INTRODUCTION:

Medications which are taken during the pregnancy have potential to show teratogenic effects and pregnancy-induced physiologic changes in the mother. Pregnancy alters the pharmacokinetics of ingested medications, and certain chemicals can reach the foetus and cause harm to it.^1,2 Public attitudes towards the use of medications during pregnancy and breast feeding have been shaped by historical events like the thalidomide crisis of the 1960s and the discovery in 1971 of teratogenic effects linked to the use of diethylstilboestrol.³

Received on 02.12.2024 Revised on 25.12.2024

Accepted on 09.01.2025 Published on 03.03.2025

Available online from March 07, 2025

Asian J. Res. Pharm. Sci. 2025; 15(1):92-98.

DOI: 10.52711/2231-5659.2025.00014

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

The process by which abnormalities arise in the foetus is known as Teratogenesis. A teratogen is what causes such a deformity. A chemical that produces anatomical defects in a developing embryo is frequently referred to as a "teratogen". Teratogens include things like radiation, chemicals (drugs), and pathogenic agents. Since many birth defects have uncertain etiology, they are the leading cause of infant death⁴. Many health issues, such as diabetes mellitus, hypertension, mental health issues, and other ailments that are inescapable and necessitate medical attention, can arise for pregnant women. Pregnancy is associated with a variety of medication prescriptions for the mother's nutritional needs and the healthy growth of the baby.

Teratogenesis, or drug-induced birth abnormalities, is special cases of adverse medication reactions. Teratogenicity is the term used to describe the long-term abnormalities in an organism's structure and function caused by drug exposure during the embryonic developing stages⁵. Expectant and pregnant women utilize medications on a regular basis^6,7. According to a different study, expectant moms were prescribed an average of 3.1 non-vitamin drugs⁸. A recent survey of pregnant French women revealed that 99% of them had at least one prescription filled, with an average of 13.6 drugs per woman⁹. However, the development of the foetus and the course of the pregnancy and breastfeeding may be adversely affected by pharmaceutical use throughout preconception, pregnancy, and lactation¹⁰. Given the widespread use of smoke and alcohol, risky lifestyle choices appear to pose the biggest risk to fetal development among environmental factors. Fetal alcohol syndrome, or at least its consequences, may be brought on by alcohol^11,12. The part that environmental contaminants such methyl mercury play in their teratogenic effects¹³.

What Is Teratology?

The term "teratology" comes from the Greek word "teratos" which meaning "monster." These anomalies may be evident or latent at birth due to the combined effects of internal and environmental stressors during the prenatal developing phase. The study of abnormal embryonic development and the reasons behind congenital defects and abnormal birth defects is known as teratology. Although these structural or anatomical defects may not be identified until later in life, they exist from birth. They may be seen inside the viscera or on the exterior of the body. Congenital defects account for about 20% of perinatal fatalities. Roughly 3% of newborns will have severe birth defects, while another 3% will have issues that are only identified later in life. The study of birth abnormalities, congenital malformations, and developmental diseases is known as teratology (sometimes known as CDDs)¹⁴.

History of Teratology:

Our knowledge of developmental toxicology was expanded by the thalidomide incident in the early 1960s, which showed an agent with minimal adult toxicity but significant embryo harm. Drug studies had to use doses high enough to cause maternal toxicity in order to boost confidence that a biologically relevant dose for that species was included in the test protocol¹⁵. Part of the solution to the problem of extrapolating results from animal experiments to humans is the realization that maternal disposition (metabolism and distribution) of the drug affects the medication's effect on the foetus. Thalidomide is not well absorbed when given orally to rats. Because of this, when the drug is administered in traditional oral teratology trials, the embryo does not receive a significant dose from the drug. The capacity of thalidomide to harm a foetus when it is made soluble in dimethyl sulfoxide and given parentally is similar to that of rabbits, a species that is particularly susceptible to the effects of thalidomide^16,17.

Pregnant pigs were fed a diet low in vitamin A as part of a 1930s investigation that revealed teratogenicity¹⁸. The teratogenic impact of thalidomide was becoming better recognized in the early 1960s¹⁹. Teratology, the study of deformities caused by the environment, emerged as a contemporary field of study in the 1930s following the publishing of a series of studies in which pregnant pigs were given a diet low in vitamin A¹⁵. Mammalian development was not as safeguarded as previously thought due to its residence within the mother, as evidenced by the subsequent defects in the progeny. Actually, these test’s findings shown that even seemingly insignificant changes to the environment could have catastrophic consequences for the developing baby²⁰. A human parallel to these experiments was documented in the 1950s, when some human fetuses were aborted with aminopterin. When the medication failed to stop the pregnancies, several deformed children were born¹⁷.

