CHAPTER 9 Drug Therapy During Pregnancy and Breast-Feeding

The nurse is caring for a patient with epilepsy who is on anticonvulsant therapy and is also breast-feeding. Which patient teaching instruction should minimize the risk to the baby?

"Avoid drugs that have a long half-life." Dosing immediately after breast-feeding minimizes the drug concentration in milk. Drugs with a shorter half-life are excreted by the mother more quickly. If possible, drugs should be avoided during breast-feeding; however, patients with chronic illnesses, such as epilepsy, may require medication for their own health. The maternal fluid intake is not related to medication safety during breast-feeding.

A nurse is educating a breast-feeding patient about her medications. Which statements by the nurse are true?

"Drugs taken by lactating women can be excreted in breast milk." "Most drugs can be detected in milk, but concentrations are usually too low to cause harm." If drug concentrations in milk are high enough, a pharmacologic effect can occur in the infant." Drugs taken by lactating women can be excreted in breast milk. If drug concentrations in milk are high enough, a pharmacologic effect can occur in the infant, raising the possibility of harm. Unfortunately, very little systematic research has been done on this issue. Most drugs can be detected in milk, but concentrations are usually too low to cause harm. Although nearly all drugs can enter breast milk, the extent of entry varies greatly.

Pregnancy brings on physiologic changes that can alter drug disposition

. Changes in the kidney, liver, and GI tract are of particular interest. Because of these changes, a compensatory change in dosage may be needed.

What should be done if the exposure did occur during organogenesis?

1. First, a reference (such as Weiner C, Buhimshi C: Drugs for Pregnant and Lactating Women, 2nd ed. Philadelphia: Elsevier, 2009) should be consulted to determine the type of malformation expected. 2. Next, at least two ultrasound scans should be done to assess the extent of injury. - If the malformation is severe, termination of pregnancy should be considered. - If the malformation is minor (eg, cleft palate), it may be correctable by surgery, either shortly after birth or later in childhood.

Drug Therapy during Pregnancy: Basic Considerations

1. Physiologic Changes During Pregnancy and Their Impact on Drug Disposition and Dosing 2. Placental Drug Transfer 3. Adverse Reactions During Pregnancy

To prove that a drug is a teratogen, three criteria must be met

1. The drug must cause a characteristic set of malformations. 2. It must act only during a specific window of vulnerability (eg, weeks 4 through 7 of gestation). 3. The incidence of malformations should increase with increasing dosage and duration of exposure.

Congenital anomalies have multiple causes, including

1. genetic predisposition, 2. environmental chemicals, and 3. drugs.

Consistent with this derivation, we usually think of birth defects in terms of gross malformations, such as cleft palate, clubfoot, and hydrocephalus. However, birth defects are not limited to distortions of gross anatomy; they also include

1. neurobehavioral and 2. metabolic anomalies.

Drugs taken during pregnancy can adversely affect the patient as well as the fetus. Regular use of dependence-producing drugs (eg, heroin, barbiturates, alcohol) during pregnancy can result in the birth of a drug-dependent infant. If the infant's dependence is not supported with drugs following birth, a withdrawal syndrome will ensue. Symptoms include

1. shrill crying 2. vomiting 3. extreme irritability.

development occurs in three major stages:

1. the *preimplantation/presomite period* (conception through week 2), 2. the *embryonic period* (weeks 3 through 8), and the 3. *fetal period* (week 9 through term).

Genetic factors account for about ___of all birth defects.

25%

Drug use during pregnancy is common:

About two-thirds of pregnant patients take at least one medication, and the majority take more.

Essentially all drugs can cross the placenta, although some cross more readily than others. The factors that determine drug passage across the membranes of the placenta are the same factors that determine drug passage across all other membranes.

Accordingly, drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty. Nonetheless, for practical purposes, the clinician should assume that any drug taken during pregnancy will reach the fetus.

Although nearly all drugs can enter breast milk, the extent of entry varies greatly. The factors that determine entry into breast milk are the same factors that determine passage of drugs across membranes.

Accordingly, drugs that are lipid soluble enter breast milk readily, whereas drugs that are ionized, highly polar, or protein bound tend to be excluded.

Reducing the risk of teratogenesis also applies to female patients who are not pregnant, because about 50% of pregnancies are unintended.

Accordingly, if a patient of reproductive age is taking a teratogenic medication, she should be educated about the teratogenic risk as well as the necessity of using at least one reliable form of birth control.

The nurse is preparing to give a drug that is not classified according to a Pregnancy Risk Category. What should the nurse do?

Administer the medication, because the nurse knows that it was in use before 1983. Many drugs are not classified according to the U.S. Food and Drug Administration (FDA) Pregnancy Risk Categories. These drugs were in use before the classification system came into use in 1983. They are considered safe but may not have been studied in controlled trials. The pharmacy cannot assign a pregnancy risk category to a drug.

The nurse is caring for a pregnant patient who has chronic asthma. When administering medications to this patient, the nurse should do what?

