Fetal intracranial haemorrhage (ICH) is a rare antenatal complication that increases perinatal morbidity and mortality and may cause neurodevelopmental delay in surviving babies [2, 4]. Fetal ICH may be intraaxial or extraaxial and can be subdivided into five types- intraventricular haemorrhage (IVH), cerebellar haemorrhage, subdural hematoma (SDH), subarachnoid haemorrhage (SAH) and intraparenchymal haemorrhage [1]. Out of these, IVH is the most common type. The prognostic outcome is related to the severity of the bleeding and associated brain injury with a grave prognosis seen in higher grades of IVH [2, 3, 6]. SDH in asymptomatic neonates have a peculiar distribution along occipital lobes, tentorium cerebelli and posterior fossa [7]. Better prognosis is seen in SDH when the underlying etiology is identifiable [4]. But unfortunately, the majority of cases are idiopathic [8]. The two most common risk factors for fetal ICH are maternal trauma and fetal coagulopathy [3]. However, there is a long list of predisposing factors that may be responsible for fetal ICH. The maternal factors include trauma, advanced maternal age, hypertension, preeclampsia or eclampsia, coagulopathy, alloimmune thrombocytopenia, seizures, viral or bacterial infection (TORCH, parvovirus B -19 etc.), amniocentesis, medications (warfarin or cholestyramine) and illicit drugs (cocaine2). The fetal factors responsible for ICH are congenital coagulopathy with factor V and factor X deficiency, haemorrhage into a congenital tumour, twin–twin transfusion syndrome, demise of a co-twin, and alterations in maternal or fetal blood pressure [1, 2, 6, 8]. Apart from these, genetic factors like disruption in COL4A1, COL4A2, F11, F7, FGA, VWF, GP1BA, JAM3 and X-linked GATA1 genes have also been implicated [1].
The exact pathophysiology of fetal ICH is not clear. It is postulated that IVH in preterm infants may be because of hypoperfusion–reperfusion cycle. Around 80% of upper body blood flow goes to the brain, so when superior vena cava flow is low, the cerebral blood flow may also be low causing ischemic insult especially to germinal matrix which is the watershed area and vulnerable. So, this early low cerebral flow may be a predisposing factor for IVH [8].
There is a reported increased rate of left-side hemispheric involvement as was also seen in our case. This may be due to an inherent susceptibility of the blood vessels in the left hemisphere to rupture or to a better right carotid blood supply in fetal hypotensive situations [8]. The fetal ICH cases are mostly identified during the third trimester, again also seen in our case. The plausible explanation for this may be that there is a high brain to fluid ratio in fetus resulting in increased mobility of the fetal brain. As the pregnancy advances, the fetal head gets nearer to uterine wall and maternal abdomen and by apparently minor direct trauma to the maternal abdomen, the chances of tearing of cerebral bridging veins rises, leading to SDH [2, 4]. As the routine third trimester ultrasound scan in not done in many countries in the absence of risk factors, the number of fetal ICH cases may be underestimated.
Obstetric ultrasound can diagnose fetal ICH given various sonographic features such as loss of normal cerebral landmarks, intracranial echogenicity, lateral ventriculomegaly, avascular intracranial mass, hyperechoic acute clot adherent to nodular choroid plexus, hyperechoic clot outlining cerebral cortex, hyperechoic nodular ependyma, increased periventricular white matter echogenicity, porencephaly, hydranencephaly, macrocephaly, midline deviation of cerebral falx, and intracranial fluid collection [4, 6]. Echogenic bowel, hydrops fetalis and Doppler parameters like reversed diastolic flow in the MCA and elevated PSV of MCA which are indicative of fetal anaemia may also be seen, albeit in lesser number of cases [4]. Acute SDH is seen as echogenic collection in the intracranial subdural region while chronic SDH looks like cerebrospinal fluid only. If the SDH is showing mixed echogenicity, it is either in the transitional phase or there is acute bleeding in chronic hemorrhage [4]. Ultrasound has a low sensitivity in diagnosis of fetal ICH particularly in late gestation when it is most likely to occur. The factors like maternal obesity, overlapping fetal parts, challenging fetal position, ossified skull and multiple pregnancies may further hinder sonographic information. Fetal MRI can overcome all these sonographic limitations and can act as a problem-solving imaging modality [6]. So, in case the sonographic findings are suspicious for ICH, fetal MRI should be considered for confirmation of the diagnosis and to age hemorrhage. A complete genetic analysis including whole exome sequencing may be required to elucidate a genetic cause of fetal ICH that may be important for parental counselling so that at risk future pregnancies may be foreseen [1].
