TERATOGENIC EFFECTS OF DRUGS DURING PREGNANCY

August 13, 2020

TERATOGENIC EFFECTS OF DRUGS DURING PREGNANCY

TERATOGENIC EFFECTS OF DRUGS DURING PREGNANCY

INTRODUCTION:

Expecting a baby is just the beginning of some of life’s precious moments, if the baby is not healthy due certain reasons it’s a miserable thing for the parents and family. So, being cautious of the mother plays a major role. During pregnancy most women are prescribed to treat ASTHMA, HYPERTENSION, THYROID, the physician should be aware of the dosage, effect of the drug while prescribing because some drugs can cause birth defects. Teratogenic exposures during prenatal development cause disruptions regardless of the developmental stage or site of action. Exposure of teratogen during 1^st trimester results in loss of conceptus, 2^nd trimester results structural deformities, 3^rd trimester leads defects in growth and functions of organs.

HISTORY:

✧ Teratology evolved as a science with the publication of a set of experiments in which pregnant pigs were fed a diet deficient in vitamin A during 1930.

✧ There are several other teratological discoveries in our history

[table 1].

✧ To control birth defects there are organizations working, “International Clearinghouse of Birth Defects Surveillance and Research” Affiliated to WHO established in 1974, “Food and Drug Administration in 1906.

Historical Recognition of Chemical Teratogenesis in Humans

Year Discovered	Drug	Approximate number of cases malformed
1903	Antithyroid compounds	140
1950	Aminoglycoside antibiotics	60
1952	Anticancer agents	50
1953	Androgenic hormones	250
1956	Tetracyclines	Thousands
1961	Thalidomide	7700
1963	Phenytoin	Hundreds
1965	Hypervitaminosis A	20
1966	Coumarin anticoagulants	55
1967	Alcohol	Thousands
1970	Methadone anticonvulsants	40
1970	Lithium	25
1970	Diethylstilbestrol	Hundreds
1971	Penicillamine	5
1976	Primidone	25
1982	Valproic acid	100
1983	Vitamin A analogues	115
1987	Cocaine	Hundreds
1988	Carbamazepine	70

Reference : Teratogen exposure,March8 2016

Table:1 Updapted from Turner GM, Twining P. The facial profile in the diagnosis of fetal abnormalities. Clin Radiol 1993;47:389–395 and from Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York: Marcel Dekker.

PRECONCEPTION EXPOSURE:

In females:

✔ The preconception period is a particularly important window of susceptibility because during this time period, unfertilized female

germ cells[Primordial,Primary,Preantral Antral follicles] can be altered by chemical exposures. Effect of the exposure depends on the stage of the follicle.[ex.chemotherapeutic agents, polyaromatic hydrocarbons, and 4-vinylcyclohexene diepoxide]

✓ .Primordial follicle pool is established at birth and is non-renewable, preconception exposures that completely deplete the primordial follicle pool will cause permanent infertility, whereas exposures that partially deplete the primordial follicle pool will cause and premature ovarian failure.

✓ Recent studies suggest that some preconception exposures can cause multi-generational and transgenerational effects[figure1&2]. Multi-generational effects are effects that occur in the generations that were directly exposed to the toxicant. Transgenerational effects are effects that occur in the generations that were not directly exposed to the toxicant, thus indicating epigenetic inheritance of traits.

In males:

✔ Paternal exposures may have adverse effects on male germ cells, decreasing germ cell numbers, and/or altering germ cell integrity.

✔ These effects may lead to outcomes that include infertility, pregnancy loss or spontaneous abortion and birth defects, or effects that are manifested only later in life, such as childhood cancer, behavioral effects or learning deficits and metabolic syndrome.

✔ We also now have evidence that some paternally-mediated adverse effects on progeny may be transmitted to subsequent generations.

✔ Usually, male germ cells require 64 days to mature into functional spermatogonia, drug exposure during the 2 months before conception could cause gene mutations, it may be that epigenetic pathways suppress germ-cell apoptosis or interfere with imprinting.

✔ Another possibility is that during intercourse the developing embryo is exposed to a teratogenic agent in seminal fluid.

ROLE OF PLACENTA:

✔ It was assumed that human placenta serves as a barrier, protecting the fetus from exposure to xenobiotics circulating in the mother, but the thalidomide disaster completely changed this view.

✔ Almost all drugs pass through the placenta, some help in the development and other drugs may even have the teratogenic potential.

Mechanism of drug transfer:

Drugs that transfer from the mother to fetus blood must be carried into the intervillous space and pass through the syncytiotrophoblast, fetal connective tissue, and the endothelium of fetal capillaries. The rate-limiting barrier for placental drug transfer is the layer of syncytiotrophoblast cells covering the villi.

