Monozygotic twinning, cerebral palsy and congenital anomalies.

BACKGROUND: The majority of cases of cerebral palsy (CP) have their pathogenesis during fetal development and are a form of congenital anomaly, the aetiology of which is uncertain. Anomalous development of other organs evident at birth is also a congenital anomaly. A small proportion of these are known to be caused by chromosomal or gene abnormalities, environmental teratogens and dietary deficiencies. The majority are of unknown aetiology. METHODS: A review of monochorionic (MC) monozygotic (MZ) placentation in the pathogenesis of congenital anomalies and CP was conducted using the PubMed, MEDLINE, EMBASE and Cochrane databases. RESULTS: Zygote division and MC placentation have serious implications for the development of both conceptuses. Most reports observe predominantly cerebral abnormalities in one or both conceptuses. These cerebral abnormalities often present as CP or other disabilities attributable to central nervous system impairment. In addition to the anomalies in central nervous system development, anomalies in the fetal development of a wide variety of other organs have been reported with MC MZ twinning. CONCLUSIONS: CP and congenital anomalies share a common pathogenic mechanism attributable to MZ twinning. These abnormalities in singletons are coincident with very early loss of one conceptus. The quantitative contribution of monozygosity and monochorionicity to the genesis of CP and congenital anomalies needs to be made.

Congenital anomalies in multiple births after early loss of a conceptus.

BACKGROUND: Congenital anomalies are more common in twins than singletons but in the majority, aetiology is not known. Our aim was to test the hypothesis that survivors of an early loss in a multiple conception, compared with all singletons, are at increased risk of congenital anomaly. METHODS: Data were abstracted from the UK population-based Northern Multiple Pregnancy Register and Northern Congenital Abnormality Survey, 1998-2004. RESULTS: Among 3311 twin conceptions, both conceptuses were lost at <16 weeks gestation in 67, and one conceptus in 142 conceptions. Of the 142 singleton survivors, two died in infancy, two were terminated for a congenital anomaly and 11 of 138 had a congenital anomaly (prevalence 915.5 per 10,000 births). There were 197 congenital anomalies among 5948 registered twin births (331.2 per 10,000). The relative risk (RR) of congenital anomalies in a singleton with early loss of a conceptus and twins was 2.40 [95% confidence interval (CI): 1.34-4.29]. There were 4265 infants with a congenital anomaly among the 206 914 singletons [206.1 per 10,000 births: RR twin:singleton 1.61 (95% CI 1.40-1.89)]. CONCLUSIONS: A highly significant increase in the risk of congenital anomaly in survivors from a multiple conception following early loss of a conceptus supports the hypothesis that many congenital anomalies are associated with monozygotic multiple conceptions.

Life expectancy in severe cerebral palsy.

Cerebral palsy comprises an important component of paediatric and obstetric practice and has major medico-legal implications. The prognosis for survival in cerebral palsy determines the financial provision made in cases that come to litigation. Issues of data quality and estimation methods are critical. Estimating the probability of survival in cerebral palsy based on clinical experience is liable to serious error unless numerical data can be produced. Only an actuarial analysis based on a standard life table of cases of cerebral palsy will enable a valid estimate of survival. Construction of the table requires a total cohort of cases of cerebral palsy with their date of birth. Each case must conform to a specified definition of the syndrome. Notification of all those who die, with their date of death is mandatory. Estimating the probability of survival according to the severity of functional disability requires specific definitional criteria for each severity category and for those categories to be mutually exclusive. Survival is significantly poorer in those with severe disability. Severe cognitive, motor (manual and ambulatory), and visual disabilities have independent effects on the probability of survival. Severe hearing disability does not add additional information when the other four functional disability categories are included.

General Certificate of Secondary Education performance in very low birthweight infants.

