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Matar and Elsaba: Warfarin- and aspirin-associated fetal intracranial haemorrhage

Introduction and objective

Warfarin can cross the placental barrier and can cause perinatal intraventricular haemorrhage irrespective of maternal INR (international normalized ratio) level. The prevalence of perinatal intraventricular haemorrhage related to maternal warfarin is 4.6–5.1% in autopsy studies of stillbirth.1,2 Previously reported cases of warfarin-associated fetal intracranial haemorrhage in pregnant women with a mechanical heart valve are shown in Table 1. This is a case report of a neonate who experienced perinatal intraventricular haemorrhage related to maternal warfarin.


Warfarin-associated fetal intracranial haemorrhage in pregnant women with mechanical heart valves

Reference Warfarin (mg/day) Start of warfarin (GA) PT/INR Site of haemorrhage Onset of haemorrhage (GA) Delivery (GA) Fetal outcome
Lee et al.3 6–7 14 2.2–3.0 Subdural 23 25 Neonatal death
Robinson et al.4 NA 5 NA Subdural 32 34 Neonatal death
Ville et al.5 3–6 26 1.7–2.5 Intraventricular 32 36 Stillbirth
5–6 15 0.7–1.9 Intraventricular 29 29 Stillbirth
Oswal and Agarwal6 NA 24 NA Subdural 24 24 Termination
Matsuda et al.7 NA 14 NA Subdural 31 31 Alive

[i] GA, gestational age (weeks); NA, not available; PT/INR, prothrombin time/international normalized ratio.

Case report

A male infant was delivered at 31 weeks gestational age by elective lower segment Caesarean section (LSCS) at the request of the parents. Antenatal ultrasound at 26 weeks’ gestation revealed intra- and subdural haemorrhages that developed at different times during gestation, with porencephalic cyst formation and marked hydrocephalus, which on subsequent ultrasongraphy were found to have progressed (Figure 1). Bilateral mild hydronephrosis and dilated fetal intrahepatic vasculature were also evident. The parents requested LSCS to preserve the remaining brain tissue. The 27-year-old mother had been receiving warfarin for 14 years after mitral and aortic valve replacement. She has another boy who is 3 years old and exhibits normal growth and development. Aspirin was added to warfarin because of transient ischaemic attack (INR 3.6–4).


Antenatal ultrasound image showing intracranial haemorrhage with intracranial fluid collection increasing progressively and causing midline shift.


The infant’s Apgar score was 4 and 7 at 1 and 5 minutes, respectively. Birthweight was 2.020 kg and head circumference was 34 cm (above the 97th centile). His vital signs were stable and the anterior fontanelle was wide and full but not bulging. He required nasal support for 1 week. Ultrasound imaging of the brain showed hydrocephalus. Magnetic resonance imaging (MRI) of the brain showed large bilateral subdural haematomas causing severe compression of the cerebral hemisphere with midline shift towards the left side (Figure 2). A haemorrhagic posterior fossa cyst was also noted to be compressing the cerebellar hemisphere. His haemoglobin level was 8.2 g/dl and haematocrit was 26%, and he received packed red blood cell transfusion. His prothrombia (PT) and partial thromboplastin time were normal. The neurosurgeon advised conservative management and to monitor his head circumference regularly. Daily monitoring of head circumference showed that it was increasing by 0.5 cm/week. No surgical interference was carried out. He had mild convulsions, which were controlled by phenobarbitone. He exhibited poor sucking behaviour and was fed through a nasogastric tube. He remained in the Neonatal Intensive Care Unit, Dubai Hospital, for 1 month. The mother was trained for nasogastric tube feeding and discharged with follow-up by a multidisciplinary team, including neonatologist, neurosurgeon, paediatric neurologist and physiotherapist.


Postnatal brain MR image showing large bilateral subdural haematoma. A haemorrhagic posterior fossa cyst can also be seen compressing the cerebellar hemisphere.



Warfarin is used for the prevention of systemic thromboembolism in patients with prosthetic heart valves or atrial fibrillation, for the prevention of myocardial infarction or stroke, and for the treatment of deep vein thrombosis.8 Unfortunately, warfarin is known to have some teratogenic effects. Warfarin embryopathy, characterized by nasal hypoplasia and/or stippled epiphyses, is associated with exposure to warfarin in the first trimester.9

Anomalies of the central nervous system, i.e. agenesis of corpus callosum, Dandy–Walker syndrome, midline cerebellar atrophy and optic nerve atrophy, are associated with warfarin exposure in the second or third trimester.9 Warfarin exposure can also lead to fetal intracranial haemorrhage, as noted in this case.

In the present case, the fetal subdural haemorrhage was assumed to be due to maternal warfarin exposure because (a) warfarin can cross the placental barrier to reach the fetal blood circulation and (b) exposure occurred during the second trimester. The intracranial haemorrhage occurred only after aspirin was added to warfarin, which was administered after the mother experienced a transient ischaemic attack at 24 weeks’ gestation. Aspirin is known to increase the risk of bleeding in patients receiving warfarin.

The rationale for low-dose aspirin is that cyclooxygenase is fully acetylated in the platelets of the presystemic (prehepatic) circulation, but insufficient aspirin is present in the systemic circulation to inhibit arachidonic acid metabolism in other tissues, in particular the systemic vascular endothelium, placental vasculature and the fetus.10 However, there have been reports that even this low dose in a few patients can enter the systemic circulation, and can readily cross the placental barrier and lead to fetal complications.

Prevention of warfarin-induced fetal intracranial haemorrhage is very important as it is fatal in most cases or will lead to hydrocephalus and subsequent mental retardation, as in our case.

To prevent fetal haemorrhage, the best management of pregnant women with prosthetic heart valves is the discontinuation of warfarin and use of only heparin throughout the pregnancy. This is because it is well known that heparin cannot cross the placental barrier. Indeed, no case of fetal haemorrhage associated with maternal heparin injection has been reported. However, women treated with heparin are more prone to spontaneous abortion and stillbirth.9,11 In addition, some studies have revealed that unfractionated heparin is more dangerous than warfarin in pregnant women with mechanical heart valves.11 Low-molecular-weight heparin can be a suitable alternative regimen in those women, but no randomized studies exploring permanent use of low-molecular-weight heparin are yet available. It is used only during the first trimester and some weeks before delivery, during which times warfarin is contraindicated.


In conclusion, warfarin-associated fetal haemorrhage is a fatal event. The risk may be increased by concomitant use of aspirin. Unfortunately, at present there is no alternative regimen that can replace warfarin for pregnant women with mechanical heart valves. Regular monitoring of the fetus using ultrasound and strict control of warfarin dose with regular measurement of PT are the best ways to prevent intrauterine fetal death due to bleeding, although, at present, there is no direct way to prevent fetal intracranial haemorrhage.



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