Principle of Teratology:

Principles of therapy in pregnancy:

A pregnant woman should be counseled about the use of immunizations during pregnancy and should avoid them. Prescription drugs should only be prescribed when clearly indicated, after weighing the benefits to the mother against the risks to the foetus and taking into account the stage of pregnancy and drug information. Drugs should be given at low effective doses and for the shortest effective time. Live vaccines: potential risks to the developing foetus²¹.

Principles of Therapy in Lactation:

Drugs taken systemically can enter the infant's system through breast milk; therefore, the lowest effective doses for the shortest amount of time should be administered. It is also advised to avoid taking contraindicated drugs or to cease breastfeeding. It is not advised to cease breastfeeding during mother medication therapy unless absolutely essential. Women who are HIV positive should not breastfeed. In certain instances, a mother may refuse to nurse her infant while taking medicinal medicines in order to continue lactation^22,23.

MECHANISM OF ACTION OF TERATOGENESIS:

Hyper acetylation: Histone acetylation status is impacted by this disorder, which interferes with embryonic development by altering chromatin structure and gene expression. Histone deacetylase (HDAC) enzyme inhibition may be the cause. In order to treat cancer when carcinogenesis is halted, HDAC inhibitors are employed as anticonvulsants (valproic acid). Epicedian, sodium butyrate, and TSA are examples of anticancer drugs. The axial skeletal abnormalities and neural tube anomalies that result from hyper acetylation caused by these medicines in animal embryos are examples of congenital malformations²⁴.

Cholesterol imbalance: For foetal growth, an excess of cholesterol is needed. This causes the levels of cholesterol to become unbalanced. During early pregnancy, the mother provides this biomolecule and passes it to the foetus through the placenta, as opposed to late pregnancy, which is dependent on the fetus's creation. For instance, the enzyme HMG CoA reductase, which is necessary for the synthesis of cholesterol, is inhibited by statins. A growing foetus may be harmed by the conversion of HMG-CoA reductase to mevalonate, which reduces cholesterol synthesis²⁴.

Alteration in folate metabolism and folate antagonism: Folate, sometimes known as water-soluble vitamin B, is a co-enzyme that takes part in the creation of purines and pyrimidine’s, methylate DNA, and transfers or receives a single carbon unit during biochemical reactions. During embryogenesis, increased cell growth and tissue proliferation require increased DNA synthesis, which is dependent on the availability of folate. To stop folate from being converted to tetra hydro folate, certain drugs compete with dihydrofolate reductase. The most common birth malformations associated with these medications include or facial clefts, neural tube abnormalities, and limb deformities²⁴.

Retinoic acid imbalance:

Due to the strong relationship between this precursor of vitamin A and vertebrate morphogenesis, an imbalance in the production and breakdown of retinoic acid can result in either an excess or a deficiency, which can be harmful to cells and embryos. For example, iso tretinoin may cause retinoic acid imbalance, which may lead to abnormalities of the axial and craniofacial skeleton²⁴.

Physiological Changes in Pregnancy:

When a sperm enters an egg, pregnancy results. The woman's fallopian tube is often where this process, known as fertilization, occurs. The fertilized egg starts dividing right away into a clump of developing cells. After ovulation, the fertilized egg implants into the uterine wall and begins to create the placenta, usually within five to seven days. Through the transfer of O2, CO2, amino acids, lipids, vitamins, and minerals from the mother's blood, the placenta sustains and nourishes the developing child. It permits the waste materials from the developing infant to be transferred as well. Until the kid reaches around the eighth week of life after being inserted into the uterus, it is referred to as an embryo. During this phase, development picks up speed as the specialized cells start to form the blood, muscles, bones, nervous system, and essential organs. The growing child is referred to as a foetus after the eighth week of pregnancy. It is 2.4cm long, with most of its internal organs developed and the beginnings of its external characteristics, including eyes, mouths, noses, and ears ²⁵.