AIM: To compare children of very low birth weight with matched controls for their performance in the General Certificate of Secondary Education (GCSE). METHODS: GCSE examination results of 167 children of birth weight < or =1500 g attending mainstream schools and without clinical disability and 167 individually matched classroom controls were analysed. RESULTS: In 143 instances, both children of a matched pair were entered for examination in one or more GCSE subjects. The total points score obtained was greater in the comparison group than in the index cases (difference between means 4.45: 95% CI 0.95 to 7.94; p = 0.01). The mean point score per examination subject was also significantly greater in the comparison group than in the index cases (mean of differences 0.43: 95% CI 0.12 to 0.73; p < 0.01). CONCLUSIONS: As the children were closely matched for school and several social variables, factors acting during fetal or early postnatal development of very low birthweight infants probably compromise performance in the GCSE examination to a greater extent than school or childhood social environmental factors.

Lung function and respiratory health in adolescents of very low birth weight.

AIMS: To determine if very low birth weight (VLBW; birth weight <1500 g) is associated with reduced lung function and respiratory health in adolescence and, if it is, whether this impairment is associated with prematurity or intrauterine growth restriction. METHODS: A geographically defined cohort of 128 VLBW infants and an age, sex, and school matched comparison group born in 1980/81 were studied. The cohort and comparison group were assessed at 15 years of age. The birth weight ratio of the index cases (observed birth weight/expected birth weight for the gestation) was determined to assess the degree of growth restriction. Respiratory support received during the neonatal period was obtained from hospital records. Smoking habits and respiratory morbidity were obtained through questionnaires. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow when 25-75% of FVC is expired (FEF(25-75%)) were measured using a portable spirometer. The values are expressed as percentage predicted for height, age, and gender using standard reference values. Adjustments were made for smoking habits of mother and children. RESULTS: The differences in means between index and comparison groups for FEF(25-75%) (-12.42%; p < 0.001) and FEV1/FVC (-3.53%; p < 0.001) ratio were statistically significant. The differences in FVC and FEV1 were not significant. No correlation was found between the birth weight ratio and lung function among the index cohort. Chronic cough, wheezing, and asthma were more common among the index cohort than in the comparison group. Within the index group, there was no difference in lung function between those who received and those who did not receive respiratory support. CONCLUSION: Adolescents who were VLBW compared with matched controls showed medium and small airways obstruction. This was associated with prematurity rather than intrauterine growth restriction or having received respiratory support during the neonatal period. The index VLBW cohort compared with their controls were also more prone to chronic cough, wheezing, and asthma.

The epidemiology of sudden infant death syndrome.

BACKGROUND: Twins compared to singletons are at increased risk of sudden infant death syndrome (SIDS). AIMS: To compare the epidemiology of SIDS in twins and singletons and to test the hypothesis that monozygous (MZ) were at greater risk of SIDS than dizygous (DZ) twins. METHODS: Data from the Office for National Statistics on all registered live births and infant deaths with registered cause of death "sudden unexpected death in infancy" in England and Wales from 1993 to 1998 were obtained, together with the registered birth weight and, for twins, whether they were of like or unlike sex. RESULTS: The crude relative risk of SIDS in twins is twice that in singletons. There has been a significant temporal decline in SIDS mortality. There is also a significant increase in risk with decreasing birth weight for both twins and singletons. The birth weight specific risk of SIDS in all except for those > or =3000 g is greater in singletons than in twins. There is no significant difference in risk of SIDS in like compared with unlike sex twins. CONCLUSIONS: In spite of a lower risk of SIDS in twins compared with singletons for each birth weight group <3000 g, one component of the higher crude relative risk of SIDS in twins is attributable to the higher proportion of twins that are of low birth weight. A second component is the higher risk in twins compared with singletons for those of birth weight > or =3000 g. Like sex are at no greater risk than unlike sex twins, which suggests that zygosity is not a significant factor in SIDS.

Neurological outcome in twins.

