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Probably, the most well-known teratogenic drug is thalidomide. It was developed near the end of the 1950s by Chemie Grűnenthal as a sleep inducing aid and antiemetic. Because of its ability to prevent nausea it was prescribed for pregnant women in almost 50 countries worldwide between 1956–1962. Until William McBride published the study leading to its withdrawal from the market at 1961, about 8- 10 000 severely malformed children were born. The most typical disorder induced by thalidomide were reductional deformities of the long bones of the extremities. Phocomelia otherwise a rare deformity, which therefore helped to recognise the teratogenic effect of the new drug. Among other malformations caused by thalidomide were those of ears, eyes, brain, kidney, heart, digestive and respiratory tract. 40% of the prenatally affected children died soon after birth. As thalidomide is used today as a treatment for multiple myeloma and leprosy, several births of affected children were described in spite of the strictly required use of contraception among female patients treated by it.
Vitamin A, or retinol, is the sole vitamin which is embryotoxic even in a therapeutic dose, for example in multivitamins, because its metabolite, the retinoic acid, plays an important role as a signal molecule in the development of several tisues and organs. Its natural precursor, the β-carotene, is considered safe, whereas the consumption of animal liver can lead to malformation, as the liver stores lipophile vitamins, including retinol. Isotretinoin (13-cis-retinoic-acid; brand name Roaccutane), vitamine A analog, which is often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman (even transdermally) may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess. Vitamine A and similar substances can induce spontaneous abortions, premature births, defects of eyes (microphthalmia), ears, thymus, face deformities, neurological (hydrocephalus, microcephalia) and cardiovascular defects, as well as mental retardation.
Tetracycline, an antibiotic, should never be prescribed to women in the reproductive age or children, because of its negative impact on bone mineralization and teeth mineralization. The "tetracycline teeth" have brown or grey colour as a result of a defective development of both the dentine and the enamel of teeth.
Several anticonvulsants are known to be highly teratogenic. Phenytoin, also known as diphenylhydantoin, along with carbamazepine is responsible for the fetal hydantoin syndrome, which may typically include broad nose base, cleft lip and/or palate, microcephalia, nails and fingers hypoplasia, intrauterine growth restriction and mental retardation. Trimethadione taken during pregnancy is responsible for the fetal trimethadione syndrome, characterized by craniofacial, cardiovascular, renal and spine malformations, along with a delay in mental and physical development. Valproate has anti-folate effects, leading to neural tube closure-related defects such as spina bifida. Lower IQ and autism have recently also been reported as a result of intrauterine valproate exposure.
Hormonal contraception is considered as harmless for the embryo. Peterka and Novotná do however state that syntethic progestines used to prevent miscarriage in the past frequently caused masculinization of the outer reproductive organs of female newborns due to their androgenic activity. Diethylstilbestrol is a synthetic estrogen used from the 1940s to 1971 when the prenatal exposition has been linked to the clear-cell adenocarcinoma of the vagina. Following studies showed elevated risks for other tumors and congenital malformations of the sex organs for both sexes.
All cytostatics are strong teratogens, abortion is usually recommended when pregnancy is found during or before chemotherapy. Aminopterin, a cytostatic drug with anti-folate effect, was used during the 1950s and 1960s to induce therapeutic abortions. In some cases the abortion didn´t happen, but the newborns suffered a fetal aminopterin syndrome consisting of growth retardation, craniosynostosis, hydrocephalus, facial dismorphities, mental retardation and/or leg defomities
Studies suggest that prenatal care for mothers during their pregnancies can prevent congenital amputation. Knowing environmental and genetic risks is also important. Heavy exposure to chemicals, smoking, alcohol, poor diet, or engaging in any other teratogenic activities while pregnant can increase the risk of having a child born with a congenital amputation. Folic acid is a multivitamin that has been found to reduce birth defects.
For the survivors of the atomic bombing of Hiroshima and Nagasaki, who are known as the "Hibakusha", no statistically demonstrable increase of birth defects/congenital malformations was found among their later conceived children, or found in the later conceived children of cancer survivors who had previously received radiotherapy.
The surviving women of Hiroshima and Nagasaki who were able to conceive, though exposed to substantial amounts of radiation, later had children with no higher incidence of abnormalities/birth defects than in the Japanese population as a whole.
Relatively few studies have researched the effects of paternal radiation exposure on offspring. Following the Chernobyl disaster, it was assumed in the 1990s that the germ line of irradiated fathers suffered minisatellite mutations in the DNA, which was inherited by descendants. more recently however, the World Health Organization states, "children conceived before or after their father's exposure showed no statistically significant differences in mutation frequencies". This statistically insignificant increase was also seen by independent researchers analyzing the children of the liquidators. Animal studies have shown that incomparably "massive" doses of X-ray irradiation of male mice resulted in birth defects of the offspring.
