- Email: [email protected]
Aiming for perfection: outcome of fetal and neonatal medicine
THE
Aiming for perfection:
LANCET
outcome of fetal and neonatal medicine
C G D Brook
Attempts to improve outcome need to begin even before a couple contemplates the practical business of procreation: pregnancy spacing is clearly relevant to the pursuit of healthy babies.7 The value of preconceptual vitamin supplementation is well established8 and the social class 1 mother-to-be is now obsessional about avoiding alcohol, tobacco, and unpasteurised milk products. It is clear that neonatal encephalopathy and cerebral palsy are far from being associated exclusively with perinatal events. Data from Australia show that the of encephalopathy in the newborn are causes heterogeneous. Many causal pathways start in the even for diseases such as antepartum period,g schizophrenia which may not become manifest for two decades.” Improvements in monitoring and early gestation using a range of techniques, especially ultrasound, have made a striking impact in assessing fetal wellbeing but the
techniques are highly observer-dependent and have sensitivities and specificities which need to be clearly understood in the context of individual cases. In Boyd and colleagues pivotal study,” ultrasound assisted in the detection of more than half the malformed fetuses antenatally but the increasing observation of ultrasound “soft” markers led to a large increase in false-positive findings, with psychological effects on the pregnant mother-to-be. The concept of using ultrasound to assess the velocity of fetal growth, which is the cornerstone of growth assessment in childhood,‘” is rather poorly understood by most obstetricians and is rarely pursued with any degree of accuracy. Anyway, improving fetal growth awaits the results of extensive research in placentology and the means to optimise placental function, not to mention the maternal much wider perspective of preventing malnutrition worldwide. amniocentesis, The increasing availability of cordocentesis, fetoscopy, fetal surgery, and chorion villus biopsy has contributed to the pursuit of healthy babies, especially when coupled to techniques of molecular genetics. Such tools need, however, to be handled with discretion, as exemplified in clinical paediatric endocrine practice by the case of congenital adrenal hyperplasia (adrenogenital syndrome). After the genes for 21-hydroxylase deficiency were identified on chromosome 6, it seemed only a matter of time before genotypic diagnosis would allow the rational prescription of steroids to the mother in the prenatal period to prevent masculinisation of the female fetus by suppressing unwanted fetal adrenal androgen secretion in utero. In the event, the complexity of the arrangement of the gene and pseudogene for this recessively inherited condition has meant that patients can have the disease without demonstrable genetic mutations.13 We have identified two unaffected fathers genotypically identical to their affected offspring. We have treated one female fetus throughout gestation because of a genotype identical to her proband sibling only to find, when we congratulated ourselves on the normality of her genitalia at birth, that we were unable then (and over the next 3 years) to confirm the biochemical defect despite confirmation of the genotype. Antenatal exposure to steroids in the short term has been beneficial for maturing the lungs of babies threatened with premature deliveryI but there are anxieties, both theoretical on renal vasculature’5 and practical on neurodevelopmental progress,16 about longterm therapy. Interventions with the best intentions and based on the best pathophysiological knowedge can be two-edged swords.