Twins are at greater risk of death and severe morbidity than singletons which is in excess of that attributable to their greater prematurity. Monozygous, specifically monochorionic, twins are at greater risk than dichorionic twins. The major morbidity is neurological impairment usually presenting as cerebral palsy or severe learning disability and frequently, but not always, associated with fetal death of a co-twin. The likely pathogenesis of the neurological impairment is ischaemia attributable to haemodynamic imbalance via placental vascular anastomoses. In addition to the neurological impairment, congenital cardiac, renal, intestinal and other anomalies are more common but discordant in monozygous twins. It has been hypothesized that cerebral palsy and other neurological impairment in apparently singleton infants is attributable to early loss of a twin, the 'vanishing' twin phenomenon. It is also postulated that other congenital anomalies in singletons may be attributable to the same phenomenon.

Cerebral palsy in twins: a national study.

BACKGROUND: Cerebral palsy is more common in twins than singletons. Among twins, if one twin suffers a fetal death or dies in infancy, the prevalence of cerebral palsy in the surviving co-twin is considerably increased, and those from like-sex pairs are particularly at high risk. AIM: To compare birthweight specific cerebral palsy prevalence in like-sex and unlike-sex twins where both twins survive infancy and to provide a comparative and composite picture of cerebral palsy prevalence according to whether a co-twin died or where both twins survived. METHODS: Parents of twins born in England and Wales in 1994 and 1995 completed a booklet with open ended questions asking whether their twins had any medical, physical, visual, genetic, or chromosomal problems. Any mention of cerebral palsy, hemiplegia, diplegia, or quadriplegia allowed the child to be included as a case of cerebral palsy. Birthweight specific prevalence rates of cerebral palsy were determined for like and unlike-sex twins in birthweight groups < 1000 g, 1000-1499 g, 1500-1999 g, 2000-2499 g, and > or = 2500 g. RESULTS: When both twins survived infancy, like-sex were at greater risk of cerebral palsy than unlike-sex twins, but the difference was not statistically significant. If both twins survived infancy, the birthweight specific prevalence of cerebral palsy was significantly less than if the co-twin had died. CONCLUSIONS: Among the generality of twins, like-sex compared with unlike-sex twins are at greater risk of cerebral palsy particularly if one twin suffers a fetal or infant death. Although it is not possible to subdivide the twins according to zygosity, it is postulated that monozygosity and, specifically, monochorionicity may be the crucial feature that leads to the higher prevalence of cerebral impairment among like-sex twins.

Effects of cognitive, motor, and sensory disabilities on survival in cerebral palsy.

BACKGROUND: Cerebral palsy presents with a range of severity of cognitive, motor, and sensory disabilities, which might affect survival. AIMS: To quantify the effects of motor, cognitive, and sensory disabilities, year of birth, birth weight, and gestational age on survival in cerebral palsy. METHODS: A cohort of children with cerebral palsy born between 1966 and 1989 to mothers resident in a defined geographical region was subdivided into early impairment (EICP: cerebral insult prenatally or within 28 days of birth) or late impairment (LICP: insult at least 28 days after birth). Deaths are notified by the National Health Service Central Register. Birth and disability details were obtained from clinical records. Survival analyses were carried out. RESULTS: Severe motor disability was associated with a 30 year survival of 42% and severe cognitive disability with a 30 year survival of 62%. Severe visual disability was associated with a 30 year survival of 38%, but the association of survival with hearing disability was weak. EICP had better survival than LICP but the difference was not significant after allowing for severity of functional disabilities. Normal birth weight infants (>/= 2500 g) showed no birth cohort effect, but the 10 year survival of low birth weight (<2500 g) infants declined from 97% for 1966 to 89% for 1989 births. CONCLUSIONS: Survival in cerebral palsy varies according to the severity and number of functional disabilities and by birth weight. Among low birth weight children, survival declined steadily from 1966 to 1989 after allowing for disability. The disabilities reported do not capture all the factors affecting survival of preterm infants.

