DRUG AND SUBSTANCE USE IN PREGNANCY (TERATOGENITY)
• All kinds of agents (chemicals, viruses, environmental factors, physical factors, drugs) that cause permanent loss of structure or function by acting in the embryonic or fetal period are called teratogens.
• The effects of teratogens differ according to the developmental period exposed:
► The first 2 weeks after fertilization is called the "all or nothing period" During this period, the pregnancy is either not affected at all or ends in miscarriage.
► Since there is organogenesis between the first 2 and 8 weeks after fertilization (embryonic period), teratogens taken during this period cause structural malformations.
► Maturation and functional development continue after the 8th week (fetal period). Some organs may also be affected during this period (brain and heart, etc.).
Known teratogens
Alcohol
Leflunomide
acitretin
Lithium
ACE inhibitors
methimazole
Angiotensin receptor blockers
methotrexate
Androgens
misoprostol
bexarotene
mycophenolate
Bosentan, Ambrisentan, Macitentan
paroxetine
Mercury
radioactive iodine
danazol
ribavirin
Diethylstilbesterol (DES)
Cigarette
Efavirenz
cyclophosphamide
phenytoin
tamoxifen
phenobarbital
Thalidomide, Lenalidomide
fluconazole
Tetracycline
Isotretinoin
Toluene
carbamazepine
Topiramate
chloramphenicol
Trastuzumab
Cocaine
Tretinoin
corticosteroids
Valproate
Bullet
warfarin
lamotrigine
Nitrofurantoin and sulfonamides are considered low-risk teratogens, and they can be used in the treatment of urinary infections in the first trimester if there is no alternative.
Anticonvulsants
• The most common fetal malformations in anticonvulsant users are orofacial clefts (the risk of cleft lip and palate increases 10 times), cardiac malformations and neural tube defects. While this risk is slightly lower in monotherapies, the risk may increase considerably in polytherapies.
• Of all anticonvulsants, valproic acid increases the risk of fetal malformations the most (9% major malformation risk, NTD risk 4%), and was associated with significant lower IQ compared with those exposed to other antiepileptics.
Risk of Major Congenital Malformation with Antiepileptic Use in the First Trimester
Antiepileptic ------------------------------------------------ ----Relative Risk
Gabapentin ------------------------------------------------ -------------------► 0.6
Lamotrigine ------------------------------------------------ ---------------------► 1.8
Oxcarbazepine ------------------------------------------------ --------------► 2.0
Levatiracetam ------------------------------------------------ ---------------► 2.2
Phenytoin ------------------------------------------------ -----------------------► 2.6
Carbamazepine ------------------------------------------------ ---------------► 2, 7
Clonazepam ------------------------------------------------ -------------------► 2.8
Topiramate ------------------------------------------------ ---------------------► 3.8
Phenobarbital ------------------------------------------------ -----------------► 5, 1
Valproic acid ------------------------------------------------ ------------------► 9.0
Antihypertensives
• ACE inhibitors are fetotoxic and cause ACE inhibitor fetopathy. Since angiotensin receptor blockers act by the same mechanism, these drugs are considered fetotoxic like ACE inhibitors.
• Both groups of drugs disrupt the renin-angiotensin system, which is necessary for the renal development of the fetus during the fetal period. In addition, they cause renal ischemia, renal tubular dysgenesis and anuria as a result of prolonged fetal hypotension and hypoperfusion. Developing oligohydramnios leads to pulmonary hypoplasia and limb contractures. In addition to its effects on the kidney, hypoperfusion in the fetus causes short limbs, IUGR and calvarium developmental defects (ACE inhibitor fetopathy).
Anti-inflammatory
Non-steroidal Anti-Inflammatory Drugs
► Not considered a major risk factor for birth defects; however, their use in the third trimester causes undesirable fetal side effects.
► Indomethacin causes premature closure of the ductus arteriosus and consequently pulmonary hypertension. It decreases the urine production of the fetus by increasing the sensitivity and amount of vasopressin. Thus, it leads to oligohydramnios (especially when used over 72 hours). All these side effects improve if NSAID use is discontinued after 34 weeks, so they should not be used after 34 weeks (E-08).
► In addition to these, intraventricular hemorrhage, bronchopulmonary dysplasia and necrotizing enterocolitis can be seen in babies born within 48 hours.
Aspirin
► Does not increase the risk of congenital malformation.
Leflunpmid
► Use in pregnancy is contraindicated. In animal studies, it has been shown to cause hydrocephalus, eye anomalies, skeletal anomalies and embryo death.
antimicrobials
antibiotics
► Aminoglycoside (gentamicin, streptomycin, etc.): Although ototoxicity and nephrotoxicity are observed when used in preterm newborns, congenital defects due to exposure to these drugs have not been demonstrated.
