TERATOGENIC Antibiotics

Mohammad.K.Lahmud

Noor .A.AhmedMaha.H.Ali

Key pointsWHAT IS TERATOGEN AND ITS MECHNISM ?WHAT IS TRIMESTER ?WHAT ARE THE FDA PREGNANCY CATEGORIS ?WHAT ARE TERATOGENIC ANTIBIOTICS ?

Teras-”monster” Gensis-”producing”A teratogen is defined as any agent that results in structural or functional abnormalities (malformation ) in the fetus, or in the child after birth, as a consequence of maternal exposure during pregnancy. Classes of teratogens include radiation, maternal infections, chemicals, and drugs Birth defects are known to occur in 3-5% of all

newborns. They can do direct damage to the fetus, causing

abnormal development. They can compromise the function of the

placenta, often by constricting blood vessels and reducing the supply of oxygen and nutrients from the mother to the fetus. This can lead to underdevelopment or low birth weight, which are risk factors for birth defects.

They can trigger forceful uterine contractions, potentially injuring the fetus or prompting premature birth.

MECHANISM OF TERATOGENESIS• Direct effect on maternal tissue with secondary effect on fetus

• Indirect-such as interfering with O2 or nutrients.• Teratogenesis maybe direct-malformations of structures. e.g.

i. Vitamin A analogs (isotretinoin,etretinate)ii. Deficiency of a critical substance (folic acid causing

neural tube defects)iii. Continues exposure to teratogen may produce

cumulative effect (Fetal Alcohol Syndrome)

• a period of three months, especially as a division of the duration of pregnancy.

• Pregnancy has three trimesters, each of which is marked by specific fetal developments .

TRIMESTER

FIRST TRIMESTER• In the first four weeks from conception, fetal growth of the ovum begins with development of the spinal cord, nervous system, gastrointestinal system, heart and lungs. By eight weeks, in the embryonic stage, the face is forming, arms and legs move, the baby's heart begins beating and the brain and other organs form. By 12 weeks, the baby, now called a fetus, grows to 3 inches long and weighs 1 ounce , can move fingers and toes. Fingerprints are present. The baby smiles, frowns, sucks, swallows and urinates. The sex of the baby can be discerned by this time.

SECOND TRIMESTER• During the second three months of pregnancy, the baby kicks, can hear and has a strong grip. At 16 weeks a strong heartbeat is evident. The skin is transparent and fingernails and toenails form. The baby can roll over in the amniotic fluid. At 20 weeks, the heartbeat can be heard with a stethoscope. The baby has hair, eyelashes and eyebrows. He can suck his thumb and may have hiccups. By 24 weeks, the baby is 11 to 14 inches long and weighs 1 to 1 1/2 pounds. His skin is covered with a protective coating, his eyes are open and meconium, which will be his first bowel movement after birth ( first stool ) , is collecting in his colon.

THIRD TRIMESTER• The baby is very active at 28 weeks and initial breathing movements begin. The baby is adding body fat. By 32 weeks, the baby experiences periods of sleep and wakefulness and responds to sounds. A six months supply of iron is accumulating in the liver. By 36 to 38 weeks the baby is 19 or more inches long and weighs 6 pounds or more. At this point the baby is less active and gains immunities from the mother.

FDA PREGNANCY CATEGORIES

CATEGORY A• failed to

demonstrate a risk to the fetus in the first trimester of pregnancy

• no evidence of risk in later trimesters

CATEGORY C• shown an

adverse effect on the fetus

• no adequate and well-controlled studies in humans

• potential benefits may warrant the use of drug despite potential risks.

CATEGORY D• positive

evidence of human fetal risk based on adverse reaction data

• potential benefits may warrant use of the drug in pregnant women despite potential risks

CATEGORY B• failed to

demonstrate a risk to the fetus

• no adequate and well-controlled studies in pregnant women.

CATEGORY X• demonstrate

s fetal abnormalities

• positive evidence of human fetal risk based on adverse reaction data

• the risks involved in use of the drug in pregnant women

CATEGORY N• FDA has

not classified the drug.