As the foetus and placenta grow and put increasing burden on the mother, amazing changes in metabolism occur. The two most obvious physical changes are weight gain and changes in body shape. Weight gain is caused by increases in breast tissue, blood volume, and water volume in the form of extracellular and extravascular fluid. Cellular water content increases in fat and protein deposits as well as maternal storage. An average weight gain of 12.5 pounds kg is caused by pregnancy. Due to protein, the average pregnant woman adds one kilograms of weight. Furthermore, there is an increase in fibrinogen and a decrease in plasma albumin levels. Total body fat increases during pregnancy. Triglycerides, cholesterol, and lipoproteins decrease right after birth, while plasma lipid levels rise in the latter stages of pregnancy. The ratio of LDL to HDL increases throughout pregnancy²⁶.

Pharmacokinetics in Pregnancy:

The pharmacokinetics of drugs used by pregnant moms are impacted by the physiological changes that occur during pregnancy. The plasma volume of an expecting female increases by 30 to 50%, but her cardiac output and glomerular filtration rate increase in proportion. These variables may lead to sub therapeutic medication dosages and decreased circulation concentrations of some drugs (particularly those the kidneys remove). Furthermore, because body fat levels grow during pregnancy, there is a greater distribution of fat-soluble drugs. For heavily protein-bound drugs like anticonvulsants, the volume of distribution rises during pregnancy while the concentration of plasma albumin falls. The kidney and liver, which eliminate unbound drugs more quickly, counteract expanded distribution volume²⁷. When used with other common pregnant treatments like iron, vitamins, and antacids, some pharmaceuticals may bind to these other substances and become inactive.

Better blood flow promotes systemic drug absorption, which quickens the absorption of intramuscular drugs and speeds up the rate at which an effect begins. Last but not least, progesterone and estrogen modify the activity of hepatic enzymes, which may cause drugs to accumulate or impede their removal²⁸. Pregnancy-related physiological changes have an impact on the pharmacokinetics of medications taken by expectant mothers. During pregnancy, a woman's heart and plasma volume increase by 30% to 50%, respectively. Both the output and the rate of glomerular filtration increase correspondingly. These factors cause some drugs to have lower blood concentrations in a pregnant woman, possibly to sub therapeutic drug levels (especially for those that are removed by the kidneys). Additionally, body fat increases during pregnancy, increasing the amount of drugs that are distributed in a fat-soluble manner. Reduces in plasma albumin level associated with pregnancy increase the volume of distribution of drugs that are highly protein bound, including anticonvulsants. The effects of the higher volume of distribution are offset, though, by the kidneys and liver, which get rid of the unbound medications more quickly. Progesterone's action slows down the rate at which food leaves the stomach, especially during the third trimester, which delays the start of the medication's effects²⁷.

Placental Transfer of Drugs:

The placenta, which combines the mother's and the foetus' blood, is a helpful organ. The placenta maintains the health of the woman and the foetus by performing tasks including feeding, respiration, metabolism, excretion, and endocrine activity. A medication must diffuse through the placenta from the mother's circulation to the foetal circulation in order to have a teratogenic or pharmacological effect on the foetus. The drug's molecular weight, lipid solubility, pH difference, and protein binding are among its chemical properties that influence the rate of transfer. Medication that is unbound can pass through the placenta. Throughout pregnancy, foetal albumin levels rise while maternal albumin levels fall. As a result, the concentration of free medicine rises and passes through the placenta to reach the developing foetus²⁹. Medications that are low molecular weight-less than 500g/mole-cross the placenta easily. A higher molecular weight (between 500 and 1000 g/mole) causes some drugs to have trouble passing the placenta, while a lower molecular weight medication does not cross at all. Because of increased maternal and placental blood flow, decreased placental thickness, and increased surface area, medication trans placental transfer rises throughout the third trimester³⁰.

How Drugs Affect the Fetus:

Drug use by pregnant women can affect the growing baby in a number of ways. They might have an immediate negative impact on the foetus, leading to injury or abnormal development that might cause birth defects or even death. Additionally, they have the power to alter the placenta's normal functioning, typically by constricting blood vessels and reducing the quantity of oxygen and nutrients the foetus gets from the mother. An underweight and underdeveloped infant may result from this. They may also cause indirect harm to the foetus by cutting off its blood supply or by pushing the uterine muscles to contract violently, which could result in an early labor and delivery³¹.

Pregnancy and Drug Use:

One important aspect of improving human health and wellbeing is the use of drugs. To achieve the intended result, they must be utilized sparingly and with safety, effectiveness, and judgment³². Pregnant women who consume medications may expose her foetus to injury by way of the placenta, which also carries nutrients and oxygen that are vital to the fetus's growth and development. Consequently, unless it is absolutely necessary, drugs shouldn't be taken when pregnant³³.