Lancet 1999;
Perinatal
A woman in the UK in 1996 could expect to deliver on average 1.73 children in her reproductive lifetime, a fecundity second only to Ireland (1.91) in Europe, though less than that in the USA (2.02 in 1995).’ With a life expectancy of roughly 75 years, today’s adults expect these children to survive and (at the very least as taxpayers) to look after them in their old age-in short, to be perfect children. Roughly 1 child in every 100 in the UK dies before the age of 15 years (the exact figure is 0.86 per loo), most in the first 5 years of life and especially in the first year. Bates of death and morbidity are significantly increased in social class 5, being roughly double those in social classes 1 and 2. About 1 boy in every 100 and one girl in every 150 has a major congenital abnormality, and social class plays a part here too.’ The prevalence of lesser causes of disadvantage caused by congenital anomaly is likely to be 10 times higher. The studies of Barker and colleague? have demonstrated retrospectively that antenatal events influence morbidity and mortality in adult life. The experimental evidence underlying the power of these influences is not new.3a4 The geographical studies of Barker’s group and the follow-up of cohorts with known birthweight have been confirmed, for example, in the risk of non-fatal coronary heart disease and stroke in the US Nurses Health Study.5 Studies in many countries have shown that babies born small-for-dates have raised systolic blood pressure in childhood and adult life, associations which are independent of current body mass and alcohol consumption. Postnatal events are obviously important but prenatal ones are too.6
Prenatal
period
354
(SUPPI
II): 25-27
London Centre for Paediatric Endocrinology, Great Ormond Street and Middlesex Hospitals, London, and University College London, London, UK (Prof C G D Brook FRCP) Correspondence Mottimer Street,
Paediatrics
to: Prof C G D Brook, Middlesex London WlN 8AA, UK
- Vol 354 * September
- 1999
Hospital,
period
The greater knowledge which fetal monitoring has given to the understanding of fetal wellbeing has been reflected in the introduction of an era of more benign obstetric practice. I believe that the well-known association between breech delivery and growth-hormone deficiency SII2 5
THE
LANCEI-
in children” must have been causal because, when breech delivery was effectively outlawed in the UK, at least for primigravidae, the prevalence of severe idiopa&ic is&ted growth-hormone deficiency (IGHD) fell sharply. At the London Centre for Paediatric Endocrinology in the 1970s and 198Os, we were starting upwards of 100 children a year on growth-hormone replacement treatment for this condition but we have seen only two severely affected children in the past 12 months. In the 1960s it was rare to see truly normal survivors of neonatal special care units. This may have been because of inappropriate interventions in some instances (eg, starving and cooling of newborn babies), albeit with the best intentions, but the progressive lowering of the legal definition of gestational age of viability reflects the strides neonatal intensivists have taken. The pioneering work of those whose careful long-term follow-up studies matched attention to the details of neonatal intensive care,‘* means that today’s paediatricians and the parents of their patients expect a healthy outcome. This has been achieved by using exogenous surfactant and improved ventilatory techniques, such as high-frequency oscillatory ventilation, for respiratory distress syndrome, and other methods for the rearing of babies with birthweights less than 1000 g, sometimes delivered at the end of the second trimester. None of this has been achieved without its cost in human and financial terms but it is worth reflecting that the quest to save lives, which is what can most easily be measured, conceals the parallel aim of preventing handicap in survivors. It is important not to overlook this benefit when weighing the cost of neonatal intensive care. In the decade to come we can hope further to improve pregnancy outcomes, although new challenges such as rising maternal age and infertility treatments may frustrate us. One area might be to reduce the incidence of preterm labour by better detection and management of antenatal infection. Neuroprotective interventions, such as selective cranial hypothermia, might ameliorate cerebral injuries. The technology is becoming available to permit continuous monitoring of brain perfusion and oxygenation during intensive care. The introduction of extracorporeal membrane oxygenation may presage the use of fluorocarbons for the (liquid) oxygenation of preterm patients at the margins of viability without incurring the risks of the lung damage association with conventional (gas) regimens. Efforts to help extremely preterm babies to survive will find their reward in safer management of the older preterm baby or of the baby born small for gestational age who is destined to become the victim of hypertension, coronary artery disease, and stroke in later life.”