Advise the patient that taking asthma medications during pregnancy improves fetal outcomes. Essentially all drugs can cross the placenta. Renal blood flow increases during pregnancy, which increases the clearance of some drugs, such as lithium. Lack of proof of teratogenicity does not mean that a drug is safe; it only means that the available data are insufficient to make a definitive judgment. Uncontrolled maternal asthma is more dangerous to the fetus than the drugs used to treat it.

A nurse prepares to administer a newly prescribed medication to a 22-year-old woman. The insert in the medication package states, "Category X." Select the nurse's best action.

Ask the pt the date of her last menstral period Category X means that the drug will be harmful to the fetus if the patient is pregnant. The patient may not know she is pregnant; therefore, asking her when her last menstrual period occurred gives the nurse a better indication of whether the patient might be pregnant.

When a pregnant woman has been exposed to a known teratogen, what is the first step in identifying risks for malformation?

Determine exactly when the drug was taken. Determine exactly when the pregnancy began. When a pregnant woman has been exposed to a known teratogen, the first step is to determine exactly when the drug was taken and exactly when the pregnancy began. Other information is helpful but not necessary.

Most drugs can be detected in milk, but concentrations are usually too low to cause harm. While breast-feeding is usually safe, even though drugs are being taken, prudence is in order: If the nursing patient can avoid drugs, she should. Moreover, when drugs must be used, steps should be taken to minimize risk. These include

Dosing immediately after breast-feeding (to minimize drug concentrations in milk at the next feeding) • Avoiding drugs that have a long half-life • Avoiding sustained-release formulations • Choosing drugs that tend to be excluded from milk • Choosing drugs that are least likely to affect the infant Avoiding drugs that are known to be hazardous (see Table 9-3) • Using the lowest effective dosage for the shortest possible time

Of the genetically based anomalies, .

Down's syndrome is the most common

Pregnancy Risk Category C

Greater Risk Than B: Animal studies show a risk of fetal harm, but no controlled studies have been done in women. or No studies have been done in women or animals.

One of the greatest challenges in identifying drug effects on a developing fetus has been the lack of clinical trials, which, by their nature, would put the developing fetus at risk. To address this challenge, in 2009, the (FDA) launched the

Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP), a collaborative effort between the 1. FDA 2. Kaiser Permanente 3. Vanderbilt University 4. consortium of health maintenance organizations (HMOs) called the HMO Research Network Center for Education and Research in Therapeutics.

Which statement regarding adverse reactions during pregnancy is false?

One in five children is born with a malformation related to drug use during pregnancy.

PREGNANCY RISK CATEGORY X

Proven Risk of Fetal Harm: Studies in women or animals show definite risk of fetal abnormality. or Adverse reaction reports indicate evidence of fetal risk. The risks clearly outweigh any possible benefit. A statement on risk will appear in the "CONTRAINDICATIONS" section of drug labeling.

Pregnancy Risk Category D

Proven Risk of Fetal Harm: Studies in women show proof of fetal damage, but the potential benefits of use during pregnancy may be acceptable despite the risks (eg, treatment of life-threatening disease for which safer drugs are ineffective). A statement on risk will appear in the "WARNINGS" section of drug labeling

Pregnancy Risk Category A

Remote Risk of Fetal Harm: Controlled studies in women have been done and have failed to demonstrate a risk of fetal harm during the first trimester, and there is no evidence of risk in later trimesters.

A teratogenic drug, such as methotrexate, is most likely to cause learning deficits during which phase of fetal developmet?

Second and third trimesters Exposure to teratogens during the second and third trimesters usually disrupts function rather than producing obvious anatomic abnormalities. Exposure to teratogens during the first 2 weeks of pregnancy usually results in an "all-or-nothing" response that may result in fetal death. Exposure during the remainder of the first trimester may result in anatomic malformations.

Pregnancy Risk Category B

Slightly More Risk Than A: Animal studies show no fetal risk, but controlled studies have not been done in women. or Animal studies do show a risk of fetal harm, but controlled studies in women have failed to demonstrate a risk during the first trimester, and there is no evidence of risk in later trimesters.

For a drug to be a proven teratogen, which criteria must be met?

The drug must cause a characteristic set of malformations. The drug must act only during a specific window of vulnerability. The incidence of malformations should increase with increasing dosage and duration of drug exposure. To prove that a drug is a teratogen, three criteria must be met: The drug must cause a characteristic set of malformations; the drug must act only during a specific window of vulnerability (eg, weeks 4 through 7 of gestation); and the incidence of malformations should increase with increasing dosage and duration of exposure. Drugs are not tested in pregnant women. Studies in animals may be of limited value, in part because teratogenicity may be species-specific.

The incidence of major structural abnormalities (eg, abnormalities that are life threatening or require surgical correction) is between 1% and 3%. Half of these are obvious and are reported at birth. The other half involve internal organs (eg, heart, liver, GI tract) and are not discovered until later in life or at autopsy.

The incidence of minor structural abnormalities is unknown, as is the incidence of functional abnormalities (eg, growth delay, intellectual disabilities).

Through MEPREP, data were collected on 1,221,156 children born to 933,917 mothers who used drugs during pregnancy. Research based on these data sets has generated knowledge on drugs used to manage a large number of conditions, such as diabetes, depression, and fibromyalgia.

