While some cases of TEV are part of a recognized syndrome or sequence, many occur without a clear cause; this is known as isolated talipes equinovarus (ITEV). There are several theories about the etiology of ITEV, however the actual mechanism for this disorder is not known (Miedzybrodzka 2003). TEV may be caused by mechanical forces within the uterus due to low amniotic fluid volume or insufficient expansion of the uterus. The latter etiology is suggested because of the increased incidence in first-born children, in pregnancies in which there is low amniotic volume and twin pregnancies (Carey 2003, Byron-Scott 2005, Moorthi 2005, Engell 2006). A second theory is that TEV is caused by an abnormality of the connective tissue of the fetus. Other possible causes are bone malformations within the foot and ankle, in utero vascular disruption, or an underlying neurological disorder. This theory is supported when TEV occurs with other neurological defects as part of a syndrome or sequence. Finally, it has been theorized that TEV represents an arrest of the developmental process; that is, the lower limb does not rotate to its final anatomical position (Miedzybrodzka 2003).
It is also possible that underlying all of these theories is a genetic cause. Family history has been significantly associated with increased risk of ITEV (Lochmiller 1998), with the risk of increasing greatly if a first-degree family member (parent, sibling) also has it (Dietz 2002). ITEV is also more common in specific ethnic/racial groups, including the Maori/Pacific Islanders and Australian Aborigines (Chapmen 2000, Carey 2003). Within these groups, family lineages have indicated multiple instances of the defect. Several studies have also suggested that a single as-yet unknown dominant gene or many interacting genes of small effect as the etiology of ITEV (Wynne-Davies 1982, de Andrade 1998, Chapman 2000, Dietz 2002, Miedzybrodzka 2003).
DEMOGRAPHIC AND REPRODUCTIVE FACTORS
The secular trend for ITEV has remained consistent throughout various recording periods (Carey 2005, Moorthi 2005). The birth prevalence for this defect ranges from 0.39 to 6.8 per 1000 births (dependent on race/ethnicity and/or genetic background); the prevalence for the U.S. population was approximately 0.74 per 1000 births, excluding incidences of TEV that were part of a syndrome or associated with other defects.
Race/ethnicity was not determined to be a risk factor for ITEV among Hispanics, African Americans, Chinese Americans, or Caucasians in some studies (Moorthi 2005, Lochmiller 1998). However, it was found to be a risk factor among Australian Aborigines, Hawaiians, Pacific Islanders, and Maoris (Chapman 2000, Lochmiller 1998).
Infant sex is a risk factor for ITEV, with a consistent 2:1 (male:female) ratio found across demographic groups (Byron-Scott 2005, Carey 2005, Moorthi 2005, Lochmiller 1998). The relationship between parity and TEV is unclear (Moorthi 2005), as is the relationship between ITEV and breech presentation at birth (Lochmiller 1998). First-born children were also more likely to have TEV than children from subsequent pregnancies (Moorthi 2005).
There is some evidence that advanced maternal age is a risk factor for ITEV (Hollier 2000). However, this risk has been described as slightly higher, but not significant (Moorthi 2005, Barker 2002). Paternal age has not been associated with this defect.
Mothers with a college education were less likely to have a child with ITEV than mothers who only had a high school education (Moorthi 2005). This is likely due to the fact that college-educated women are more likely to have a higher socio-economic status, more access to healthcare, and better diets
Prevalence of ITEV has been tentatively associated with seasonality. One study reported that a higher incidence of TEV was reported in July, while the fewest incidences were reported in March (Barker 2002, Lochmiller 1998). Another study reported that infants born in autumn/winter had a slightly higher risk for TEV (OR 1.35) (Carey 2005), while another found no variation (Loder 2006).
FACTORS IN LIFESTYLE OR ENVIRONMENT
Maternal smoking has been associated with ITEV (Skelly 2002, Honein 2000). For those with a family history of TEV and exposure to maternal smoking, the risk is greatly increased (OR 20.30) (Honein 2000). Additionally, exposure to maternal smoking appears to be dose related (Skelly 2002). The risk of ITEV increased significantly, with the OR for maternal smoking of 20 or more cigarettes a day (without family history of ITEV) increasing to 4.6 (Skelly 2002).
Low amniotic fluid volume (oligohydramnios) has been linked inconclusively to ITEV (Carey 2005, Miedzybrodzka 2003). The hypothesis is that low amniotic fluid volume will lead to decreased uterine space, limiting the movements of and crowding the fetus. Because of the effect on amniotic fluid volume, amniocentesis has also been tentatively linked to increasing risk for ITEV (Philip 2004); however, one study did not find later amniocentesis (15 to 16 weeks) to be linked to TEV (Miedzybrodzka 2003).
A single study reported a link between maternal anemia and TEV; this same study indicated a connection between hypermesis gravidarium (very severe vomiting due to pregnancy) (Bryon-Scott 2005), and another found no association with in utero enterovirus infection (Loder 2006).
Maternal obesity and maternal diabetes have not been found to be a risk factor for ITEV (Cedergreen 2004, Becerra 1990). Folic acid reduces the risk of most birth defects; however, its effect on ITEV is unclear (Green 2002); one study found no decrease in rates after folic acid fortification of the U.S. grain supply (Moorthi 2005). However, both folic acid and multivitamins have been proven effective at reducing the risk of numerous other birth defects.
Living in proximity to landfills or solid waste incinerators, exposure to nitrate or chlorination byproducts in drinking water, exposure to indoor pesticides or biomedical solvents does not increase the risk of ITEV (Harrison 2003, Cordier 2004). (Cedergren 2002 (Berkowitz 2003, Wennborg 2005).
Maternal alcohol consumption is not linked to TEV (Honein 2000). Maternal consumption of marijuana and methamphetamines do not appear to be risk factors for TEV (Fried 2002, Jeng 2005). However, it is not recommended that pregnant women consume alcohol or illicit drugs.
The use of chemotherapy does not increase the risk for TEV (Cardonick 2004), nor does the use of fluoxetine (Prozac™) (Chambers 1996). Anticonvulsant drugs have multiple effects on the developing fetus, however TEV is not one of them (Holmes 2001). Antihistamine drugs have not been found to increase the risk of TEV (Kallen 2002). Corticosteroids and calcium channel blockers have not been found to increase the risk for TEV (Park-Wyllie 2000, Sorensen 2001). Finally, the drug thalidomide has been found to cause serious limb defects. However, thalidomide has not been found to cause TEV (Stromland 2002).
ITEV affects 7.4 pregnancies per 10,000 live births in Texas (Moorthi 2005). Other studies have found the birth prevalence to be between 10.0 and 12.5 in other locations (Wynne-Davies 1972, Carey 2005).
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Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.