It is recognised that there is a higher prevalence of congenital anomalies in children with CP than in the general population. However, previous studies have examined the generality rather than specific groups of congenital anomaly.7
The observation has been used to support a prenatal pathogenesis in the majority of children with CP but a pathogenic mechanism that explains the coexistence of CP and congenital anomalies has not been postulated.
The increased risk of congenital dislocation of the hip and talipes in children with CP is probably explained by the muscular weakness that is characteristic of CP affecting in utero positioning of the limbs. Similarly, the excess risk observed for microcephaly and hydrocephaly is the direct consequence of the prenatally acquired cerebral impairment that may be manifest clinically as CP. The coexistence of these anomalies with CP confirm that the cerebral impairment occurs during fetal development. It has been proposed that the form of cerebral impairment may vary depending on the timing of feto–fetal transfusion episodes. The damage to the brain may lead to neuronal migration abnormalities, porencephaly, multicystic encephalopathy, subcortical leucomalacia and other cerebral pathologies.12
Some of these pathologies may manifest clinically as CP, other clinical manifestations may not present with motor disability and will not be diagnosed as CP.
What is already known on this topic
- The cerebral impairment that presents clinically as cerebral palsy occurs prenatally in most cases
- Children with cerebral palsy are at higher risk of other congenital anomalies but the level of risk and the specificity of congenital anomalies are unclear.
What this study adds
- Highly increased relative risks for specific congenital anomalies in children with cerebral palsy are reported.
- The pathogenesis and possible pathogenic pathways linking cerebral palsy and congenital anomalies are postulated.
Some of the children with CP who have other congenital anomalies may have had surgical correction of the latter. It is possible that adverse events during the surgical procedure may result in postnatally acquired CP. Coexisting congenital cardiac abnormalities, particularly those with right to left shunts and polycythaemia will be at heightened risk. However, this mechanism cannot be evoked for the majority of congenital anomalies, including those cardiac anomalies that were not surgically corrected.
The coexistence of so many disparate congenital anomalies with CP suggests that there is probably a common pathogenic mechanism. Intrauterine infection has been implicated as a pathogenic mechanism for CP.15
However, correlation between markers of intrauterine infection and CP should not be inferred as being causal. It is possible that the presence of the remains of a vanished twin predisposes to infection occurring. Perinatal exposure to neurotropic viruses has also been found to be associated with preterm delivery and CP.18
However, evidence of perinatal exposure neither accounts for CP of prenatal origin neither does it provide a satisfactory explanation of the coexistence of CP with a disparate group of congenital anomalies.
An alternative pathogenic mechanism for CP relates to the role of twinning, specifically monochorionic twinning. Death of one twin late in gestation is recognised as being a significant risk factor for CP.19
It has been hypothesised that early loss as a “vanishing” twin may be causal of prenatally acquired CP in apparently singleton infants.25
This hypothesis has been extended to include monochorionic twinning in the pathogenesis of many congenital anomalies.12
While the underlying basis for the hypothesis is monochorionicity in a twin conception, the specific pathogenic pathway for different congenital anomalies may vary. Figure 1 adapts a proposed pathogenic classification of congenital cardiovascular malformations.26
Some anomalies of organ laterality, such as partial or complete situs inversus, atrial isomerism and the heterotaxias—for example, the asplenia/polysplenia syndromes—may be attributable to an abnormality at the time of zygote division. Although cardiac anomalies are most frequently reported among the heterotaxias, extracardiac anomalies of midline fusion such as cleft palate frequently coexist with the cardiac anomaly.27
Laterality abnormalities are a feature of twinning. They are more common in mono‐ than dizygous twins28
and conjoined twins are at particularly high risk.29
Figure 1Pathogenic pathways for cerebral palsy (CP) and congenital anomalies. TOF, tetralogy of Fallot.
Neural crest cells and their migration during embryonic development have an important role in the development of the heart. Perturbation of this process may give rise to abnormalities of conotruncal septation, tetralogy of Fallot and transposition of the great vessels.26
Furthermore, inadequate migration or proliferation of neural crest ectomesenchyme may affect closure of the facial clefts. Similarly, neuronal migration abnormalities produce serious cerebral malformations, many of which are clinically manifest as CP. Twin–twin haemodynamic instability could have a role in a variety of congenital abnormalities attributable to anomalies of neural crest or neuronal migration.
Blood flow and haemodynamic forces also influence the early embryonic development of the heart.31
Disturbance of the laminar blood flow within the primitive cardiac tube results in hypoplasia of some structures and chambers of the heart with reciprocal enlargement of contralateral structures.26
Other congenital anomalies such as intestinal atresias, oesophageal atresia with or without tracheo‐oesophageal fistula and renal agenesis also may be attributable to haemodynamic factors affecting embryonic organ development.
The increased prevalence of congenital anomalies in children with CP may be an underestimate. Post‐mortem examination of a stillbirth or infant who has succumbed to a congenital anomaly may have only a cursory examination of the brain and major cerebral pathology may be missed. Such infants will not have survived long enough to have CP or other clinical manifestation of cerebral impairment recognised. A detailed post‐mortem examination of the brain will allow the underestimate of the coexistence of cerebral impairment and other congenital anomalies to be quantified.
Gene and chromosomal defects and environmental teratogens are undoubtedly responsible for many congenital anomalies. Nevertheless, most anomalies are of unknown aetiology. The coexistence of CP with a wide variety of other congenital anomalies suggests a common pathogenic mechanism that may be distinct from genetic or teratogenic influences. A monochorionic twin conception, with its common placental vasculature and potential for perturbation of inter‐fetal haemodynamics, provides a plausible explanation for such a common pathogenic mechanism. If haemodynamic perturbation is causal of the CP and congenital anomaly in one fetus, reciprocal lethal damage to the co‐fetus is highly probable, resulting in its early loss as a vanishing twin.
To test the hypothesis, ultrasound diagnosis very early in gestation is needed. This may be achieved, fortuitously, by following up women who present very early in gestation for a variety of reasons. Those women who present with a threatened miscarriage, but subsequently deliver a singleton infant, are of particular relevance as the miscarriage may be the vanishing twin. Alternatively a resource intensive study with subsequent long‐term follow up could be designed, inviting women to have an ultrasound examination as soon as pregnancy is suspected.