Fetal thrombophilia, perinatal stroke, and novel ideas about CP
Recent research findings point to thrombophilia and to stroke before or right after birth as one more basis for cerebral palsy. But can the knowledge make a difference in outcome?
IN THIS ARTICLE
The authors report no financial relationships relevant to this article.
Thrombosis is hypothesized to be the more common mechanism underlying cerebral palsy in many cases of maternal or fetal thrombophilia; for that reason, understanding the impact of maternal and fetal thrombophilia on pregnancy outcome is of paramount importance when counseling patients.
Is a maternal and fetal thrombophilia work-up needed in women who give birth to a term infant with cerebral palsy? Prospective studies are needed to evaluate whether that is the case. In this article, we review the literature on fetal thrombophilia and its role in explaining some cases of perinatal stroke that lead, ultimately, to cerebral palsy.
The several causes of cerebral palsy
Cerebral palsy is the most common chronic motor disability of childhood. Approximately 2 to 2.5 of every 1,000 children are given a diagnosis of this disorder every year.1,2 The condition appears early in life; it is not the result of recognized progressive disease.1 Risk factors for cerebral palsy are multiple and heterogenous1,3,4-6:
- Prematurity. The risk of developing cerebral palsy correlates inversely with gestational age.7,8 A premature infant who weighs less than 1,500 g at birth has a risk of cerebral palsy that is 20 to 30 times greater than that of a full-term, normal-weight newborn.3,4
- Hypoxia and ischemia. These are the conditions most often implicated as the cause of cerebral palsy. Fetal heart-rate monitoring was introduced in the 1960s in the hope that interventions to prevent hypoxia and ischemia would reduce the incidence of cerebral palsy. But monitoring has not had that effect—most likely, because some cases of cerebral palsy are caused by perinatal stroke.9 In fact, a large, population-based study has demonstrated that potentially asphyxiating obstetrical conditions account for only about 6% of cases of cerebral palsy.6
- Thrombophilia. Several recent studies report an association between fetal thrombophilia and both neonatal stroke and cerebral palsy.10-14 That association provides a possible explanation for adverse pregnancy outcomes that have otherwise been ascribed to events during delivery.15-23 Although thrombophilia is a recognized risk factor for cerebral palsy, the strength of the association has still not been fully investigated. TABLE 1 and TABLE 2 summarize studies that have examined this association. Given the rarity of both inherited thrombophilias and cerebral palsy, however, an enormous number of cases would be required to fully establish a causal relationship.
Case reports reveal an association
between fetal thrombophilias and cerebral palsy
Cases of CP
Harum et al36 (case report)
Factor V Leiden
Thorarensen et al37 (case report)
Factor V Leiden
Lynch et al2 (case series)
Factor V Leiden
Halliday et al38 (case series)
Factor V Leiden; prothrombin mutation
Smith et al39 (case series)
Nelson et al40 (case series)
Factor V Leiden; protein C deficiency
How often is a fetal thrombophilia
the likely underlying cause of cerebral palsy?
Prevalence of CP†
Factor V Leiden
* Heterozygous or homozygous
† Among 354 subjects with thrombophilia studied41
Key: MTHFR, methyltetrahydrofolate reductase
“Thrombophilia” describes a spectrum of congenital or acquired coagulation disorders associated with venous and arterial thrombosis.24 These disorders can occur in the mother or in the fetus, or in both concomitantly.
Fetal thrombophilia has a reported incidence of 2.4 to 5.1 cases for every 100,000 births.25 Whereas maternal thrombophilia has a substantially higher incidence, both maternal and fetal thrombophilia can lead to adverse maternal and fetal events.
The incidence of specific inherited fetal thrombophilias is summarized in TABLE 3. Maternal thrombophilia is generally associated with various adverse pregnancy outcomes, particularly cerebral palsy and perinatal stroke.9,26
Inherited thrombophilias among the general population
Factor V Leiden
Protein gene mutation
Gibson et al41 (2003)
Dizon-Townson et al42 (2005)
Infante-Rivard et al43 (2002)
43% to 49%
Stanley-Christian et al44 (2005)
Currie et al45 (2002)
Livingston et al46 (2001)
Schlembach et al47 (2003)
Dizon-Townson et al48 (1997)
* Heterozygous and homozygous carriers of MTHFR C677T and A1298C
Key: MTHFR, methyltetrahydrofolate reductase
Thrombophilia leads to thrombosis at the maternal or fetal interface (FIGURE):
- When thrombosis occurs on the maternal side, the consequence may be severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss.27-29
- Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain.30 As a result, the newborn can sustain a catastrophic event such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.25
Thrombophilia can lead to thrombosis at the maternal or the fetal interface
Thrombosis on the maternal side may lead to severe preeclampsia, intrauterine growth restriction, abruptio placenta, or fetal loss. Thrombosis on the fetal side can be a source of emboli that bypass hepatic and pulmonary circulation and travel to the fetal brain and cause a catastrophic event, such as perinatal arterial stroke via arterial thrombosis, cerebral sinus venous thrombosis, or renal vein thrombosis.
