Intracranial hemorrhage (ICH) develops most often in premature newborns, while its occurrence is relatively uncommon and may represent an incidental finding in term neonates (1, 2). Thanks to increased clinical awareness and improved neuroimaging techniques, however, ICH at term has been diagnosed more often in recent years (1, 3). In some cases, the clinical impact of such a condition may deeply influence the perinatal course and affect neonatal morbidity and mortality (4–7). ICH may develop in utero or after birth. The rates of fetal ICH are 0.46 per 1,000 deliveries and 0.9 per 1,000 pregnancies at referral centers (8). In full-term infants, possible risk factors for the development of perinatal cerebral bleeding include infections, malformations, asphyxia, and thrombophilia (4, 5, 7, 9). Besides these conditions, familial susceptibility with a genetic predisposition to a hereditary form of porencephaly may play a role, but available data are still inconsistent.

Type IV collagen a1 chain (COL4A1) gene mutations are responsible for a hereditary autosomal dominant cerebrovascular disease, characterized by a wide phenotypical spectrum, which may include the development of ICH. To date, only a relatively small number of neonates carrying COL4A1 gene mutations and developing ICHs has been reported (10–15). However, the diagnosis of COL4A1 gene mutations is probably underestimated because of the failure to search for the mutation because of its heterogeneous clinical presentation. When focusing on the perinatal period, the data available are even more infrequent, and the exact clinical features of such disorders are still far from clear.

The aim of this study was to describe the case of two term neonates affected by ICH of apparently unclear origin who showed mutations of the COL4A1 gene, expanding the spectrum of perinatal disease attributable to COL4A1 mutations and adding information in a field where knowledge is still far from clear. This study also provides a review of the currently available scientific literature on this topic, specifically focusing on the perinatal period.

We describe the clinical history of two neonates with apparently unexplainable ICH. A COL4A1 gene mutation was detected in both patients.

COL4A1 and type IV collagen a2 chain (COL4A2) form the (a1)2(a2) IV heterotrimers and represent key components of basement membranes (28–31). COL4A1 is detectable ubiquitously in all tissues, including the vasculature, renal glomeruli, ocular structures, and muscles, and plays a role in the development of basement membrane during embryogenesis, in the cohesiveness of these membranes, and in the maintenance of vascular tone (32–34). The COL4A1 gene is located on the telomeric region of 13q (13q34) and is made up of 52 exons (35). Mutations of the COL4A1 gene may lead to a wide range of abnormalities variably affecting the brain (including the development of ICHs), retinal vasculature, ocular structures, renal glomeruli, and muscles, but no clear genotype–phenotype association has been identified yet, even within the same family (15). COL4A1 mutations are inherited as an autosomal dominant trait and have near 100% penetrance with variable expression; de novo mutations or low-level parental mosaicism have been described (25).

Neonates described in the present case series were both born at term after pregnancies with no history of infections, traumatic injuries, or thrombotic events and had a normal cardiorespiratory adaptation at birth. The heterozygosity of the MTHFR gene was highlighted in both cases, but no other anomalies were detected concerning the coagulative tests, platelet counts, and thrombophilia screening. ICH was diagnosed postnatally in both cases, although the radiologic findings of patient 1 showed the presence of glio-malacic lesions that were presumably of antenatal origin; even if it was not possible to assess the exact onset of the ventricular dilation detected in patient 2, the entity of the lesion was probably consistent with a prenatal origin. In our cases, prenatal MRI was not performed because of the late detection of anomalies during pregnancy in the first case and the low risk of pregnancy in the second case. However, as recently described by George et al. (36), prenatal COL4A1/A2 variations can show a range of ICH affecting the frontal lobes and basal ganglia, such as minor and/or unifocal ICH, as well as multifocal and bilateral lesions. In all cases of prenatal ICH, genetic testing for COL4A1/A2 variations should be taken into consideration because of the wide range of severity observed on fetal brain MRI. However, both patients came to our observation in the postnatal period; therefore, we had no other information regarding the decision-making process that took place during pregnancy.

The neurologic outcome was heterogeneous since it ranged from normal neurodevelopment (patient 2) to severely impaired neurologic development (patient 1).

