1 8 – 2 4 .
1224 THE LANCET • Vol 354 • October 9, 1999
Should all pregnant women be screened for
hy p o t hy r o i d i s m ?
Screening of all pregnant women for hy p o t hy r o i d i s m , preferably in the first tri m e s t e r , has been proposed by r e s e a r c h e rs whose large-scale retrospective study showe d t h at mild or subclinical mat e rnal hy p o t hyroidism duri n g p r e g n a n cy is associated with the child’s poor perform a n c e on neuropsychological tests.1 This proposal has been
e n d o rsed by the Endocrine Society in the USA, which has called for the development of a cost-effective screening p r o gramme of pregnant women for hy p o t hy r o i d i s m ( h t t p : w w w. e n d o - s o c i e t y. o r g / m at e rn a l t hy r o i d d e f i c i e n cy [accessed on Oct 4, 1 9 9 9 ] ) .
The findings by James Haddow and colleagues1 a r e
i m p o rtant in emphasising the susceptibility of the d e veloping brain to thyroid disturbances during gestat i o n . There is evidence that the developing human brain needs t hyroid hormone from the first trimester of gestat i o n ,2a n d
until the fetal thyroid starts to produce thy r oxine in m i d g e s t at i o n , the fetus obtains its hormone entirely from the mother. M at e rnal serum concentrations of free t hy r oxine (FT4) at or below the tenth percentile at 12 we e k s ’ g e s t ation (but not at 32 weeks) are associated with d e l ayed psychomotor development at age 10 months.3T h i s
f i n d i n g—t h at mat e rnal FT4 concentrations at the lowe r end of the normal range at the end of the first tri m e s t e r result in an insufficient placental transfer of t hy r ox i n e—i n d i c ates that the risk of impaired neurodeve l -opment due to low exposure to the hormone is not confined to children of mothers with thyroid disease. H owe ve r , is there sufficient evidence that screening of pregnant women for thyroid function, f o l l owed by t r e atment of those with mild hy p o t hy r o i d i s m , will prov i d e wo rthwhile benefit to the children?1 , 4
In Haddow and colleagues’ s t u d y, 15 tests relating to i n t e l l i g e n c e , at t e n t i o n , school perform a n c e , and visual motor skills were gi ven to 62 children aged 7–9 ye a rs whose m o t h e rs ’ s e rum collected during pregnancy indicat e d hy p o t hy r o i d i s m . There was a significant 4-point difference b e t ween the groups in mean IQ, but this difference represents only a small effect size.5 More important than
the overall group difference, t h o u g h , is whether there is a difference in proportions of children with low IQ scores. I n the general populat i o n , about 16% of children have IQs t h at are more than 1 SD (15 points) below the mean (ie, IQs lower than 85).3A similar percentage (15%) was found
the difference might be due to high performance among the controls rather than poor functioning among the cases.
Another point to consider is that the effects of thy r ox i n e d e f i c i e n cy or thy r oxine supplementation may differ for va rious neurodevelopmental feat u r e s. For example, H a d d ow and colleagues’ findings indicate that attention is a d ve rsely affected among children of women treated for hy p o t hy r o i d i s m .1In another study,6c o g n i t i ve deve l o p m e n t
was appropri ate among children with congenital hy p o -t hyroidism gi ven thy r oxine supplements early, but when the children were examined according to horm o n e c o n c e n t r at i o n s , attention deficits and subtle motor problems were commoner among those with the highest FT4 concentrat i o n s , although these concentrations we r e within the normal range.4 Such findings suggest that
t r e atment with thy r oxine might not be free of adve rs e e f f e c t s , and this point must be clarified before a decision to screen is taken.
Once the benefit of screening is decided upon, i t s practicability and its sensitivity and specificity should also be considered, as the Endocrine Society plans to do. Fo r i n s t a n c e , w h at va riable should be used for the screening? Should it be thy r o t r o p i n , F T 4 , or thyroid perox i d a s e antibody (TPO-Ab)? Generally, the detection of thy r o i d dysfunction is based initially on thyrotropin concentrat i o n , and the society has recommended that for now this h o rmone should be measured for women with personal or family history of thyroid disease or symptoms suggestive of hy p o t hy r o i d i s m . But how accurate is thyrotropin as an index of mat e rnal FT4 concentrations or of adequacy of t hy r oxine transfer to the fetus? Low concentrations of m at e rnal serum FT4 have been associated with norm a l t hyrotropin concentrations during pregnancy, and this p at t e rn has been termed gestational hy p o t hy r ox i n a e m i a , a s t ate in which the “ t hy r oxine env i r o n m e n t ” is inappropri at e for the fetus rather than for the mother.7 If FT4 is the
va riable to be used in screening, w h at cut-off value should be used to define gestational hy p o t hy r oxinaemia? Inform e d choice would require knowledge of the frequency d i s t ri bution of FT4 concentrations in iodine-replete wo m e n (probably for each trimester of pregnancy ) .7The predictive
p ower of TPO-Ab is too low for use in screening, e ve n though women with these antibodies are at increased risk of h aving FT4 concentrations at the low end of the norm a l range at 12 we e k s ’g e s t at i o n .1 , 3
The next question to consider is when the woman should be screened. The first antenatal visit, e ven if it is in the firs t t ri m e s t e r , might be too lat e . The logistics of preconception screening are enorm o u s. B e s i d e s , the relation betwe e n m at e rnal FT4 concentrations before pregnancy and those d u ring early pregnancy is not know n .
