PHARMACY AND PREGNANCY: A REVIEW

PHARMACY AND PREGNANCY: A REVIEW

Aditi Thakur*¹, Harman Kaur Gill ¹, Ajay Sharma ², Nipun Mahajan ¹ and Shruti Rawal ¹

Department of Pharmaceutical Sciences, Lovely School of Pharmaceutical Sciences, Lovely Professional University ¹, Phagwara- 144402, Punjab, India

Department of Chemistry, Lovely School of Sciences (Chemistry), Lovely Professional University ², Phagwara- 144402, Punjab, India

ABSTRACT

Pregnancy is a state of double danger i.e. any drug that a pregnant woman takes can easily cross placenta and can produce a teratogenic effects on fetus. It can interfere with normal embryonic or fetal development and induce abnormal post natal structure or function. Teratogens alter the genetic function of fetus. This review provides practitioners with summary of information regarding teratology risks for drugs, chemical exposure during pregnancy.

Thalidomide

INTRODUCTION: Pregnancy is the term used to describe when a woman has a growing fetus inside of her. In most cases, the fetus grows in the uterus. Human pregnancy lasts about 40 weeks or just more than 9 months, from the start of the last menstrual period to childbirth. Each pregnancy is divided into three trimesters. These three trimesters have different emotional and physical happenings that make them unique.

• The First Trimester (Weeks 1-12)
• The Second Trimester (Weeks 13-27)
• The Third Trimester (Weeks 28-40)

A Double Danger: For a pregnant woman, drug abuse is doubly dangerous. First, drugs may harm her own health, interfering with her ability to support the pregnancy. Second, some drugs can directly impair prenatal development. Drugs taken by a pregnant woman reach the fetus primarily by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the fetus's growth and development.

Drugs that a Pregnant Woman takes during Pregnancy can affect   the Fetus in several ways:

• They can act directly on the fetus, causing damage, abnormal development (leading to birth defects), or death.
• They can alter the function of the placenta, usually by causing blood vessels to narrow (constrict) and thus reducing the supply of oxygen and nutrients to the fetus from the mother. Sometimes the result is a baby that is underweight and underdeveloped.
• They can cause the muscles of the uterus to contract forcefully, indirectly injuring the fetus by reducing its blood supply or triggering preterm labor and delivery.

How Drugs Cross the Placenta: Some of the fetus's blood vessels are contained in tiny hair like projections (villi) of the placenta that extend into the wall of the uterus. The mother's blood passes through the space surrounding the villi (intervillous space). Only a thin membrane (placental membrane) separates the mother's blood in the intervillous space from the fetus's blood in the villi. Drugs in the mother's blood can cross this membrane into blood vessels in the villi and pass through the umbilical cord to the fetus ¹.

Drug Metabolism in Pregnancy: During pregnancy, changes in drug absorption, metabolism, distribution, and elimination occur. Because of the dynamic nature of these changes, it is often difficult to predict which factors will have a significant impact on drug pharmacokinetics. Changes in gastrointestinal function that occur during pregnancy may affect the drug absorption ². Delayed gastric emptying may delay peak drug levels ³. Prolonged intestinal transit time may increase the absorption of some relatively water-insoluble drugs or increase the metabolism of drugs by intestinal wall enzymes. Decreased gastric acid secretion may change the gastric pH and alter drug solubility.

Changes in body fluid compartments during pregnancy can profoundly affect drug distribution. Increases in maternal plasma volume and the enlarging fetal compartment increase the volume of distribution of many drugs, altering maternal plasma drug concentrations and elimination half-life. The progressive decrease in maternal albumin concentration causes a corresponding increase in unbound drug fraction.

Because pharmacological efficacy and toxicity are related primarily to the concentration of unbound drug, pregnancy-induced changes in protein binding may have important clinical implications, especially for acidic drugs that are highly protein-bound ³. The 50% increase in the maternal glomerular filtration rate that occurs during pregnancy results in the increased elimination of renally excreted drugs. Drug levels of phenytoin (Dilantin) and carbamazepine (Tegretol) decrease in pregnancy, presumably because of increased P450 activity ⁴. Progesterone induces certain cytochrome P450 enzymes and other mixed function oxidase enzymes. These hormone activities can have confounding effects on drug metabolism and make drug levels difficult to predict. Placental and fetal factors influence the effect of maternal medications on the developing fetus. Although most chemicals enter the fetal circulation by simple diffusion, some cross the placenta by facilitated or active transport processes ⁵. The placenta contains enzymes capable of drug oxidation, reduction, hydrolysis, and conjugation.