Developmental stages

Pre-Embryonic period

Embryonic period

Fetal period

Teratogenic susceptibility

Low

High

Moderate

Potential outcome

Spontaneous abortion

Major malformations

Growth, minor malformations,

Functional abnormalities

Medications that shows teratogenic effects:

ANTIBIOTICS

TERATOGENS

Trimester

Malformations

Recommendations

Aminoglycosides

[streptomycin,

Amikacin,

gentamicin, neomycin,

Spectinomycin]

Mostly in 1^st trimester but not consistent

Ototoxicity, Nephrotoxicity

Should only be used parenterally in life threatening infections when first line choice antibiotics fail. Serum levels should be monitored regularly.

Tetracyclines

[ Doxycycline,

Demeclocycline,

Minocycline,

Tigecycline ]

2^nd and 3^rd trimester

Yellow-Brownish discoloration of the bone and teeth.

Local therapy is not problematic.

Sulfonamides

Trimethoprim

[folate antagonist]

Sulfamethoxazole and trimethoprim

3^rd trimester

1^st trimester

Increase the unbound bilirubin.

Neural Tube and cardiac defects.

Urinary tract defects.

Antineoplastic medications:

Teratogens

Period

Malformations

Anti -neoplastic agents

[busulfan, chlorambucil]

1^st ,2^nd ,3^rd trimesters

Retarded growth, cleft palate, spinal defects, ear defects& club foot.

Thalidomide

1^st ,2^nd ,3^rd trimesters

Malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies, phocomelia

Cardiovascular medications:

Teratogens	Period	Malformations	Recommendations
Ace inhibitors [benazepril, captopril,fosinopril, Lisinopril, perindopril, Ramipril,tandropril]	1^st ,2^nd ,3^rd trimesters	oligohydramnios, intrauterine growth restriction , premature labor, and fetal and neonatal renal failure[during pregnancy]. Bony malformations, limb contractures, persistent patent ductus arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged hypotension, neonatal death, fetal calvarial hypoplasia or aplasia, oligohydramnios, and renal anomalies[birth defects].	Accidental application during pregnancy requires an immediate change to recommended antihypertensive drugs. A follow-up sonography can be offered,and the newborn should be watched for his or her renal function and possible hypotension.
Aspirin	1^st ,2^nd ,3^rd trimesters	oculoauriculovertebral dysplasia, neonatal salicylate toxicity, constricted ductus arteriosus [high doses]	Low dose of aspirin is indicated if necessary.
Atenolol [tenormin]	1^st ,2^nd ,3^rd trimesters	Immature and premature births.
Statins [HMG CoA reductase inhibitors]	1^st ,2^nd ,3^rd trimesters	Spina bifida

Neurological medications:

Teratogens

Period

Malformations

Recommendations

Anticonvulsants

[phenytoin,

Phenobarbitone,

valproic acid]

Carbamazepine

1^st ,2^nd ,3^rd trimesters

Neurological hyperexcitability and Multiple malformations, Facial dysmorphia, Gingival hyperplasia.

Microcephaly, limb defects, complete or partial absence of a limb, overgrowth, or underdevelopment of the fingers, toes, and nails, fused limbs; spina bifida.

If used , the medication

level needs to be regularly monitored. A follow-up sonography should be

offered to ascertain the normal development of the fetus.

Trimethadione

1^st ,2^nd ,3^rd trimesters

cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities; delayed mental and physical development

Psychiatric Medications:

Teratogens

Period

Malformations

Recommendations

Lithium[anti-

depressants]

Unknown

Cardiac defects, lethargy, Ebstien anomaly[tricuspid valve malformation]

Exposure to lithium in the early first trimester, ultrasound examination or a fetal echocardiogram done to evaluate fetal cardiac development.

The frequency of dosing should be increased . Discontinue dose 24–48 hours before a scheduled induction or caesarean delivery or with the

onset of labour.