In the 1980s, a relatively high prevalence of pediatric leukemia cases in children living near a nuclear processing plant in West Cumbria, UK, led researchers to investigate whether the cancer was a result of paternal radiation exposure. A significant association between paternal irradiation and offspring cancer was found, but further research areas close to other nuclear processing plants did not produce the same results. Later this was determined to be the Seascale cluster in which the leading hypothesis is the influx of foreign workers, who have a different rate of leukemia within their race than the British average, resulted in the observed cluster of 6 children more than expected around Cumbria.
The complete absence of an arm or leg in amelia occurs as a result of the limb formation process being either prevented or interrupted very early in the developing embryo: between 24 and 36 days following fertilization. Tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance - that is, the parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. In a few cases, amelia may be attributed to health complications during the early stages of pregnancy, including infection, failed abortion or complications associated with removal of an IUD after pregnancy, or use of teratogenic drugs, such as thalidomide.
Ectromelia is a congenital condition where long bones are missing or underdeveloped.
Examples include:
- Amelia
- Hemimelia
- Phocomelia
- Sirenomelia
The diagnosis of tetra-amelia syndrome is established clinically and can be made on routine prenatal ultrasonography. WNT3 is the only gene known to be associated with tetra-amelia syndrome. Molecular genetic testing on a clinical basis can be used to diagnose the incidence of the syndrome. The mutation detection frequency is unknown as only a limited number of families have been studied. Affected infants are often stillborn or die shortly after birth.
The exact cause of congenital amputation is unknown and can result from a number of causes. However, most cases show that the first three months in a pregnancy are when most birth defects occur because that is when the organs of the fetus are beginning to form. One common cause is amniotic band syndrome, which occurs when the inner fetal membrane (amnion) ruptures without injury to the outer membrane (chorion). Fibrous bands from the ruptured amnion float in the amniotic fluid and can get entangled with the fetus, thus reducing blood supply to the developing limbs to such an extent that the limbs can become strangulated; the tissues die and are absorbed into the amniotic fluid. A baby with congenital amputation can be missing a portion of a limb or the entire limb, which results in the complete absence of a limb beyond a certain point where only a stump is left is known as transverse deficiency or amelia. When a specific part is missing, it is referred to as longitudinal deficiency. Finally, phocomelia occurs when only a mid-portion of a limb is missing; for example when the hands or feet are directly attached to the trunk of the body.
Amnion ruptures can be caused by:
- teratogenic drugs (e.g. thalidomide, which causes phocomelia), or environmental chemicals
- ionizing radiation (atomic weapons, radioiodine, radiation therapy)
- infections
- metabolic imbalance
- trauma
Congenital amputation is the least common reason for amputation, but it is projected that one in 2000 babies are born each year with a missing or deformed limb. During certain periods in history, an increase in congenital amputations has been documented. One example includes the thalidomide tragedy that occurred in the 1960s when pregnant mothers were given a tranquilizer that contained the harmful drug, which produced an increase in children born without limbs. Another example was the 1986 Chernobyl catastrophe in Ukraine, where the radiation exposure caused many children to be born with abnormal or missing limbs .
Treatment of Roberts syndrome is individualized and specifically aimed at improving the quality of life for those afflicted with the disorder. Some of the possible treatments include: surgery for the cleft lip and palate, correction of limb abnormalities (also through surgery), and improvement in prehensile hand grasp development.
Tetra-amelia syndrome has been reported in only a few families worldwide.
According to a 2011 study by Bermejo-Sanchez, amelia – that is, the lacking of one or more limbs – occurs in roughly 1 out of every 71,000 pregnancies.
Dysmelia can be caused by
- inheritance of abnormal genes, e.g. polydactyly, ectrodactyly or brachydactyly, symptoms of deformed limbs then often occur in combination with other symptoms (syndromes)
- external causes during pregnancy (thus not inherited), e.g. via amniotic band syndrome
- teratogenic drugs (e.g. thalidomide, which causes phocomelia) or environmental chemicals
- ionizing radiation (nuclear weapons, radioiodine, radiation therapy)
- infections
- metabolic imbalance
Roberts syndrome is an extremely rare condition that only affects about 150 reported individuals. Although there have been only about 150 reported cases, the affected group is quite diverse and spread worldwide. Parental consanguinity (parents are closely related) is common with this genetic disorder. The frequency of Roberts syndrome carriers is unknown.
Tetra-amelia syndrome ("" + "amelia"), also called autosomal recessive tetraamelia, is an extremely rare autosomal recessive congenital disorder characterized by the absence of all four limbs. Other areas of the body are also affected by malformations, such as the face, skull, reproductive organs, anus and pelvis. The disorder is caused by mutations in the WNT3 gene.