Although it could be preferable to avoid medication while pregnant, some women have medical conditions (such asthma, epilepsy, or hypertension) that require intermittent treatment before becoming pregnant, so this isn't always possible and could even be dangerous. In addition, pregnancy can exacerbate pre-existing medical disorders like migraine headaches, which require prescription therapy, as well as cause the onset of new ones. If these conditions go untreated, the mother's and her child's health could deteriorate³¹. Pregnancy-related drugs that are essential to the developing fetus's health include vitamins, minerals, iron, and nutritional supplements. 8% of expectant mothers are said to need pharmaceutical therapy for a range of chronic conditions and pregnancy-related problems ³². Before even realising they are pregnant, many women take medicine in the first few weeks of their pregnancy. Pregnant women who receive a prescription for a drug other than a vitamin or mineral supplement comprise 59% of the population. Approximately 13% of expectant mothers consume herbal supplements through diet³¹. A well-established concern regarding medical therapy is the potential for certain drugs used during pregnancy to have adverse effects on the developing foetus³⁴.

Pregnant patients are generally excluded from medical trials, and results obtained from animal research may not always apply to humans. Since most practitioners have a very narrow perspective on the usage of pharmaceuticals during pregnancy, it might be difficult to treat pregnant women with particular medications. Clinical research on the safety of medications during pregnancy has encountered several obstacles because of the concern that taking medicine during pregnancy could kill or damage the foetus. Actually, the main sources of knowledge regarding the safety of medications during pregnancy are animal studies, case reports, and epidemiological research due to these limitations. The assessment of the dangers related to drug use during pregnancy is complicated by these methodologies³⁵. An investigation conducted in 2001 found that little was known about the safety or possible dangers of taking nearly 90% of the medications that the FDA approved between 1980 and 2000. This makes deciding whether or not to take medicine difficult for both medical professionals and expectant patients³¹.

How Nutrition Influence Development?

In humans and animals alike, congenital defects can be caused by deficiencies in specific vitamins. An iodine deficiency, which is necessary for the production of thyroid hormones, may be the cause of cretinism, a neurologic disorder marked by severe cognitive impairment. This discovery marks the earliest documented link between diet and birth outcome, dating back to the eighteenth century. A foetus that experiences an iodine deficiency during pregnancy may experience significant growth limitation, poor bone formation, and varied degrees of mental disability. When vitamin A deficiency was discovered in the 1930s, it was demonstrated that pigs were teratogenic. Warkany and collaborators then went on to outline the defects brought about by a vitamin A shortage in almost every organ system in the mouse. The most common cause of visual impairment and blindness in developing nations is still vitamin A insufficiency, even if it does not always lead to abnormalities in humans. Low levels of vitamin D in the mother are linked to decreases in newborn hypocalcaemia, limited growth, and decreased bone mineralization. Animals experiencing zinc shortage experience teratogenic effects that affect nearly every organ system as they mature. Maternal acrodermatitis enteropathy, a hereditary condition affecting zinc absorption, is associated with a higher frequency of defects in offspring. The negative effects of low copper during pregnancy have been demonstrated in numerous species, including humans. Heart atrophy and neonatal ataxia are observed in lambs deficient in copper. Severe cardiovascular and connective tissue abnormalities, together with cognitive dysfunction, usually result in the children' death by the age of three³⁶.

Diagnosis Of Birth Defects:

There is a 2-4 percent chance that a live birth will result in a birth defect. There isn't yet a prenatal screening or diagnostic procedure that can identify each of these concerns. Chorionic villi, mother blood, amniotic fluid, ultrasonography, or foetal blood are used in prenatal screening and diagnostic procedures³⁷.

Ultrasound:

Sonography, or ultrasonography, creates an image of a tissue's surface by reflecting sound waves. The level of detail in these embryonic and foetal pictures sometimes verges on photography. A gestational age can be determined, a healthy pregnancy can be confirmed, and twins or other multiple pregnancies can be identified with an ultrasound. The only prenatal test typically available to detect foetal abnormalities in cases of suspected or confirmed teratogenic exposure is ultrasound³⁷.

