**Causes of birth defects
**
It was only in the 20th century that the causes ofparticular birth defects began to be recognized. Thecauses of birth defects are many and complex; evennow, approximately 50 percent of birth defects cannotbe ascribed to a specific cause (Nelson and Holmes,1989; Turnpenny and Ellard, 2005). However, knowncauses can be divided broadly into two groups: (1)genetic and partially genetic causes, originatingmostly before conception (preconception) and (2)causes developing after conception, but before birth(post-conception).
CAUSES ORIGINATING BEFORE CONCEPTION
Most birth defects originate before conception andare due to abnormalities of the genetic material—chromosomes and genes. Partially genetic birthdefects are due to a combination of genes that putsthe fetus at risk in the presence of specific environmentalfactors. Genetic abnormalities can be inherited,in which case they are found in families, or theycan occur as an isolated event in a particular pregnancy.They include chromosomal abnormalities,single gene defects and conditions known as multifactorialdisorders, which are caused by the interactionof genes and the environment.
CHROMOSOMAL ABNORMALITIES
Chromosomal abnormalities are due to changes inthe number or the structure of chromosomes fromthe normal state that result in a gain or loss of geneticmaterial. Such abnormalities account for approximately6 percent of birth defects in industrializedcountries (Turnpenny and Ellard, 2005). Downsyndrome, generally caused by an extra chromosome21 (trisomy 21), is the most common chromosomalabnormality in man. Described clinically byLangdon Down in 1866, it became the first birthdefect ascribed to a chromosomal disorder (Lejeuneet al., 1959).
SINGLE GENE DEFECTS
Single gene defects are caused by alterations in genestructure, called mutations, which result in abnormalcell functioning. More than 7,000 single gene defectshave been described (OMIM, 2000). The first clinicallydocumented single gene defect produced shorthands and fingers (brachydactyly) in a large Pennsylvanianfamily (Farabee, 1903). All single gene defectscombined account for an estimated 7.5 percent of allbirth defects in industrialized countries (Turnpennyand Ellard, 2005).
MULTIFACTORIAL DISORDERS
The concept of multifactorial inheritance (i.e., birthdefects due to complex genetic and environmentalinteraction) was proposed by Boris Ephrussi in1953 and is now broadly accepted (Passarge, 1995).Other terms to describe this etiological category—for example, non-Mendelian complex inheritance—have been used, but the term that remains in generaluse is multifactorial inheritance. This categoryaccounts for an estimated 20-30 percent of all birthdefects, a number of which are lethal (Turnpennyand Ellard, 2005). Examples of multifactorial birthdefects are numerous, are usually malformations ofa single organ system or limb, and include congenitalheart disease, neural tube defects, cleft lip and/or cleft palate, clubfoot and developmental dysplasiaof the hip.Multifactorial inheritance is also the cause ofthe many common diseases with a genetic predispositionthat present later in life, are usually systemicand do not involve malformations. Included amongthese disorders are hypertension, diabetes, stroke,mental disorders and cancer.
CAUSES ORIGINATING AFTER CONCEPTION
Causes of birth defects originating after conceptionare primarily non-genetic. In these disorders,the genetic material inherited by the fetus is normaland the birth defect is caused by an intra-uterineenvironmental factor. These include teratogens thatinterefere with normal growth and development ofthe embryo or fetus, mechanical forces that deformthe fetus, and vascular accidents that disrupt thenormal growth of organs. This category accounts foran estimated 5-10 percent of all birth defects (Nelsonand Holmes, 1989; Turnpenny and Ellard, 2005).Teratogens are broadly categorized into fivegroups: (1) physical agents such as radiation, (2)environmental pollutants like methyl mercury; (3)maternal illness or disturbances of the mother’smetabolism such as maternal insulin-dependentdiabetes mellitus or maternal iodine deficiency;(4) maternal infections, including rubella and toxoplasmosis;and (5) drugs, both medicinal and recreational(Seashore and Wappner, 1996).
UNKNOWN CAUSES
As noted above, a specific cause cannot be designatedin approximately 50 percent of all children born withbirth defects. Some of these birth defects may be dueto new autosomal dominant mutations, submicroscopicchromosome deletions or uniparental disomy(Turnpenny and Ellard, 2005). Causes for birthdefects continue to be identified, so the percentageof birth defects of unknown cause can be expectedto decrease in the future.
https://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-full-report.pdf