TETRACYCLINE Pregnancy category - DTrimesters of risk - Second and third • Protein synthesis inhibitor

• Inhibit the binding of aminoacyl-tRNA to the mRNA- ribosomes complex

Aminoacyl-tRNA mRNA-ribosomes complex

by binding to the 30S ribosomal subunit in mRNA translation complex

SIDE EFFECTS• IN PREGNANCY….. Dental discoloration in children Maternal hepatotoxicity with large parenteral doses

CHLORAMPHENICOL• category C• Bacteriostatic drug that stop bacterial growth by inhibiting protein synthesis

• Prevent protein chain elongation by inhibiting peptidyl transferase activity of bacterial chromosome

• Intravenous chloramphenicol use has been associated with Gray Baby syndrome This occur in newborn infants because they liver enzymes not yet fully developed chloramphenicol remains unmetabolized in body

ADVERSE EFFECTS• Hypotension• Cyanosis The condition can be prevented by using the drug at

recommended doses & monitoring blood levels

Gray Baby Syndrome

AMINOGLYCOSIDES•tobramycin, Gentamicin , amikacin, netilmicin, streptomycin, kanamycin are category D

• because eighth cranial nerve damage has been reported in children whose mothers received streptomycin as long-term therapy for tuberculosis. No cases of deafness have been reported for gentamicin, tobramycin, or amikacin. However, there is still potential for ototoxicity, so these agents should be avoided during pregnancy. If gentamicin is used, patients should be monitored using serum gentamicin concentrations (concentrations in amniotic fluid range from 30% to 50% of maternal concentrations). Renal function also should be assessed periodically by monitoring serum creatinine. Data regarding safety of once-daily

SULFONAMIDE & TRIMETHOPRIM• Category c• Sulfonamides have a bacteriostatic effect by inhibiting bacterial folic acid synthesis , used in urinary tract infections .

• Trimethoprim binds to dihydrofolate redustase and inhibit reduction of DHF to THF

• Sulfamethoxazole inhibit dihydrofolate synthetase

TERATOGENIC EFFECTS• 1) NEONATAL HAEMOLYSIS• 2)METHAEMOGLOBINAEMIA ( a form of hemoglobin)

Macrolides• Erythromycin crosses the placenta, but fetal concentrations are generally low due to erratic absorption from the maternal gastrointestinal tract and unpredictable transplacental passage. Erythromycin is also a category B drug -- the base and succinate forms are considered safe for use during pregnancy. However, erythromycin estolate should not be used during pregnancy because it has been associated with a 10% to 15% incidence of reversible hepatotoxicity in mothers during the second half of pregnancy.

• Less is known about the newer macrolides. Azithromycin (category B) has shown no teratogenic effects in animal studies, but there are no adequate controlled studies in pregnant women. Clarithromycin (category C )  has been shown to cause teratogenic effects in animals, but its effects in humans are unknown.

Fluoroquinolones • category C•  not recommended for use in pregnancy because they have been shown to cause arthropathy in weight-bearing joints as well as noninflammatory joint effusions, fluid-filled blisters, fissures, erosions, and clusters of chondrocytes in immature animals. It is hypothesized that the fluoroquinolones may impair skeletal development in fetuses and infants, especially in their weight-bearing joints.

• One study of 38 patients exposed to norfloxacin and ciprofloxacin during pregnancy failed to show any adverse effects on the musculoskeletal system. The majority of women took these agents during the first trimester of pregnancy. Assessment was based on information obtained about the child from mothers and physicians; however, no diagnostic procedures, such as MRI, were done.

Griseofulvin• Category C• In animal experiments griseofulvin is teratogenic and, at high doses,

• cancerogenic. It crosses the placenta at term. One publication,

• based on birth defects data, reported two pairs of conjoined

• twins after the use of griseofulvin in early pregnancy• As griseofulvin is not used to treat life-threatening fungal infections, its application in pregnancy should be avoided. If treatment took place in the first trimester, a detailed ultrasound examination should be offered to ascertain the normal development of the fetus

Treatment and prevention• The best course is to prevent teratogen exposure, or

reduce the exposure as much as possible. • Prevention is complicated because very often women

may not realize they are pregnant until the middle of the period of susceptibility.

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