quality of life in childhood and better long-term outcome in adulthood. With screening, or indeed any investigation, we need to remember that every test has its sensitivity and specificity every time it is used. Merely repeating tests, or using two tests where one would do, does not increase diagnostic precision (the “product law for independent events”“). This has been demonstrated in the repeated physical examination of the newborn.22 Despite the uncovering of more suspected abnormalities, there was no evidence of net health gain from a policy of two hospital examinations. For every step forward there are uncomfortable reminders of our failure to assure the longer-term future of our children. One puzzle is the increased incidence of asthma and atopy in school-age children. Strachan has proposed that the protection of infants against infection at an early age may make us more liable to allergy later.23 The higher prevalence of atopy amongst children who attended day nursery at an older age than those who started to attend at a younger age, coupled with the loss of this effect in children from large families,z4 reinforces the feeling that we may not be doing a service to our children if we wrap them up too well. They might even be allowed to walk to school. Immunisation has been one of the great medical triumphs of the past 200 years. The WHO programme to eradicate smallpox and the current one for poliomyelitis must be supported by all right-thinking persons. But we cannot yet do everything that we should: for example, we still need vaccines against type B meningococcal disease, malaria, and AIDS. More importantly, we also need to understand why some children fail to respond to immunisation; most cases of measles nowadays are in immunised rather than in unimmunised children. A parallel with the failing antibody responses to influenza vaccination in the stressed elderly carers of spouses with dementia may have relevance for children brought up in disadvantaged circumstances.25
Neonatal
Conclusion
period
Screening for congenital abnormalities is part of the dayto-day life of paediatricians. In paediatric endocrinology, for example, the early diagnosis of congenital hypothyroidism has greatly reduced the need for special education facilities for infants born with a hypoplastic, ectopic, or dyshormonogenic thyroid. Nevertheless, prenatal hypothyroidism, undetectable by our current methodology, does still carry the burden of irreversible neurodevelopmental sequelae. It is hoped that the identification and treatment of diseases which start to have their adverse effects from the time of birth, such as cystic fibrosi? and phenylketonuria, will lead to a better ~126
Diseases
of poverty
and affluence
The tackling of poverty is not usually regarded as a responsibility of the medical profession but the continual demonstration of the consequences of poverty to health in every society cannot be ignored.26 Affluence too brings its problems. The rising incidence of obesity, gallstones, renal stones and cancers of the breast, ovary, and prostate2’ needs explanation and preventive action, And there are other diseases such as osteoporosis, schizophrenia, and depression, for which evidence can be adduced for an effect of in-utero programming,” which we do not yet understand at all.
Trying to alter the lifestyle of adults, who see little immediate benefit from behavioural modifications, is formidably difficult. The more powerful the evidence for programming of human health becomes the more relevant will be policies for improving the health and welfare of children, both born and unborn. References 1 2
Platt MJ. Child health statistics review, 1998. Arch Dis Child 1998; 79: 523-27. Barker DJP. Mothers, babies and health in later life. Edinburgh, Churchill Livingsone, 1998.
Paediattics
* Vol354
- September
- 1999
THE
3
4
5
6
7
8 9
10
11
12 13
14
15
Widdowson EM, McCance RA. The effect of finite period of under nutrition at different ages on the composition and subsequent developmentof the rat. Proc Roy Sot LondB 1963; 158: 329-42. Widdowson EM, McCance RA. Some effects of accelerating growth I: general somatic development. Proc Roy Sot Lond B 1960; 152: 188-206. Rich-Edwards JW, Stampfer MJ, Manson JE, et al. Birtbweight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997; 315: 396-400. Hindmarsh PC, Brook CGD. Evidence for an association between birth weight and blood pressure. Acta Pediatr 1999; 428 (suppl): 66-69. Zhu B-P Folfs RT, Nangle BE, Horan JM. Effect of the interval between pregnancies on perinatal outcomes. N EnglJMed 1999; 340: 589-94. MRC Vitamin Research Group. Prevention of neural tube defects: results ofthe MRC Vitamin Study. Lancet 1991; 338: 131-37. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Antepartum risk factors for newborn encephalopathies: the Western Australian case control study. B&f? 1998; 317: 1549-53. Hultman CM, Sparen P, Takei N, Murray RM, Cnattinguis S. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case control study. BMJ 1999; 318: 421-26. Boyd PA, Chamberlain P, Hicks NR. 6 year experience of prenatal diagnosis in an unselected population in Oxford, UK. Lancet 1998; 352: 1577-81. Brook CGD, Hindmarsh PC, Healy MJR. A better way to detect growth failure. BMJ 1986; 293: 1186. Nimkam S, Cerame BI, Wei J-Q, et al. Congenital adrenal hype@& (21 hydroxylase deficiency) without demonstrable genetic mutations. 3 Clin Endocrinol Metab 1999; 84: 3’78-81. Crowley I’, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. BrJ Obstet Gynaecol 1990; 97: 1 l-25. Celsi G, Kistner A, Aizman R, et al. Prenatal dexamethasone causes
Paediatrics
* Vol 354 . September.
