Smart screening: Maternal thyroxine and childhood development
01 September 2001
Thyroxine, the thyroid hormone produced from iodine by the thyroid gland, plays a key role in human growth and development, both in the womb and after birth. If thyroxine levels are too low, a child may suffer from a range of impairments, affecting their thinking and behaviour (cognition) or movement and coordination. Thyroid hormone deficiency thus places significant emotional and economical burdens on individuals, their families, and society as a whole.
Because of these risks, newborn babies are routinely screened for underactive thyroid function in many countries, including the UK, so they can be treated before any adverse effects are felt.
In the last decade, however, it has also become clear that thyroxine is critical to the development of the fetal brain. In early pregnancy, the fetus is unable to make its own thyroxine and is therefore dependent on maternal thyroxine traversing the placenta. So, if a pregnant woman is suffering from thyroxine deficiency, chances are the fetus will also be affected.
Despite a growing awareness of this phenomenon, the impact of thyroid deficiency has never been determined, points out Dr John Lazarus, Reader in Medicine at the University of Wales College of Medicine. "In this country, nobody screens for thyroid deficiency in pregnant women, yet they screen for syphilis, which has got an incidence of one in a million." Funded by the Wellcome Trust, Dr Lazarus has begun a large-scale clinical trial to determine whether routine antenatal screening of maternal thyroid function, and thyroxine supplements for those with low levels, can reduce the incidence of intellectual disability in children.
Maternal thyroxine
There is currently no routine screening for thyroid deficiency in pregnant women in the UK - even though it is actually far more common than underactive thyroid function in newborns. Studies suggest that 2-2.5 per cent of otherwise normal healthy women have low levels of thyroxine early in pregnancy.
One of the problems is that the degree of thyroid underactivity in the mother may be slight, so she may not feel any symptoms, and will therefore be unaware of her condition. Nevertheless, a large study recently carried out by Haddow and colleagues in the USA found clear evidence that thyroid underactivity has a significant impact. The US researchers looked at selected blood samples collected from 25 000 apparently normal pregnant women, none of whom showed any symptoms of thyroxine deficiency, and measured the IQs of their offspring at ages seven to nine. Strikingly, women with thyroid underactivity during pregnancy were three times more likely to have a child with an IQ of less than 85 (100 is normal). "That paper has caused a lot of public interest in women's groups, certainly in America," says Dr Lazarus. "It was the final impetus that has stimulated us to apply for this grant."
In his trial, Dr Lazarus aims to confirm the relationship between thyroid underactivity and lower IQ in the child. The study will go on to address whether thyroxine supplements, begun early in pregnancy, might avoid IQ problems in the offspring of hypothyroid mothers. "We don't know whether the interventions are effective. We've got a pretty good idea that they are, but this has not been adequately tested in a large number of women to reach a scientific and definite answer."
Ultimately, Dr Lazarus aims to provide an evidence base to help health policy officials decide whether to implement routine screening for thyroid disorders. "Screening is just a simple blood test, nothing complicated, and we hope to be able to prove that thyroxine is an effective intervention. The screening committees will have to look at the cost-benefit ratio of that kind of screening strategy and decide whether it's worthwhile doing it. Certainly, we hope to give the authorities enough evidence from this trial to persuade them that there's a good case for it, so there's a strong possibility the trial will have a positive impact on medical practice."
Finding the answer
Dr Lazarus hopes to screen 22 000 women as early in pregnancy as possible, preferably at 12 weeks, when they first meet midwives. Women will be contacted at four hospitals in or near Cardiff then divided randomly into two groups of 11 000: the treatment group and the control group. A blood sample will then be taken from each of the 22 000 women.
The team will be using thyroid-stimulating hormone (TSH) levels as an indicator of thyroxine levels - high TSH levels correspond to low thyroxine levels and vice versa. They will also check children whose mothers have low thyroxine levels who may or may not have high TSH levels. "In this country, where we haven't got a problem with iodine deficiency, TSH levels are considered to be the best measure of thyroid status," says Dr Lazarus. "We'll be measuring the TSH levels in the blood of the treatment group immediately, and if the levels are too high (meaning thyroxine levels are low), we'll give them thyroxine."
In the control group, however, the blood sample will be stored until after delivery and the TSH levels measured once the baby is born. "So that group will not have had any treatment during pregnancy. Because this is an intervention trial, and since most women with these forms of hypothyroidism are not usually found and treated, the design does not contravene normal care and is ethically sound."
The next step in the trial incorporates an important methodological innovation. "In a standard randomised trial you would have to measure the IQ of all the children, which would be expensive and have low statistical power because some kids with low IQ will be born to women with normal TSH. In this trial, we're only going to assess the IQs of children born to women with high TSH levels (in both the control and treatment groups), and compare them to a reference group of children whose mothers are known to have had normal TSH, to determine the normal range of IQ levels for this population." The design will have high statistical power, but be much easier to carry out. This approach is an important scientific innovation in its own right, with applications in other areas of medical investigation.
The intellectual development of the children will be measured at two and five years. Based on Haddow's US data, 41 children from the untreated mothers with high TSH should have impaired IQ, compared with 14 from the treated group - a statistically significant difference.
The trial represents a vast multidisciplinary effort. "Everybody is an important link in the chain," says Dr Lazarus. "The midwives are the first point of contact with the pregnant mother, and they're going to have to explain the trial and recruit the 22 000 women over a two-year period. We'll also be relying on the specialist advice of psychologists and obstetricians, and collaborating with biochemists regarding TSH and thryoxine measurements." Statistical analysis and randomisation will be carried out in Bart's Hospital, London, under the leadership of epidemiologist Professor Nicholas Wald, who was also an adviser to the Haddow study.
"We're doing this trial to try and provide the prospect of evidence for something that most of us believe, but for which there isn't any definite proof," says Dr Lazarus. "Our view is that we have here a probable specific cause of impaired IQ in children which is very important. It may not be a large percentage in the totality of impaired childhood development but at least it's something and it can be relatively easily screened for."
See also
- Brainy babies: Article on prenatal stimulation and brain development
External links
- Department of Medicine at the University of Wales College of Medicine: Dr John Lazarus of the Cardiff Thyroid Group
- Report in Endocrine News on US research by Dr James Haddow on testing pregnant women for thyroid disorder
- Professor Nicholas Wald: Contact details at the Department of Environmental and Preventive Medicine, St Bartholomew's and Royal London School of Medicine and Dentistry
Further reading
Haddow J E, Palomaki G E, Alan W C (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine. 341: 549-55.
Morreale de Escobar G, Obregon M J, Escobar del Rey F C (2000). Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J. Clin. Endo. and Met. 85: 3975-87.