Fetal or infant death in twin pregnancy: neurodevelopmental consequence for the survivor.

AIM: To determine the neurodevelopmental morbidity in the surviving twin after fetal or infant death of the co-twin. METHODS: Twin pregnancies with an antepartum or infant death delivered between 1981 and 1992 were identified from the Northern Perinatal Mortality Survey. Information on the neurodevelopmental morbidity of infant survivors of a deceased co-twin was obtained by a questionnaire sent to the community paediatrician or general practitioner. RESULTS: A total of 111 children who survived infancy after the fetal death of the co-twin (group 1) and 142 from liveborn twin pairs in which one twin died in infancy (group 2) were traced. Responses were received from 97 (87%) and 130 (92%) respectively. In group 1, the cerebral palsy prevalence was 93 (95% confidence interval (CI) 43 to 169) per 1000 infant survivors; it was more common in like-sex pairs (8/70) with a prevalence of 114 (95% CI 51 to 213) compared with 45 (95% CI 1 to 228) per 1000 infant survivors in unlike-sex pairs (1/22). The overall prevalence of neurodevelopmental morbidity (including developmental delay) was 175 (95% CI 106 to 266) per 1000. In group 2, the cerebral palsy prevalence was 154 (95% CI 84 to 223) per 1000 infant survivors in like-sex (16/104) and 77 (95% CI 9 to 251) in unlike-sex (2/26) survivors; the overall prevalence of neurodevelopmental morbidity was 246 (95% CI 172 to 320) per 1000. CONCLUSIONS: The risk of cerebral palsy is increased in the surviving twin after a fetal or infant co-twin death compared with the general twin population. Like-sex twins are at greater risk than unlike-sex. The probable cause, in addition to the consequences of prematurity, is twin-twin transfusion problems associated with monochorionicity.

Twins and cerebral palsy.

In a national follow-up study of twin births, monozygous compared with dizygous twins were at significantly increased for both to die in utero, one to die in utero and the co-twin to die in infancy, or both to be livebirths but both die in infancy. The prevalence of cerebral palsy among survivors of a co-twin fetal death was 80.2 and other cerebral impairment was 107.0 per 1000. Many apparently singleton cases of cerebral palsy and impairment may be due to fetal death of a twin that has not been recognized or has been recognized but not registered.

Cerebral palsy in the surviving twin associated with infant death of the co-twin.

BACKGROUND: Monozygotic twins are at greater risk of dying and of serious morbidity than dizygotic twins, and both are at greater risk than singletons. This is only partly explained by the higher proportion of low birthweight infants among twins. AIM: To compare, in same sex and different sex twins, birth weight specific neonatal death rates and cerebral palsy prevalence rates in the surviving twin when the co-twin has died in infancy. METHODS: Analysis of birth and death registration data for same sex and different sex twins for England and Wales 1993-1995 where both were live births. Death certificates of all liveborn twins who died were obtained from the Office for National Statistics. A questionnaire was sent to the general practitioners of all surviving co-twins to determine if the child had any disability. RESULTS: The neonatal death rate in same sex twins was 25.4 and in different sex twins 18.0 per 1000 live births (death rate difference 7.4; 95% confidence interval 4.7 to 10.1; p < 0.001). The higher neonatal death rate in same sex compared with different sex twins is attributable to the higher proportion of same sex twins with low birth weight. Prevalence of cerebral palsy in the low birthweight group (< 1000 g) was marginally higher in same sex (224 per 1000) than different sex (200 per 1000) twin survivors. In the birth weight group 1000-1999 g, same sex twin survivors were at a significantly higher risk of cerebral palsy than those of different sex: 167 v 21 per 1000; difference 145 (95% confidence interval 44 to 231; p < 0.01) per 1000 infant survivors. CONCLUSION: There are two components to the cause of cerebral palsy in twins. Immaturity per se predisposes to cerebral damage. Also, same sex twins may sustain cerebral damage that is in excess of that due to immaturity.