1999
16
17 18
19
20
21 22
23
24 25
26
27 28
LANCE?-
oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res 1998; 44: 3 17-22. Laic S, Wedell A, Bui TH, Ritzen EM, Holst M. Long term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocnml Metrab 1998; 83: 3872-80. Rona RJ, Tanner JM. Aetiology of idiopathic growth hormone deficiency in England and Wales. Arch Dis Child 1977; 52: 197-208. Reynolds EOR. Effect of alterations in mechanical ventilator settings on pulmonary gas exchange in hyaline membrane disease. Arch Dis Child 1971; 46: 152-59. Eriksson JG, Forsen T, Tuomliehto J, Winter PD, Osmond C, Barker DJP. Catch up growth in childhood and death from comary heart disease: longitudinal study. BMJ 1999; 318: 427-31. Waters DL, Wilcken B, Itwig L, et al. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child Fetal Neonatal Ed 1999; 80: Fl-F7. Chatfield C. The concept of probability. In: Statistics for technology. 3rd edn. London: Chapman&Hall, 1983: 45. Glazener CMA, Ramsay CR, Campbell MK, et al. Neonatal examination and screening trial (NEST): a randomised, controlled, switchback trial of alternative policies for low risk infants. BMJ 1999; 318: 627-32. Strachan DP, Harkins LS, Johnston DA, Anderson HR. Childhood antecedents of allergic sensitisation in young British adults. J A&Q Clin Immunol 1997; 99: 6-12. Kramer U, H&rich J, Wjist M, Wichmann H-E. Age at entry to day nursery and allergy in later childhood. Lancet 1999; 352: 45-54. Vedhara K, Cox NKM, Wilcock GK, et al. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 1999; 353: 627-31. Black D, Morris JN, Smith C, Townsend P. Better benefits for health: plan to implement the central recommendation of the Acheson report. BMJ 1999; 318: 724-27. Barker DJP. The rise and fall western diseases. Nature 1989; 338: 371-72. Barker DJP. Mother, babies and health in later life. Edinburgh: Churchi Livingstone, 1998: 199-201.
su27
Aiming for perfection:
LANCET
outcome of fetal and neonatal medicine
C G D Brook
Attempts to improve outcome need to begin even before a couple contemplates the practical business of procreation: pregnancy spacing is clearly relevant to the pursuit of healthy babies.7 The value of preconceptual vitamin supplementation is well established8 and the social class 1 mother-to-be is now obsessional about avoiding alcohol, tobacco, and unpasteurised milk products. It is clear that neonatal encephalopathy and cerebral palsy are far from being associated exclusively with perinatal events. Data from Australia show that the of encephalopathy in the newborn are causes heterogeneous. Many causal pathways start in the even for diseases such as antepartum period,g schizophrenia which may not become manifest for two decades.” Improvements in monitoring and early gestation using a range of techniques, especially ultrasound, have made a striking impact in assessing fetal wellbeing but the
techniques are highly observer-dependent and have sensitivities and specificities which need to be clearly understood in the context of individual cases. In Boyd and colleagues pivotal study,” ultrasound assisted in the detection of more than half the malformed fetuses antenatally but the increasing observation of ultrasound “soft” markers led to a large increase in false-positive findings, with psychological effects on the pregnant mother-to-be. The concept of using ultrasound to assess the velocity of fetal growth, which is the cornerstone of growth assessment in childhood,‘” is rather poorly understood by most obstetricians and is rarely pursued with any degree of accuracy. Anyway, improving fetal growth awaits the results of extensive research in placentology and the means to optimise placental function, not to mention the maternal much wider perspective of preventing malnutrition worldwide. amniocentesis, The increasing availability of cordocentesis, fetoscopy, fetal surgery, and chorion villus biopsy has contributed to the pursuit of healthy babies, especially when coupled to techniques of molecular genetics. Such tools need, however, to be handled with discretion, as exemplified in clinical paediatric endocrine practice by the case of congenital adrenal hyperplasia (adrenogenital syndrome). After the genes for 21-hydroxylase deficiency were identified on chromosome 6, it seemed only a matter of time before genotypic diagnosis would allow the rational prescription of steroids to the mother in the prenatal period to prevent masculinisation of the female fetus by suppressing unwanted fetal adrenal androgen secretion in utero. In the event, the complexity of the arrangement of the gene and pseudogene for this recessively inherited condition has meant that patients can have the disease without demonstrable genetic mutations.13 We have identified two unaffected fathers genotypically identical to their affected offspring. We have treated one female fetus throughout gestation because of a genotype identical to her proband sibling only to find, when we congratulated ourselves on the normality of her genitalia at birth, that we were unable then (and over the next 3 years) to confirm the biochemical defect despite confirmation of the genotype. Antenatal exposure to steroids in the short term has been beneficial for maturing the lungs of babies threatened with premature deliveryI but there are anxieties, both theoretical on renal vasculature’5 and practical on neurodevelopmental progress,16 about longterm therapy. Interventions with the best intentions and based on the best pathophysiological knowedge can be two-edged swords.