To date, only a few authors have specifically investigated the role of COL4A1 mutations in the pathophysiologic mechanisms leading to intracerebral bleeding, and most of them focused on pediatric/adult patients rather than on neonates (37–39). Vahedi et al. found that some COL4A1 gene mutations may remain completely asymptomatic for years with no vascular changes on brain MRI, suggesting that the clinical expression may be heterogeneous even within the same family (37). Such findings are in agreement with subsequent data showing that brain MRI is abnormal in the majority of COL4A1-mutated patients (even in asymptomatic ones), but normal brain MRI may also be detectable in some mutation carriers with no brain manifestations (39).

Although there has been increasing interest regarding this condition in recent years, clinical experience about COL4A1-related perinatal ICHs only results from sporadic case reports (Table 1). Gould et al. were the first to demonstrate in both a mice model and in humans that mutations in the COL4A1 gene may compromise the vascular basement membrane and lead to perinatal ICH (10). Since then, other authors reported the association between COL4A1 gene mutation and perinatal ICHs, but no exact genotype–phenotype association has been identified yet.

The involvement of the central nervous system in the presence of COL4A1 gene mutations varies widely from case to case in terms of onset timing, injury entity, and location (17–27, 40, 41). Features suggestive of COL4A1 mutations include severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, especially when such injuries are associated with porencephaly (27).

A deeper understanding of the relationship between COL4A1 mutations and the development of perinatal porencephaly may have important implications for disease prevention and optimization of perinatal care. Some authors suggested a possible interaction between environmental triggers and the genome (10). Although some neonatal cases were diagnosed after birth (as in our cases), the postnatal neuroimaging features were mostly consistent with an antenatal onset of ICH (Table 1).

It is crucial to emphasize the importance of the mother–placental–fetal triad in the developing of illness processes that cause brain abnormalities in fetuses or newborns. Gene–environment interactions affect the brain development of newborns, children, and the mother–placental–fetal triad in both the short and long term. These interactions start at conception (40). During the initial 1,000 days of brain maturation, critical/sensitive periods are more likely to result in lifelong developmental neuroplasticity (40). The hazardous stressor interaction between internal and external sources modifies the neural exposome by means of maladaptive developmental neuroplasticity. The first 1,000 days are when epilepsy and developmental problems mostly manifest (41).

Prenatal environmental factors, such as premature uterine contractions or other traumatic injuries, may activate some triggering mechanisms leading to vascular damage in at-risk patients (17, 42). It was hypothesized that specific preventive strategies, such as cesarean delivery instead of spontaneous delivery in at-risk individuals, might decrease the stress on the abnormal brain vasculature and, therefore, the severity of ICH in high-risk populations (10); however, further studies are needed. Nevertheless, according to the literature, perinatal ICHs occurred in neonates born both by spontaneous and cesarean delivery, and brain injury has sometimes already occurred during pregnancy (Table 2).

Finally, the neonates described in the literature were born either at term or prematurely (Table 2), and it might be put forward that some COL4A1 mutations may carry a higher risk for preterm birth and/or higher susceptibility to environmental factors than others (17).

Regarding the importance of prevention, it is also important to highlight that many children with developmental disabilities live in low-resource countries low or middle income country (LMICs) or high-income desert countries (HICMDs).

In these places, it is even more important to implement strategies aimed at identifying at-risk pregnancies as early as possible to provide families with accurate diagnoses and subsequent effective interventions. To this end, a biosocial model was developed that emphasizes women's reproductive health with trimester-specific maternal and pediatric health interactions (43).

The ability to perform genetic, neurophysiological, and neuroimaging assessments improves clinical decision-making for more effective interventions before pathological expression.

Support for the family, especially in the case of neurological pathologies in which we know how fundamental the first 1,000 days of life are, continues in the postnatal period (40).

Synergy between obstetric and pediatric healthcare providers can reduce neurological morbidities (43).

In conclusion, mutations of the COL4A1 gene as a potential risk factor for perinatal ICH are probably underestimated because of low clinical awareness, poor available data, and wide phenotypical spectrum; COL4A1 mutations should be suspected when otherwise unexplainable ICHs occur prenatally or in the neonatal period; if COL4A1 carriers are identified, familiar genetic counseling is advisable (37, 44); and genetic testing can be performed both prenatally and postnatally (24). There is still a lack of long-term follow-up data about the risk of ICH recurrence as long-term neurologic outcomes are missing. The current gap in knowledge in this field represents a call to action for clinicians/researchers and deserves further investigations.