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Retrospective Obstetric Study in Severe Congenital Protein C Deficiency
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Retrospective Obstetric Study in Severe Congenital Protein C Deficiency


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The study aims to retrospectively investigate the obstetric history of mothers who have given birth to children with severe congenital protein C deficiency (SCPCD) to determine the incidence of fetal loss during pregnancy and document the occurrence of previous neonatal death, which might be due to undiagnosed SCPCD.

Patients with severe congenital protein C deficiency (SCPCD) typically present in the neonatal period with purpura fulminans often accompanied by evidence of intracranial and retinal vessel thrombosis.  The condition is autosomal recessive and heterozygous parents often have with slightly low protein C levels (normal range 65 – 135IU/dl). Severe protein C deficiency is defined as having a protein C level <1IU/DL [Goldenberg & Manco-Johnson 2008 (1)]. Occasionally patients have levels in the lower end of the moderate range (1 – 20 IU/dl.) For the purposes of this study, we will include patients with protein C levels <1IU/dl in whom acquired protein C deficiency has been excluded (both parents heterozygous, repeat low protein C levels or mutation analysis shows homozygosity or compound heterozygosity). We will also include patients with protein C levels in the range 1 – 20 IU/dl if they have a typical clinical presentation and acquired protein C deficiency has been excluded.

The estimated prevalence of SCPCD based on a carrier rate of 0.3% of the population is 2.25/million. There should be 135 cases in the UK. However, there are only 10 UK cases so far reported.  Similarly, in the USA, there are fewer than 20 cases (1). This discrepancy could be due to high fetal loss of affected babies due to miscarriage or stillbirth.  Another possibility is that cases of SCPCD are not being diagnosed, perhaps dying in early infancy due to presumed septicaemia or cerebral haemorrhage or rarely presenting with massive thrombosis and not being diagnosed in adulthood.  

The incidence of miscarriage and stillbirth in mothers of children with SCPCD is unknown.  The extent to which mothers of children with severe protein C deficiency have had previous children who succumbed to presumed septicaemia or intracranial haemorrhage in the neonatal period, which might have been due to undiagnosed SCPCD is also unknown. It would be of interest to know if mothers of children with SCPCD have a higher incidence of excessive pregnancy loss or have lost babies in the neonatal period, possibly because of undiagnosed SCPCD in the baby. 

If the study shows that mothers of children with SCPCD have previously lost children in early infancy with possible undiagnosed SCPCD, then there is a case for increasing awareness of this condition among neonatologists and pediatricians.

If the study shows that mothers of children with SCPCD have an increased incidence of fetal loss and/or neonatal deaths possibly due to undiagnosed SCPCD, this could support the concept of targeted screening for at risk couples eg the consanguineous couple with otherwise unexplained fetal loss. There are beneficial implications in identifying at risk couples. Antenatal diagnosis by chorionic villus biopsy can determine if the fetus is affected if the genetic mutation is known. If so, the parents may elect for termination of pregnancy or if they do not, early elective delivery may be beneficial. It is to be noted that the incidence of blindness and neurological handicap in severe protein C deficiency is high. It is suspected that the origin of this long-term morbidity is retinal vessel and cerebral thrombosis in the fetus in the later stages of pregnancy.  It is now felt that if severe protein C deficiency is diagnosed antenatally, early (32-34 weeks) elective delivery should be strongly considered to avoid blindness and neurological handicap.                                                                                         

Aim and Objective:

To collect data relating to maternal obstetric history from clinicians who are known to have or have had patients with severe inherited protein c deficiency. 


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Expected timeline: Reporting June 2019


Project Investigators:

Dr. Adrian Minford, Prof. Rezan Abdul-Kadir, Dr. Sue Pavord, and Dr. Rachel Farnell



(1)     Goldenberg NA and Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008, 14, 1214-1221

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