Lancet 1999;
Perinatal
A woman in the UK in 1996 could expect to deliver on average 1.73 children in her reproductive lifetime, a fecundity second only to Ireland (1.91) in Europe, though less than that in the USA (2.02 in 1995).’ With a life expectancy of roughly 75 years, today’s adults expect these children to survive and (at the very least as taxpayers) to look after them in their old age-in short, to be perfect children. Roughly 1 child in every 100 in the UK dies before the age of 15 years (the exact figure is 0.86 per loo), most in the first 5 years of life and especially in the first year. Bates of death and morbidity are significantly increased in social class 5, being roughly double those in social classes 1 and 2. About 1 boy in every 100 and one girl in every 150 has a major congenital abnormality, and social class plays a part here too.’ The prevalence of lesser causes of disadvantage caused by congenital anomaly is likely to be 10 times higher. The studies of Barker and colleague? have demonstrated retrospectively that antenatal events influence morbidity and mortality in adult life. The experimental evidence underlying the power of these influences is not new.3a4 The geographical studies of Barker’s group and the follow-up of cohorts with known birthweight have been confirmed, for example, in the risk of non-fatal coronary heart disease and stroke in the US Nurses Health Study.5 Studies in many countries have shown that babies born small-for-dates have raised systolic blood pressure in childhood and adult life, associations which are independent of current body mass and alcohol consumption. Postnatal events are obviously important but prenatal ones are too.6
Prenatal
period
354
(SUPPI
II): 25-27
London Centre for Paediatric Endocrinology, Great Ormond Street and Middlesex Hospitals, London, and University College London, London, UK (Prof C G D Brook FRCP) Correspondence Mottimer Street,
Paediatrics
to: Prof C G D Brook, Middlesex London WlN 8AA, UK
- Vol 354 * September
- 1999
Hospital,
period
The greater knowledge which fetal monitoring has given to the understanding of fetal wellbeing has been reflected in the introduction of an era of more benign obstetric practice. I believe that the well-known association between breech delivery and growth-hormone deficiency SII2 5
THE
LANCEI-
in children” must have been causal because, when breech delivery was effectively outlawed in the UK, at least for primigravidae, the prevalence of severe idiopa&ic is&ted growth-hormone deficiency (IGHD) fell sharply. At the London Centre for Paediatric Endocrinology in the 1970s and 198Os, we were starting upwards of 100 children a year on growth-hormone replacement treatment for this condition but we have seen only two severely affected children in the past 12 months. In the 1960s it was rare to see truly normal survivors of neonatal special care units. This may have been because of inappropriate interventions in some instances (eg, starving and cooling of newborn babies), albeit with the best intentions, but the progressive lowering of the legal definition of gestational age of viability reflects the strides neonatal intensivists have taken. The pioneering work of those whose careful long-term follow-up studies matched attention to the details of neonatal intensive care,‘* means that today’s paediatricians and the parents of their patients expect a healthy outcome. This has been achieved by using exogenous surfactant and improved ventilatory techniques, such as high-frequency oscillatory ventilation, for respiratory distress syndrome, and other methods for the rearing of babies with birthweights less than 1000 g, sometimes delivered at the end of the second trimester. None of this has been achieved without its cost in human and financial terms but it is worth reflecting that the quest to save lives, which is what can most easily be measured, conceals the parallel aim of preventing handicap in survivors. It is important not to overlook this benefit when weighing the cost of neonatal intensive care. In the decade to come we can hope further to improve pregnancy outcomes, although new challenges such as rising maternal age and infertility treatments may frustrate us. One area might be to reduce the incidence of preterm labour by better detection and management of antenatal infection. Neuroprotective interventions, such as selective cranial hypothermia, might ameliorate cerebral injuries. The technology is becoming available to permit continuous monitoring of brain perfusion and oxygenation during intensive care. The introduction of extracorporeal membrane oxygenation may presage the use of fluorocarbons for the (liquid) oxygenation of preterm patients at the margins of viability without incurring the risks of the lung damage association with conventional (gas) regimens. Efforts to help extremely preterm babies to survive will find their reward in safer management of the older preterm baby or of the baby born small for gestational age who is destined to become the victim of hypertension, coronary artery disease, and stroke in later life.”