Placental cytochrome P450 enzymes may play a role in fetal protection in the bio-oxidation of xenobiotics; including drugs ⁶. Fetal tissues are also capable of metabolizing drugs. Although this contributes little to drug clearance, which is largely effected by maternal systems, it may contribute to fetal toxicity through the accumulation of toxic drug metabolites.

This mechanism may be particularly important for polar drugs, which do not readily cross the placenta back to the maternal circulation. Fetal albumin concentrations are below maternal levels early in pregnancy and then rise progressively.  Early in pregnancy, fetal unbound drug concentrations may be high, even when maternal drug concentrations are low, resulting in toxicity to the fetus. This potential toxicity during the first trimester, the period of major organogenesis, underlies the recommendations for the conservative use of medications during early pregnancy.

Drugs and the Stages of Pregnancy: Some drugs can be harmful when used at any time during pregnancy; others, however, are particularly damaging at specific stages.

The stage of Organ Formation: Most of the body organs and systems of the baby-to-be are formed within the first ten weeks or so of pregnancy (calculated from the date of the last menstrual period). During this stage, some drugs and alcohol in particular can cause malformations of such parts of the developing fetus as the heart, the limbs, and the facial features.

The Stage of Prenatal Growth: After about the tenth week, the fetus should grow rapidly in weight and size. At this stage, certain drugs may damage organs that are still developing, such as the eyes, as well as the nervous system. Continuing drug use also increases the risk of miscarriage and premature delivery. But the greatest danger drugs pose at this stage is their potential to interfere with normal growth. Intrauterine growth retardation (IUGR) is likely to result in a low-birth weight baby- a baby born too early, too small, or both.

The Stage of Birth: Some drugs can be especially harmful at the end of pregnancy. They may make delivery more difficult or dangerous, or they may create health problems for the newborn baby.

TERATOGEN: Teratogen is a substance, organism, physical agent, or deficiency state present during gestation that is capable of inducing abnormal postnatal structure or function (biochemical, physiologic or behavioral) by interfering with normal embryonic or fetal development if fetal exposure to these agents occurs during pregnancy. A child born with any kind of malformation or with any birth defect may create societal problems and therefore this subject needs concern ⁷.

FDA Rating System for the Teratogenic Effects of Drugs: FDA provides the most widely used system to grade the teratogenic effects of medications. The FDA assigns a safety category for medications by using a 5-letter system: A, B, C, D, and X. This safety category must be displayed on the labels of all drugs intended to be used during pregnancy ⁸. The category & the labeling of drugs are summarized in table 1.

TABLE 1: SUMMARY AND LABELING ON DRUGS TO BE INTENDED DURING PREGNANCY

Principles of Teratogenesis:

1. Susceptibility to a teratogenic agent is dependent upon the genotype of the embryo and the manner in which the agent interacts with environmental factors.
2. Susceptibility to teratogenic agents is dependent on the timing of the exposure and the developmental stage of the embryo.
3. Teratogenic agents act in specific ways on cells or tissues to cause pathogenesis.
4. The final manifestations of abnormal development are death, malformation, growth restriction and functional disorders.
5. Access to the embryo by environmental Teratogens depends on the nature of the agent.

1. As the dosage increases, manifestation of deviant development increases.

Drug Exposure in the Male Partner: Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy. Certain exposures may alter the size, shape, performance, and production of sperm. This observation suggests that drug exposure in the male may put the fetus at risk. Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop. However, unlike teratogenic agents affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development. Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure ^{9 10}.

TABLE 2: LIST OF TERATOGENIC AGENTS AS PER FDA

Drugs Withdrawn From Market Because Of Their Teratogenic Effects:

Diethylstilbestrol (DES): It is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers. From about 1940 to 1970, DES was given to pregnant women under the mistaken belief it would reduce the risk of pregnancy complications and losses. In 1971, DES was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in uterus ¹⁰⁸. The US FDA subsequently withdrew DES from use in pregnant women.

Thalidomide: Thalidomide is an immunomodulatory agent used for the acute treatment of erythema, nodosum leprosum, a cutaneous manifestation of Hansen's disease (leprosy). Thalidomide was introduced into clinical medicine in West Germany in 1956.