Dermatoglyphic patterns, very low birth weight, and blood pressure in adolescence.

AIMS: To test the null hypotheses that finger and palm prints have no relation with fetal growth or adolescent blood pressure. METHODS: All 128 singleton, unimpaired, very low birth weight (VLBW; < or =1500 g) infants born to mothers resident in the county of Merseyside in 1980 and 1981 were studied retrospectively. The comparison group consisted of 128 age, sex, and school matched children. Main outcome measures were blood pressure at age 15 years, birth weight ratio, fingerprint patterns, and palmar AtD angles. RESULTS: The VLBW index population had a significantly higher systolic blood pressure than the comparison group (mean difference 3.2 mm Hg). The difference in diastolic blood pressure between the VLBW index and the matched comparison group was not significant. No significant differences were found in the palmar AtD angles or in the fingerprint proportions of arches, loops, and whorls and no correlation was found between fingerprint patterns and blood pressure. Among the VLBW index population, both height and right palmar AtD angle were independently and significantly correlated with and explained 12.1% of the variance in the systolic blood pressure. Birth weight ratio, as a measure of fetal growth restriction, had no significant correlation with systolic blood pressure. CONCLUSIONS: The higher systolic blood pressure of adolescents who were of very low birth weight compared with the matched comparison group is not associated with fingerprint patterns or birth weight ratio as markers for fetal growth restriction.

The effects of assisted reproduction on the trends and zygosity of multiple births in England and Wales 1974-99.

Assisted reproductive techniques have led to an increase in the proportion of maternities that are multiple. Though predominantly dizygotic, they are at greater risk of monozygotic division than those spontaneously conceived. England and Wales data 1974-99 on stillbirths and livebirths were analysed for 4 periods: 1974-80 (pre-assisted reproduction; 1982-8; 1989-91 (pre-redefinition of stillbirth); 1993-9 (post-redefinition of stillbirth). For twin data, Weinberg's rule was applied to estimate the proportions that were mono- (MZ) and dizygotic (DZ). Compared with the period before assisted reproduction, the most recent period shows an increase in twin maternities of 3.81 per 1,000 comprised of 3.22 (95% CI 3.10 to 3.33; p < 0.0001) DZ and 0.60 (95% CI 0.51 to 0.68; p < 0.0001) MZ twins. It is estimated that 15.7% of assisted reproduction twins are MZ. Higher order multiple births showed an increase of 3.06 (95% CI 2.85 to 3.29; p < 0.0001) per 10,000 maternities. Stillbirth rates in MZ twins are of the same order of magnitude as those in higher order multiple births but higher than those in DZ twins. The improvement in stillbirth rates over the 26 year study period is of the same order magnitude in singletons, DZ and MZ twins and higher order multiples. Assisted reproduction has led to a significant increase in the proportion of MZ twins. These are at high risk of fetal death and this needs to be considered when local stillbirth and perinatal mortality rates are used in auditing obstetric services.

Errors in registered birth weight and its implications for mortality statistics.

BACKGROUND: Birth weight mortality statistics are important for examining trends and monitoring the outcomes of neonatal care. AIM: To determine the effects of errors in the registered birth weight on birth weight specific mortality. METHODS: All twins born in England and Wales during 1993-95 comprise the denominator population. For those twins that died, the Office for National Statistics (ONS) provided copies of the death certificates. From the information on the death certificates, the registered birth weight was validated and amended using predetermined rules. The neonatal, postneonatal, and infant mortality rates were recalculated. RESULTS: In 2.5% of cases the registered birth weight was "not stated" and in others there were miscoding errors. Important differences between published and amended birth weight specific mortality rates especially in <500 g and >/=3500 g groups were evident. CONCLUSIONS: The bias arising from these errors should be taken into account in interpreting mortality rates and their trends.