F i n a l l y, h ow should the mother be treated? The relat i o n b e t ween low mat e rnal FT4 and impairment of the child’s n e u r o d e velopment has not been proven to be causal. T h e recent identification of metabolic pat h ways other than transplacental diffusion invo l ved in mat e rnal-fetal transfer of FT48 might mean that low concentrations of mat e rn a l
t hyroid hormone only indirectly impair the supply of t hyroid hormone to the fetus. The possibility that children at risk would benefit from treatment of the mother with t hy r oxine should be confirmed by a placebo-controlled tri a l of adequate statistical powe r , after the dose and the d u r ation of supplementation of thy r oxine have been studied in gr e ater detail.
F i n a l l y, is there an altern at i ve to screening followed by therapy? As pointed out in the commentary accompany i n g
H a d d ow and colleagues’ p a p e r ,9 e ven in areas where the
encironment contains sufficient iodine, p u b l i c - h e a l t h measures to encourage adequate iodine intake, w h i c h should be increased during pregnancy, should not be f o r g o t t e n . Such measures are easier to implement than screening of thyroid function during or before pregnancy, and will benefit the general populat i o n .
*Victor J Po p , Anneloes L van Baar, Thomas Vu l s m a
* D e p a rtment of Clinical Health Psychology, U n i v e rsity of Tilburg, 5000 LE T i l b u r g, N e t h e rlands; and Departments of Neonatalogy and P a e d i a t r i c E n d o c r i n o l o gy, E m m a ’s Children Hospital, A m s t e r d a m
1 H a d d ow JE, Palomaki GE, Allan W C , et al. M at e rnal thyroid deficiency d u ring pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1 9 9 9 ; 3 4 1 : 5 4 9 – 5 5 .
2 B u rr ow GN, Fisher DA ,L a rsen PR. M at e rnal and fetal thy r o i d f u n c t i o n . N Engl J Med 1 9 9 4 ; 3 3 1 : 1 0 7 2 – 7 8 .
3 Pop V J , Kuijpens JL, van Baar A L , et al. L ow mat e rnal free thy r ox i n c o n c e n t r ations during early pregnancy are associated with impaired psychomotor development in infa n cy. Clin Endocrinol (Oxf) 1 9 9 9 ; 5 0 : 1 4 9 – 5 5 .
4 L a z a rus JH. T hyroid hormone and intellectual deve l o p m e n t : a clinician's v i e w. T hy r o i d 1 9 9 9 ; 9 : 6 5 9 .
5 C o h e n , J. S t atistical power analysis for the behavioral sciences, r e v i s e d e d i t i o n .H i l l s d a l e :L awrence Erlbaum A s s o c i at e s ,1 9 8 8 .
6 R ovet J, A l varez M. T hyroid hormone and attention in school-age children with congenital hy p o t hy r o i d i s m . J Child Psychol Psychiat ry 1 9 9 6 ; 3 7 : 5 7 9 – 8 5 .
7 de Santiago J, Pastor I, Escobar del Rey F, M o rreale de Escobar G. T hyroid function in pregnant women from an area with mild (grade I) iodine deficiency (ID). J Endocrinol Inve s t 1 9 9 9 ; 2 2 (suppl to issue 6): 6 8 ( a b s t r ) .
8 Kester MH, van Dijk CH, Tibboel D, et al. S u l fation of thy r o i d h o rmone by estrogen sulfotransferase. J Clin Endocrinol Metab 1 9 9 9 ; 8 4 : 2 5 7 7 – 8 0 .
9 Utiger RD. M at e rnal hy p o t hyroidism and fetal deve l o p m e n t . N Engl J M e d 1 9 9 9 ; 3 4 1 : 6 0 1 – 0 2 .
THE LANCET • Vol 354 • October 9, 1999 1225
A stimulating new target for cancer
i m m u n o t h e r a py
The past few ye a rs have seen a striking expansion in k n owledge about the signals and switches invo l ved in cellular immunity. CD40 has emerged as a part i c u l a r l y i m p o rtant molecule, and its central role is starting to be exploited in studies of immunotherapy for tumours in human beings. Three recent papers1 - 3 suggest that
antibodies to CD40 can stimulate (not block) CD40 and p r ovoke immunity to tumours in mice.
CD40 induces immunity through activation and expansion of dendritic cells, B cells, and T cells. CD40 was ori ginally identified as an activator of B-lymphocy t e p r o l i f e r ation and is a transmembrane protein of the fa m i l y of tumour-necrosis-factor receptors. Interaction betwe e n CD40 on dendritic cells and the CD40 ligand (CD40L, n ow designated CD154) on naïve CD4-positive T- h e l p e r cells plays a crucial role at the start of the immune r e s p o n s e , in which the T-helper cells undergo activat i o n and the dendritic cells mat u r e . Signalling through CD40 on dendritic cells enables them to present antigen more e f f e c t i ve l y, through expression of costimulat o ry molecules and the production of interleukin-12, which in turn produces further T-cell stimulat i o n . The activated T- h e l p e r cells can then signal to B cells via CD40,4so that
CD40-a c t i vCD40-ated B cells CD40-also develop CD40-a potent CD40-antigen-presenting f u n c t i o n .5C D 4 0 - a c t i vated antigen-presenting cells can in
their turn stimulate CD8-positive cy t o t oxic T cells.6 , 7