Aspirin with its first obstetric usage in 1985 [5, 9], is being extensively prescribed worldwide in pregnant females having high risk of developing preeclampsia. Preeclampsia is defined as hypertension and proteinuria diagnosed after 20 weeks of gestation [5]. The pregnant women with pre-eclampsia have escalated platelet activation as indicated by shortened APTT and hypercoagulable state. Aspirin is a cyclooxygenase inhibitor and reduces the thromboxane A2 (TXA2) to prostacyclin (PGI2) ratio. TXA2 is a vasoconstrictor, promotes platelet aggregation and causes thrombus formation. While PGI2 has a reciprocal effect, it is a vasodilator and the most effective endogenous inhibitor of platelet aggregation. Aspirin is considered low dose if taken less than 300mg/day [10]. Low dose aspirin (LDA) selectively inhibits the secretion of TXA2 and does not change the secretion of PGI2 by endothelial cells with an overall effect of dilatation of blood vessels and lowering blood pressure. Moreover, it also prevents platelet aggregation thereby inhibiting formation of small thrombi thus preventing pre-eclampsia [5, 9].
The guidelines for screening modalities, target population, gestational period and dosage of aspirin administration for preeclampsia varies considerably from country to country. The general recommended daily dosage is between 80 -150mg. The efficacy of aspirin increases with the increasing dose. However, the safety with a daily dosage of > 100mg is not well established [5, 9]. According to the American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal – Fetal Medicine (SMFM) guidelines 2018, prophylactic aspirin should be started at 81 mg/ day between 12 to 28 weeks, preferably before 16 weeks of gestation till delivery [11]. But some studies advocate the treatment to be initiated at 8–16weeks’ gestation to reduce the risk of the severe and preterm forms of preeclampsia and risk of fetal growth restriction (FGR), preterm birth and perinatal death as well. This metanalysis also concluded that aspirin was best avoided in the last month of pregnancy and should be stopped at 36 weeks of gestation to prevent fetal ICH, although the chances are rare if dosage is below 100mg/day [10]. The indications to start LDA are presence of one high risk factor or presence of two or more moderate risk factors for preeclampsia in the pregnant female. LDA has a proven efficacy and unquestionable benefit in reducing cases of secondary eclampsia [5, 9, 11]. However, as far as the still births, FGR, preterm births and early pregnancy loss are concerned, it has conflicting results [11]. LDA is not usually associated with increased risk of haemorrhagic complication, placental abruption, post-partum haemorrhage, congenital anomalies, early ductal closure with persistent pulmonary hypertension or fetal ICH. But a few studies have shown increased incidence of gastroschisis [11]. The teratogenic effect of aspirin in the form of cardiopathies and limb anomalies are seen only at a high dose of 650 to 2600mg per day [5]. Rare cases of high fetal bleeding tendencies have also been reported as the aspirin crosses placental barrier and hinders fetal platelet aggregation [5, 9]. The inhibition of platelet thromboxane A2 formation has been observed in the neonates of women taking 100 mg of aspirin daily [10]. The reported maternal side effect of aspirin is mainly gastrointestinal discomfort seen in 10% of cases [5].
A detailed history, blood tests and genetic analysis are vital to elucidate the underlying cause of ICH. The pregnant woman should be cautioned about the dilemma in predicting perinatal outcomes based on ultrasonographic findings alone. Termination of pregnancy is an option in view of the potential significant neurological deficit. If she chooses to continue the pregnancy, serial sonography is required to follow the size of SDH and monitor the PSV of MCA. There are no specific guidelines for the mode of delivery; whether vaginal or by caesarean section which has to be individualized. Blood tests are required in neonatal period to rule out anaemia and coagulopathy [4].
The risk with regards to potential fetal haemorrhagic complications is low with LDA, but cases of such adverse effects may rise in number with inadvertent and widespread use of aspirin in pregnancy. With the broadening of indications, there is routine and extensive prescription of LDA. Hence, patient selection should be optimized for a favorable benefit to risk ratio and the needless exposure of pregnant females to aspirin should be avoided. However, due to rarity of fetal ICH, multicentred, large scale studies are required to collect high quality data to reach a robust conclusion.