Although a wide range of indications was promoted for the drug; it was used as hypnotic and sedative. Thalidomide was one of the first drugs that was clearly shown to be a human teratogen and probably has caused more known severe malformations in humans than any other drug ¹⁰⁹.

Several reviews have described the various human systems affected by thalidomide-induced embryopathy. One of these reviews presented the pregnancy history of two children (twins), born in the United States, who had very different severity of thalidomide embryopathy The first twin, a 2211-g female, was born with duodenal atresia, a rectoperineal fistula, and hypoplastic, dislocated thumbs (right thumb worse than left). The other twin, a 2240-g male, had phocomelia of both upper extremities and a midline hemangioma on the forehead. Missing or hypoplastic digits were noted on both hands.

Because of the concern over birth defects, thalidomide was withdrawn from the market in most countries in late 1961.

Teratogenic Counseling: In counseling the pregnant patient exposed to a potential human teratogen, it is important to emphasize the significance of exposure to the patient ¹⁰⁹. Ascertaining the clinical facts regarding the nature of the exposure: the length, dosage, and timing of exposure during pregnancy, as well as other exposures of concern about which the patient may not ask (e.g., alcohol, cigarette smoking). All available current data regarding the agent are then collected, and conclusions regarding the risks of exposures are drawn.

Counseling should include the background human baseline risk for major malformations, whether the fetus is at increased risk, which anomaly has been associated with the agent in question, a risk assessment, methods of prenatal detection, when available, limitations in our knowledge, and limitations of prenatal diagnostic capabilities. Additional aspects include the potential risk of the medical condition for which a drug is prescribed, known interactions (in both directions) between the disease state and the pregnancy and preventive measures, when applicable (e.g., folic acid supplementation in the case of carbamazepine exposure).

Because more than 50% of pregnancies in North America are unplanned, teratogenic risk assessment should be started prior to pregnancy.

CONCLUSION: There are no absolute teratogens; however, many agents can exhibit teratogenic effects under certain circumstances. The dose and the time of exposure to a particular agent often determine the severity of the damage and the type of defect that occurs. The dose response is obvious: the greater the dose, the greater the effect. The time of exposure is another important concept, as certain stages of embryonic and fetal development are more vulnerable than others.

In general, the embryonic stage (first trimester) is more vulnerable than the fetal period (second and third trimesters).  Thalidomide provides a classic example. The critical period of exposure is during organogenesis (the formation of the organs) from the 35th-48th day after the last menstrual period. The specificity of the malformations is linked to the time of exposure: 35-37 days, no ears; 39-41 days, no arms; 41-43 days, no uterus; 45-47 days, no tibia; and 47-49 days, triphalangeal thumbs. The types or severity of abnormalities caused by a teratogenic agent is also dependent on the genotype of the pregnant woman and the genotype of the fetus (genetic susceptibility).

For example, variation in maternal metabolism of a particular drug will determine what metabolites the fetus is exposed to and the duration of exposure. Differences in placental membranes, placental transport and biotransformation all affect fetal exposure. The genetic susceptibility of the fetus to a particular teratogenic agent will also have an effect on the final outcome.

It is therefore advised to go for the genetic counseling before conceiving the baby.

1. The use of teratogenic drugs should be avoided during pregnancy in less severe (non life-threatening) diseases such as acne and psoriasis.
2. It is necessary to select non-teratogenic drugs instead of teratogenic drugs during pregnancy if possible and not harmful for pregnant women. The best example for this strategy is to replace coumarin derivative with heparin in early pregnancy.
3. The necessary use of teratogenic drugs may have to be continued in severe maternal diseases such as epilepsy and cancer if the discontinuation of treatment causes worsening of the disease and pregnant women agree with it.
4. Teratogenic drugs cannot cause CAs if the exposure is in the first month of gestation and in general after the third month of pregnancy. However, the fetotoxic effect of some drugs should be considered in the second part of pregnancy.
5. Recent effective ultrasound scanning can detect major fetal defects about the 18th-20th week of gestation with a high degree of efficacy. Thus we have a chance to evaluate the risk after the inadvertent or necessary use of teratogenic drugs during pregnancy. If serious fetal defects are detected, the couple can then be given information to help them decide whether to terminate their pregnancy or not.

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