► Chloramphenicol: Teratogen. It should be avoided in late pregnancy as it may cause gray baby syndrome when given to preterm newborns.
► Nitrofurantoin: If used in the first trimester, the risk of cleft palate and lip increases 2 times. There are also studies stating that it increases the risk of hypoplastic left heart syndrome. However, the absolute risk remains very low and if there is no alternative, it is suitable to be used in the first trimester.
► Sulfonamides: Although there are studies showing that the use of periconceptional trimethoprim-sulfomethoxazole increases the risk of esophageal atresia or diaphragmatic hernia, the absolute risk remains very low and it is appropriate to use in the first trimester if there is no alternative.
► When tetracyclines are used after the 25th week of pregnancy, they accumulate in the teeth and long bones and cause yellow-brown discoloration.
Antivirals
► Ribavirin is highly teratogenic and causes anomalies in the skull, palate, eye, skeleton and gastrointestinal system.
► Efavirenz causes CNS and ocular anomalies in animals.
Antifungals
► Malformations associated with the use of fluconazole include cleft palate-lip, abnormal face, cardiac anomaly (tetralogy of fallot), skull, long bone and joint abnormalities. These anomalies are observed only in the first trimester, if it is used in chronic and high doses.
Antineoplastics
cyclophosphamide
► The risk of pregnancy loss has increased and the most common fetal anomalies; skeletal anomalies, extremity defects, cleft palate and eye anomalies.
Methotrexate and Aminopterin
► The critical period is between the 8th and 10th weeks and the minimal dose level required is 10 mg.
► Methotrexate-Aminopterin syndrome:
0 Craniosynocytosis (with cloverleaf skull)
0 Wide nose
0 Down-set ears
0 micrognathia
0 Limb anomalies
tamoxifen
► Pregnancy is not recommended either during the treatment or within two months of the end of the treatment, as it may cause DES-like syndrome in the long term.
Trastuzumab
► Not associated with fetal malformations; however, cases of oligohydramnios, anhydramnios and fetal renal failure have been reported. Therefore, they may be associated with pulmonary hypoplasia, limb abnormalities, and neonatal death.
Anticoagulants (Warfarin - Kumadin)
• Embryotoxic and fetotoxic. Its teratogenic effects are dose dependent and occur at doses above 5 mg. Spontaneous abortion occurs in 72% of cases as a result of exposure in the early stages of pregnancy. When exposed between the 6th and 9th weeks of pregnancy, warfarin embryopathy develops in 8% of cases (nasal hypoplasia, vertebral, femoral epiphyseal defects).
• When warfarin is used in the second or third trimester, corpus callosum agenesis, Dandy-Walker malformation (cerebellar vermian agenesis), optic atrophy and microphthalmia may be seen due to inappropriate growth and bleeding. Affected newborns are at risk of blindness, deafness and growth retardation.
Psychiatric Drugs
Lithium
► It causes Ebstein anomaly when used in the first trimester of pregnancy. In addition, it can cause hypothyroidism, diabetes insipidus, cardiomegaly, bradycardia, cyanosis and hypotonia in newborns (N-03, N-06).
SSRIs and SNRLs
► They are not considered teratogens except for paroxetine. Paroxetine increases the risk of cardiac malformation (most commonly ASD and VSD) when used in the first trimester.
antipsychotics
► They are not teratogenic; however, it may have SSRI-like effects in the neonatal period.
Sex Hormones
Testosterone and anabolic steroids
► It causes varying degrees of virilization and ambigius genitalia in female fetuses due to exposure. While labioscrotal fusion is observed as a result of exposure in the first trimester, phallic growth is observed in late fetal exposure.
danazol
► As a result of exposure in early pregnancy, dose-dependent cliteromegaly, labial fusion and urogenital sinus malformations are observed.
Diethylstilbesterol (DES)
► It increases the risk of vaginal clear cell cancer in girls with intrauterine exposure, and the risk of malignancy is not related to dose or timing of exposure. It also causes a 2-fold increase in the risk of vaginal and cervical intraepithelial neoplasia.
► In both sexes, it can cause genital tract anomalies. While hypoplasic uterus causes T-shaped uterine cavity, cervical anomalies (septum, etc.) and tubal anomalies in girls; It can cause hypospadias, epididymal cyst, microphallus, cryptorchidism and testicular hypoplasia in men. In the following years, it slightly increases the risk of early menopause and breast cancer in women.
Immunosuppressives
corticosteroids
► The use of corticosteroids in the first trimester causes a 3-fold increase in the occurrence of cleft palate-lip. However, their use in the following weeks does not cause malformation.
► Since prednisone is inactivated in the placenta, it has no effect on the fetus.
mycophenolate
► In case of exposure in the first trimester, 30% spontaneous abortion and 30% complex birth defects (mycophenolate embryopathy) are observed (Microtia, auditory canal atresia, cleft palate lip, coloboma and other eye anomalies, short fingers with hypoplastic nails, cardiac defects).