Dysmelia can refer to
- missing (aplasia) limbs: amelia, oligodactyly, congenital amputation e.g. Tibial or Radial aplasia
- malformation of limbs: shortening (micromelia, rhizomelia or mesomelia), ectrodactyly, phocomelia, meromelia, syndactyly, brachydactyly, club foot
- too many limbs: polymelia, polydactyly, polysyndactyly
- others: Tetraamelia, hemimelia, Symbrachydactyly
There is currently no treatment or cure for Waardenburg syndrome. The symptom most likely to be of practical importance is deafness, and this is treated as any other irreversible deafness would be. In marked cases there may be cosmetic issues. Other abnormalities (neurological, structural, Hirschsprung disease) associated with the syndrome are treated symptomatically.
Yim–Ebbin syndrome is a congenital disorder characterized by the absence of arms, a cleft lip and palate, hydrocephalus, and an iris coloboma. It was first described by Yim and Ebbin in 1982, and later by Thomas and Donnai in 1994. In 1996, a third case was reported by Froster et al. who suggested that the three cases were related and represented a distinct syndrome. In 2000, a similar case was reported by Pierri et al.
It is also known as "amelia cleft lip palate hydrocephalus iris coloboma".
The overall incidence is ~1/42,000 to 1/50,000 people. Types I and II are the most common types of the syndrome, whereas types III and IV are rare. Type 4 is also known as Waardenburg‐Shah syndrome (association of Waardenburg syndrome with Hirschsprung disease).
Type 4 is rare with only 48 cases reported up to 2002.
About 1 in 30 students in schools for the deaf have Waardenburg syndrome. All races and sexes are affected equally. The highly variable presentation of the syndrome makes it difficult to arrive at precise figures for its prevalence.
Turning the baby, technically known as external cephalic version (ECV), is when the baby is turned by gently pressing the mother’s abdomen to push the baby from a bottom first position, to a head first position. ECV does not always work, but it does improve the mother’s chances of giving birth to her baby vaginally and avoiding a cesarean section. The World Health Organisation recommends that women should have a planned cesarean section only if an ECV has been tried and did not work.
Women who have an ECV when they are 36–40 weeks pregnant are more likely to have a vaginal delivery and less likely to have a cesarean section than those who do not have an ECV. Turning the baby before this time makes a head first birth more likely but ECV before the due date can increase the risk of early or premature birth which can cause problems to the baby.
There are treatments that can be used which might affect the success of an ECV. Drugs called beta-stimulant tocolytics help the woman’s muscles to relax so that the pressure during the ECV does not have to be so great. Giving the woman these drugs before the ECV improves the chances of her having a vaginal delivery because the baby is more likely to turn and stay head down. Other treatments such as using sound, pain relief drugs such as epidural, increasing the fluid around the baby and increasing the amount of fluids to the woman before the ECV could all effect its success but there is not enough research to make this clear.
Turning techniques mothers can do at home are referred to Spontaneous Cephalic Version (SCV), this is when the baby can turn without any medical assistance. Some of these techniques include; a knee to chest position, the breech tilt and moxibustion, these can be performed after the mother is 34 weeks pregnant. Although there is not a lot of evidence to support how well these techniques work, it has worked for some mothers.
A breech birth occurs when a baby is born bottom first instead of head first. Around 3-5% of pregnant women at term (37–40 weeks pregnant) will have a breech baby.
Most babies in the breech position are born by a caesarean section because it is seen as safer than being born vaginally.
As most breech babies are delivered by caesarean section in developed countries, doctors and midwives may lose the skills required to safely assist women giving birth to a breech baby vaginally. Delivering all breech babies by caesarean section in developing countries may be very difficult to implement or even impossible as there are not always resources available to provide this service.
Depending on the severity, treatment involves either oral or intravenous antibiotics, using penicillins, clindamycin, or erythromycin. While illness symptoms resolve in a day or two, the skin may take weeks to return to normal.
Because of the risk of reinfection, prophylactic antibiotics are sometimes used after resolution of the initial condition. However, this approach does not always stop reinfection.
The disease prognosis includes:
- Spread of infection to other areas of body can occur through the bloodstream (bacteremia), including septic arthritis. Glomerulonephritis can follow an episode of streptococcal erysipelas or other skin infection, but not rheumatic fever.
- of infection: Erysipelas can recur in 18–30% of cases even after antibiotic treatment. A chronic state of recurrent erysipelas infections can occur with several predisposing factors including alcoholism, diabetes, and tinea pedis (athlete's foot). Another predisposing factor is chronic cutaneous edema, such as can in turn be caused by venous insufficiency or heart failure.
- Lymphatic damage
- Necrotizing fasciitis, commonly known as "flesh-eating" bacterial infection, is a potentially deadly exacerbation of the infection if it spreads to deeper tissue.