quality of life in childhood and better long-term outcome in adulthood. With screening, or indeed any investigation, we need to remember that every test has its sensitivity and specificity every time it is used. Merely repeating tests, or using two tests where one would do, does not increase diagnostic precision (the “product law for independent events”“). This has been demonstrated in the repeated physical examination of the newborn.22 Despite the uncovering of more suspected abnormalities, there was no evidence of net health gain from a policy of two hospital examinations. For every step forward there are uncomfortable reminders of our failure to assure the longer-term future of our children. One puzzle is the increased incidence of asthma and atopy in school-age children. Strachan has proposed that the protection of infants against infection at an early age may make us more liable to allergy later.23 The higher prevalence of atopy amongst children who attended day nursery at an older age than those who started to attend at a younger age, coupled with the loss of this effect in children from large families,z4 reinforces the feeling that we may not be doing a service to our children if we wrap them up too well. They might even be allowed to walk to school. Immunisation has been one of the great medical triumphs of the past 200 years. The WHO programme to eradicate smallpox and the current one for poliomyelitis must be supported by all right-thinking persons. But we cannot yet do everything that we should: for example, we still need vaccines against type B meningococcal disease, malaria, and AIDS. More importantly, we also need to understand why some children fail to respond to immunisation; most cases of measles nowadays are in immunised rather than in unimmunised children. A parallel with the failing antibody responses to influenza vaccination in the stressed elderly carers of spouses with dementia may have relevance for children brought up in disadvantaged circumstances.25
Neonatal
Conclusion
period
Screening for congenital abnormalities is part of the dayto-day life of paediatricians. In paediatric endocrinology, for example, the early diagnosis of congenital hypothyroidism has greatly reduced the need for special education facilities for infants born with a hypoplastic, ectopic, or dyshormonogenic thyroid. Nevertheless, prenatal hypothyroidism, undetectable by our current methodology, does still carry the burden of irreversible neurodevelopmental sequelae. It is hoped that the identification and treatment of diseases which start to have their adverse effects from the time of birth, such as cystic fibrosi? and phenylketonuria, will lead to a better ~126
Diseases
of poverty
and affluence
The tackling of poverty is not usually regarded as a responsibility of the medical profession but the continual demonstration of the consequences of poverty to health in every society cannot be ignored.26 Affluence too brings its problems. The rising incidence of obesity, gallstones, renal stones and cancers of the breast, ovary, and prostate2’ needs explanation and preventive action, And there are other diseases such as osteoporosis, schizophrenia, and depression, for which evidence can be adduced for an effect of in-utero programming,” which we do not yet understand at all.
Trying to alter the lifestyle of adults, who see little immediate benefit from behavioural modifications, is formidably difficult. The more powerful the evidence for programming of human health becomes the more relevant will be policies for improving the health and welfare of children, both born and unborn. References 1 2
Platt MJ. Child health statistics review, 1998. Arch Dis Child 1998; 79: 523-27. Barker DJP. Mothers, babies and health in later life. Edinburgh, Churchill Livingsone, 1998.