Retinoids
• They are derivatives of vitamin A and are the most teratogenic agents in humans (isotretinoin, acitretin and bexaroten). They cause CNS, face, heart and thymus anomalies by preventing neural crest migration during embryogenesis (retinoic acid embryopathy)
• Anomalies specific to retinoic acid embryopathy:
► Craniofacial anomalies: Microtia / anotia, micrognathia, cleft palate, facial bones and cranial deformities
► Cardiac anomalies: Conotruncal defects
► CNS anomalies: Ventriculomegaly
► Thymus anomalies: Aplasia, hypoplasia
Vitamin A:
• There are 2 natural forms of Vitamin A. The first of these is the precursor of vitamin A (Beta-carotene, which is found in fruits and vegetables. It is not teratogenic. The use of the other form, retinol, at a dose of more than 10,000 IU/day in the 1st trimester is associated with cranial neural crest defects.
Bexarotene:
• Use of bexarotene, a retinoid class, during pregnancy causes eye-ear anomalies, cleft palate and ossification defects.
Isotretinoin:
• One of the most patented teratogens. While it causes abortion at a high rate when exposed in the first trimester, malformation is observed in one third of the living fetuses.
Acitretin:
• Although it has a short half-life, it is metabolized to etretinate and, since the half-life of etretinate is 120 days, even discontinuation during the preconceptional period may not protect it from malformation. It is recommended not to become pregnant until 3 years after stopping the drug.
Other Items
Alcohol
► Ethyl alcohol is a strong teratogen and causes preventable developmental disorders (dysmorphic facial appearance, growth retardation, structural brain abnormalities, neurobehavioral disorders). There are no established ultrasonographic criteria for the prenatal diagnosis of fetal alcohol syndrome. There is no safe alcohol level during pregnancy and overdose has been associated with stillbirths. Omphalocele and gastroschisis cases have also been reported with periconceptional alcohol use.
Cocaine
► Congenital anomalies associated with cocaine use include cleft palate, cardiovascular anomalies and urinary system anomalies.
Opiads and narcotics
► They are not considered major teratogens; however, they cause a slight increase in the risk of spina bifida, gastroschisis and cardiac anomalies as a result of periconceptional exposure.
Cigarette
► Smoking is fetotoxic and has many vasoactive effects.
► Congenital anomalies associated with smoking due to vasoactive effects: Poland syndrome, congenital heart diseases, hydrocephalus, microcephaly, gastroschisis and omphalocele, cleft palate and lip, hand anomalies
► Obstetric risks associated with smoking: IUGR, low birth weight, SGA, sudden infant death syndrome, spontaneous abortion, placenta previa, ablatio placenta, premature rupture of membranes, preterm birth, uteroplacental insufficiency, fetal death.
Coffee
► Excessive consumption (5 cups/day or 500 mg of caffeine) every day
slightly increases the risk.
Caffeine, amphetamine, heroin, methadone and marijuana are not teratogens, but they can cause growth retardation.
OTHER TERATOGENS
Thalidomide and Lenalidomide
► 35-50 of pregnancy. Causes 20% malformation when taken on days Its characteristic malformation is the absence of one or more long bones (phocomelia). Cardiac, gastrointestinal, outer ear anomalies, eye anomalies and other extremity reduction defects are other common anomalies.
Radioactive iodine ( Iodine 131 )
► Radioactive iodine is contraindicated in pregnancy. It can cause severe and irreversible fetal and neonatal hypothyroidism by causing ablation of fetal thyroid tissue.
Bullet
► It is associated with fetal growth retardation and behavioral abnormalities.
Mercury
► Associated with microcephaly and severe brain damage.
Ionizing Radiation
► There is no malformation effect of ionizing radiation below 5 rad (0.05 Gy) during pregnancy .
► While microcephaly is the most common fetal anomaly when exposed to high doses of x-rays in the first 8 weeks of pregnancy, the exposure period is 8-15, when radiation-induced mental retardation is most likely. week range.
Phencyclidine and Lysergic acid are not teratogenic.
VACCINES IN PREGNANCY
Vaccines that are absolutely contraindicated
• Mumps
• Measles
• Rubella (Rubella)
• Chickenpox (Varicella zoster)
• Smallpox vaccine
• Anthrax; Theoretically, it is teratogenic.
Vaccines that can be used as needed
• influenza
• Rabies
• Hepatitis B
• Hepatitis A
• pneumococcus
• Meningococcus
• Diphtheria, pertussis and tetanus: 27-36 for each pregnant woman. A single dose is recommended between weeks.
Vaccines that are not routinely recommended but can be given as mandatory
• Oral or subcutaneous polio
• typhoid
• yellow fever
Although teratogenicity has not been observed in HPV vaccines, it is not recommended for use during pregnancy.