Maternal Serum Screening:

In order to ascertain whether the foetus is at risk for an open neural tube defect—spinal bifida being the most common—a test of the mother's serum alpha-fetoprotein (MSAFP) can be conducted between weeks 14 and 23 of pregnancy. Alpha-fetoprotein (AFP), which is excreted in the fetus's urine, is produced by the foetal liver. Nevertheless, some trans placental AFPs have been seen in maternal serum. Results are reported as a multiple of the mean, or Mom, due to the fact that amniotic and mean maternal serum AFP concentrations vary with gestational age³⁷.

Diagnostic testing:

Four different procedures can diagnose chromosomal abnormalities:

1. The earliest test that can be performed after in vitro fertilization is an early conception (IVF) biopsy, or pre implantation embryo biopsy. During days three or five, a fertilized egg breaks into progressively smaller cells, one or more of which can be taken for study. Couples who are at danger of passing on a significant genetic illness such as cystic fibrosis to their offspring occasionally use this strategy. Using molecular tools like chromosomal microarray and gene sequencing, together with nucleic acid amplification methods like polymerase chain reaction (PCR), individual genes from a single embryonic cell can be evaluated to determine whether the embryo will be damage.

2. CVS is carried out ten to twelve weeks following the last menstrual cycle. Placental tissue fragments known as chorionic villi are suctioned during CVS using a thin tube or needle. The chromosomal makeup of these placental tissue fragments is typically identical to that of the embryo. The chromosomal complement of the chorionic villi cells is examined once they have matured in culture. Samples can be taken during CVS under ultrasound observation through the cervix or the abdomen, depending on the operator's preference and the placenta's position in the uterus. The usual estimate for miscarriage rates is 1/400, although with highly skilled operators, the risk can be significantly reduced.

3. Amniotic fluid is collected during the second trimester through a procedure known as amniocentesis. Chromosome analysis uses cells derived from the foetal skin that have the same chromosomes as the remainder of the foetus. By searching for the presence of AFP in amniotic fluid, several defects, including an open neural tube, are suspected. Patients receiving amniocentesis under continuous ultrasonography supervision are advised that there is a 1/500 probability of miscarriage; however, with skilled operators, this risk can be minimized.

4. At eighteen weeks of pregnancy, foetal blood sampling entails taking a direct blood sample from the foetus. Blood must be drawn from the umbilical vein, preferably close to the placental implantation site, for this procedure, which entails a 1-3 percent risk of foetal loss. If a risk has been determined based on a family history, parent testing, or the findings of other tests, a sample of foetal blood for chromosome or genetic analysis may offer a quicker response to particular queries. Other test techniques, however, are typically chosen because of their less rigorous technological requirements³⁷.

Prevention of Birth Defects:

Preventing birth abnormalities at birth can save afflicted children and their parents a significant amount of money and effort. Primary prevention includes maintaining a healthy body weight, getting enough exercise, addressing illnesses in women before getting pregnant, quitting smoking, abusing alcohol, or using "recreational drugs," eating a diet rich in key vitamins and folic acid, and following other guidelines. Making informed decisions concerning future conception and resulting in more suitable treatment and counseling can benefit families who are aware of the possible causes of congenital abnormalities. It also has the ability to reduce anxiety and guilt. A woman and her healthcare practitioner are notified when a teratogenic reason is found, at which point birth control becomes available ³⁸.

CONCLUSION:

Teratology is the study of birth defects. It looks at how things like certain medicines, alcohol, chemicals, infections, or even the health of the mother can affect a baby while it’s growing in the womb. One important finding from teratology is that the time when a baby is exposed to something harmful is very important. For example, if a mother takes certain drugs or drinks alcohol during the early weeks of pregnancy, it might cause the baby to develop differently. This is because the early stages of pregnancy are when the baby’s organs are forming and are more easily affected. Scientists in this field have discovered which things are dangerous during pregnancy, like certain drugs and infections. Because of this research, doctors can now give better advice to pregnant women. For example, women are told not to smoke, drink alcohol, or take certain medications while they are pregnant. They are also encouraged to eat healthily and take vitamins like folic acid, which can help prevent some birth defects. In simple terms, the conclusion of teratology is that by knowing what can cause birth defects, we can help prevent them. This knowledge helps doctors give the right advice to pregnant women, leading to healthier babies.

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Received on 14.11.2024 Revised on 12.12.2024

Accepted on 06.01.2025 Published on 03.03.2025

Available online from March 07, 2025

Asian J. Res. Pharm. Sci. 2025; 15(1):87-91.

DOI: 10.52711/2231-5659.2025.00013

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.