Paediattics
* Vol354
- September
- 1999
THE
3
4
5
6
7
8 9
10
11
12 13
14
15
Widdowson EM, McCance RA. The effect of finite period of under nutrition at different ages on the composition and subsequent developmentof the rat. Proc Roy Sot LondB 1963; 158: 329-42. Widdowson EM, McCance RA. Some effects of accelerating growth I: general somatic development. Proc Roy Sot Lond B 1960; 152: 188-206. Rich-Edwards JW, Stampfer MJ, Manson JE, et al. Birtbweight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997; 315: 396-400. Hindmarsh PC, Brook CGD. Evidence for an association between birth weight and blood pressure. Acta Pediatr 1999; 428 (suppl): 66-69. Zhu B-P Folfs RT, Nangle BE, Horan JM. Effect of the interval between pregnancies on perinatal outcomes. N EnglJMed 1999; 340: 589-94. MRC Vitamin Research Group. Prevention of neural tube defects: results ofthe MRC Vitamin Study. Lancet 1991; 338: 131-37. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Antepartum risk factors for newborn encephalopathies: the Western Australian case control study. B&f? 1998; 317: 1549-53. Hultman CM, Sparen P, Takei N, Murray RM, Cnattinguis S. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case control study. BMJ 1999; 318: 421-26. Boyd PA, Chamberlain P, Hicks NR. 6 year experience of prenatal diagnosis in an unselected population in Oxford, UK. Lancet 1998; 352: 1577-81. Brook CGD, Hindmarsh PC, Healy MJR. A better way to detect growth failure. BMJ 1986; 293: 1186. Nimkam S, Cerame BI, Wei J-Q, et al. Congenital adrenal hype@& (21 hydroxylase deficiency) without demonstrable genetic mutations. 3 Clin Endocrinol Metab 1999; 84: 3’78-81. Crowley I’, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. BrJ Obstet Gynaecol 1990; 97: 1 l-25. Celsi G, Kistner A, Aizman R, et al. Prenatal dexamethasone causes
Paediatrics
* Vol 354 . September.
1999
16
17 18
19
20
21 22
23
24 25
26
27 28
LANCE?-
oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res 1998; 44: 3 17-22. Laic S, Wedell A, Bui TH, Ritzen EM, Holst M. Long term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocnml Metrab 1998; 83: 3872-80. Rona RJ, Tanner JM. Aetiology of idiopathic growth hormone deficiency in England and Wales. Arch Dis Child 1977; 52: 197-208. Reynolds EOR. Effect of alterations in mechanical ventilator settings on pulmonary gas exchange in hyaline membrane disease. Arch Dis Child 1971; 46: 152-59. Eriksson JG, Forsen T, Tuomliehto J, Winter PD, Osmond C, Barker DJP. Catch up growth in childhood and death from comary heart disease: longitudinal study. BMJ 1999; 318: 427-31. Waters DL, Wilcken B, Itwig L, et al. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child Fetal Neonatal Ed 1999; 80: Fl-F7. Chatfield C. The concept of probability. In: Statistics for technology. 3rd edn. London: Chapman&Hall, 1983: 45. Glazener CMA, Ramsay CR, Campbell MK, et al. Neonatal examination and screening trial (NEST): a randomised, controlled, switchback trial of alternative policies for low risk infants. BMJ 1999; 318: 627-32. Strachan DP, Harkins LS, Johnston DA, Anderson HR. Childhood antecedents of allergic sensitisation in young British adults. J A&Q Clin Immunol 1997; 99: 6-12. Kramer U, H&rich J, Wjist M, Wichmann H-E. Age at entry to day nursery and allergy in later childhood. Lancet 1999; 352: 45-54. Vedhara K, Cox NKM, Wilcock GK, et al. Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination. Lancet 1999; 353: 627-31. Black D, Morris JN, Smith C, Townsend P. Better benefits for health: plan to implement the central recommendation of the Acheson report. BMJ 1999; 318: 724-27. Barker DJP. The rise and fall western diseases. Nature 1989; 338: 371-72. Barker DJP. Mother, babies and health in later life. Edinburgh: Churchi Livingstone, 1998: 199-201.
su27