Endocrine medications:

Teratogens	Period	Malformations	recommendations
Oral contraceptives	1^st ,2^nd ,3^rd trimesters	variable	Stop taking the oral contraceptives or hormone replacement as soon as a positive pregnancy test is noted.
Corticosteroids	1^st trimester	Reduced birth weight, increased risk of preeclampsia, and increased risk of oral and lip clefts.	Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism
Estradiol gel 0.06 % (Estrogel, Elestrin)	1^st ,2^nd ,3^rd trimesters	Decrease in the quantity and quality of milk
Progesterones	1^st ,2^nd ,3^rd trimesters	Possible cardiovascular defects, hypospadias	Should avoid during pregnancy

Other drugs:

Teratogens	Period	Malformations	recommendations
Retinoids	1^st ,2^nd ,3^rd trimesters	Spontaneous abortion,heart defects neural tube defects.
Anticoagulants	1^st ,2^nd ,3^rd trimesters	I trimester- Fetal warfarin syndrome II & III trimester- increased malformations,decrease in the platelets in mother	Contraindicated except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism
Thyroid preparations		Overactive and enlarged thyroid gland in mother. Underactive in the fetus.

TEST FOR ASSESSMENT OF TERATOGEN PRENATALLY

There are two kinds of tests used in clinical medicine, SCREENING tests and DIAGNOSTIC tests.

Screening test gives the idea about the incidence of the condition in the general population. Diagnostic tests deal with the particular individual.But none of these tests can completely identify the abnormalities.

SCREENING TESTS:

sample

Test

Result

Maternal serum

Alpha-fetoprotein[AFP]

Open neural tube & abdominal wall defects

Maternal blood

Cell free fetal DNA

Aneuploidies

DIAGNOSTIC TESTS:

⮚ Preimplantation embryo biopsy:

This is done only in In Vitro Fertilization[IVF], biopsy is taken between day 3-5, usually done in couples for having a child with the risk of serious genetic disorders.Nucleic acid amplification such as Polymerase Chain Reaction[PCR],

Chromosomal microarray,gene sequencing are done to evaluate whether embryo is affected.

⮚ Chorionic villus sampling[CVS]:

Performed between 10-12 weeks to determine the genetic disorder based on family, personal history. CVS is obtained through suctioning the placental tissue through needle or thin tube,as the tissue has the same chromosomal make-up similar to embryo.This entire procedure is ultrasound guided and the route for tissue collection depends on the operator and the location of placenta in the uterus.

⮚ Amniocentesis:

Performed in the second trimester. Alpha-fetal protein concentration in amniotic fluid used to test the open neural defects, and the procedure is guided by ultrasound.

⮚ Fetal blood sampling:

Sample is collected directly from the fetus during the 18^th week, from the umbilical vein as close as possible to the placental insertion site.

All these procedures are associated with risk for miscarriage, hence they are not recommended, unless the couple having a greater risk of genetic and family history, under the experienced doctor.

⮚ Ultrasound imaging:

Ultrasound is useful for evaluating fetal growth and development, it cannot determine the underlying cause of an abnormality or provide much information about neurological functioning of the fetus.Ultrasound is used for both diagnostic and screening.

Ex. During the first trimester, thickening of fluid compartment in embryo’s neck is increased risk of chromosomal abnormalities[screening] but some embryo’s with increased neck fluid are normal, this has to be followed by further testing for chromosomal abnormalities.[figure.4]

Diagnostic by detecting the anencephaly.[figure.5]

Pregnant women have at least two ultrasound examinations.

One in the first trimester, second in 18-25 weeks of gestational age.

Conclusion :

The women during pregnancy should have at most care while using drugs. Some of the preventive measures in pregnancy regular intake of folate supplements,maintaining their weight, use the drugs only prescribed by doctors at mentioned dosages.

References:

1. Teratology general considerations and principles, https://www.researchgate.net/, Feb4 2018.

2. Teratology primer 3^rd edition, www.teratology.org/primer

3. Role of placenta on drug transfer and fetal exposure https://www.tandfonline.com, 16^th Jan 2018.

4. Drugs during pregnancy and Lactation Treatment options and

Risk assessment, 3rd edition by Christof Schaefer, Paul Peters, and Richard K. Miller.

5. Antibiotics in pregnancy :Toxicity and Teratogenicity, https://link.springer.com,

6. A Review of Antibiotic use in Pregnancy, https://doi.org

23^rd Nov 2015.

7. Teratology and Drugs Use During Pregnancy, https://emedicine.medscape.com, July 18^th 2017.

8. Drug Use in Pregnancy; a Point to Ponder! https://pubmed.ncbi.nlm.nih.gov, by P Sachdev, 2009.

Dr. Dwarakacharla Bhargavi

BDS

G. Pulla Reddy dental college and hospital- 2019

Clinosol I'd: CSRPL_INT_ONL_WKD_0081/20

Y. Sri Janaki

B. Pharmacy, MDHM

Dr. Samuel George Institute of pharmaceutical sciences-2012

Deccan school of hospital management-2015

Clinosol id :CSRPL_INT_ONL_WKD_0084/20