Perinatal and neonatal stroke
Perinatal stroke is defined as a cerebrovascular event that occurs between 28 weeks of gestation and 28 days of postnatal age.30 Incidence is approximately 17 to 93 cases for every 100,000 live births.9
Stroke and cerebral palsy
Arterial ischemic stroke in the newborn accounts for 50% to 70% of cases of congenital hemiplegic cerebral palsy.11 Factor V Leiden mutation, prothrombin gene mutation, and a deficiency of protein C, protein S, and antithrombin III have, taken together in two studies, been identified in more than 50% of cerebral ischemic strokes.31,32 In addition to these thrombophilias, important risk factors for perinatal and neonatal stroke include:
- thrombosis in placental villi or vessels
- use of an intravascular catheter.33
The mechanism that underlies perinatal stroke is a thromboembolic event that originates from either an intracranial or extracranial vessel, the heart, or the placenta.10 A recent meta-analysis by Haywood and colleagues found a statistically significant correlation between protein C deficiency, MTHFR C677T (methyltetrahydrofolate reductase), and the first occurrence of arterial ischemic stroke in a pediatric population.34 Associations between specific thrombophilias and perinatal stroke, as well as pediatric stroke, have been demonstrated (TABLE 4), but we want to emphasize that the absolute risks in these populations are very small.34,35 In addition, the infrequency of these thrombophilias in the general population (TABLE 3) means that their positive predictive value is extremely low.
Fetal thrombophilia is detected in as many as two thirds of study cases of perinatal and neonatal stroke
Type of thrombophilia
Golomb et al31
14 (63%) *
Bonduel et al32
9 (30%) †
deVeber et al49
35 (38%) ‡
Mercuri et al50
Günther et al35
Govaert et al51
* FVL, APCR, and ACA diagnoses overlapped.
† Three patients had anticardiolipin antibody and plasminogen deficiency.
‡ Of 35 children, 21 had multiple abnormalities (combined coagulation deficiencies).
Key: ACA, anticardiolipin antibody; APCR, activated protein C resistance; AT, antithrombin deficiency; FVL, factor V Leiden; PC, protein C deficiency; PS, protein S deficiency; n/a, not available or not studied.
The brain is the largest and most vulnerable fetal organ susceptible to thrombi that are formed either in the placenta or elsewhere.16 A review of cases of cerebral palsy has revealed a pathologic finding, fetal thrombotic vasculopathy (FTV), that has been associated with brain injury.16 Arias and colleagues17 and Kraus18 have observed a correlation among cerebral palsy, a thrombophilic state, and FTV.
Furthermore, Redline found that the presence of severe fetal vascular lesions correlated highly with neurologic impairment and cerebral palsy.19
Regrettably for patients and their offspring, evidence about the relationship between thrombophilia and an adverse neurologic outcome is insufficiently strong to offer much in the way of definitive recommendations for the obstetrician.
We can, however, make some tentative recommendations on management:
Consider screening. When cerebral palsy occurs in association with perinatal stroke, fetal and maternal screening for thrombophilia can be performed.34 The recommended thrombophilia panel comprises tests for:
- factor V Leiden
- prothrombin G20210
- anticardiolipin antibody
- MTHFR mutation.10
Family screening has also been suggested in cases of 1) multiple prothrombotic risk factors in an affected newborn and 2) a positive family history.9
The cost-effectiveness of screening for thrombophilia has not been evaluated in prospective studies, because the positive predictive value of such screening is extremely low.
Consider offering prophylaxis, with cautions. A mother whose baby has been given a diagnosis of thrombophilia and fetal or neonatal stroke can be offered thromboprophylaxis (heparin and aspirin) during any subsequent pregnancy. The usefulness of this intervention has not been well studied and is based solely on expert opinion, however, so it is imperative to counsel patients on the risks and benefits of prophylactic therapy beforehand.
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