This and continuing research will provide a body of evidence to guide safer selection of drugs to manage conditions during pregnancy.

The drug effect of greatest concern is teratogenesis.

This is the production of birth defects in the fetus.

For some drugs, *hepatic metabolism* increases during pregnancy.

Three antiseizure drugs— 1. phenytoin 2. carbamazepine 3. valproic acid— provide examples.

According to the FDA Pregnancy Risk categories, which category represents the greatest risk for fetal harm?

X

The clinical challenge is to provide effective treatment for the patient while

avoiding harm to the fetus or nursing infant. Unfortunately, meeting this challenge is confounded by a shortage of reliable data on drug toxicity during pregnancy or breast-feeding.

Use of prostaglandins (eg, misoprostol), which stimulate uterine contraction,

can cause abortion

When a pregnant patient has been exposed to a known teratogen, the first step is to

determine exactly when the drug was taken, and exactly when the pregnancy began. If drug exposure was not during the period of *organogenesis (ie, weeks 3 through 8)*, the patient should be reassured that the risk of drug-induced malformation is minimal. In addition, she should be reminded that 3% of all babies have some kind of conspicuous malformation independent of teratogen exposure. This is important because, otherwise, the drug is sure to be blamed if the baby is abnormal.

Less than 1% of all birth defects are caused by

drugs.

Some drugs are used to treat 1. pregnancy-related conditions 2. chronic disorders 3. management of invasive conditions

examples pregnancy-related conditions: nausea, constipation, and preeclampsia. chronic disorders: hypertension, diabetes, and epilepsy. management of invasive conditions - nfectious diseases or cancer In addition to taking these therapeutic agents, pregnant patients may take drugs of abuse, such as alcohol, cocaine, and heroin.

The neonate should be weaned from dependence by

giving progressively smaller doses of the drug on which he or she is dependent. Additionally, certain pain relievers used during delivery can depress respiration in the neonate. The infant must be closely monitored until respiration is normal.

During the preimplantation/presomite period, teratogens act in an "all-or-nothing" fashion. That is,

if the dose is sufficiently high, the result is death of the conceptus. Conversely, if the dose is sublethal, the conceptus is likely to recover fully.

*Tone and motility* of the bowel *decrease* in pregnancy, causing

intestinal transit time to increase.

when heparin (an anticoagulant) is taken by pregnant patients, it can cause

osteoporosis, which in turn can cause compression fractures of the spine.

use of aspirin near term can

suppress contractions in labor. and increases the risk of serious bleeding.

A pregnant patient may have a disease that requires use of drugs that have a high probability of causing teratogenesis. Some anticancer drugs, for example, are highly toxic to the developing fetus, yet cannot be ethically withheld from the pregnant patient. If a patient elects to use such drugs,

termination of pregnancy should be considered.

Fetal sensitivity to teratogens changes during development, thus

the effect of a teratogen is highly dependent upon when the drug is given.

Gross malformations are produced by exposure to teratogens during

the embryonic period (roughly the first trimester). This is the time when the basic shape of internal organs and other structures is being established. Because the fetus is especially vulnerable during the embryonic period, pregnant patients must take special care to avoid teratogen exposure during this time.

Despite the imposing challenge of balancing risks versus benefits, drug therapy during pregnancy cannot and should not be avoided Because

the health of the fetus depends on the health of the mother, conditions that threaten the mother's health must be addressed. ex: Chronic asthma is a good example. Uncontrolled maternal asthma is far more dangerous to the fetus than the drugs used to treat it. The incidence of stillbirth is doubled among those pregnant patients who do not take medications for asthma control.

By the third trimester, *renal blood flow is doubled*, causing a large increase in glomerular filtration rate. As a result,

there is accelerated clearance of drugs that are eliminated by glomerular filtration. Elimination of lithium, for example, is increased by 100%. To compensate for accelerated excretion, dosage must be increased.

Because of prolonged transit, due to decrease in tone and motility of the bowel in pregnancy,

there is more time for drugs to be absorbed. In theory, this could increase levels of drugs whose absorption is normally poor. Similarly, there is more time for reabsorption of drugs that undergo enterohepatic recirculation, possibly resulting in a prolongation of drug effects. In both cases, a reduction in dosage might be needed.

The term teratogenesis is derived from teras, the Greek word for monster. Translated literally, teratogenesis means

to produce a monster.

Teratogen exposure during the fetal period (ie, the second and third trimesters)

usually disrupts function rather than gross anatomy. Of the developmental processes that occur in the fetal period, growth and development of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities.

Not only are pregnant patients subject to the same adverse effects as nonpregnant patients, they may also suffer effects unique to pregnancy. For example,

when heparin (an anticoagulant) is taken by pregnant patients, it can cause osteoporosis, which in turn can cause compression fractures of the spine. Use of prostaglandins (eg, misoprostol), which stimulate uterine contraction, can cause abortion. Conversely, use of aspirin near term can suppress contractions in labor. In addition, aspirin increases the risk of serious bleeding.

Although the current rating system is helpful, it is far from ideal. To address these concerns, in 2008 the FDA proposed major revisions. Specifically, the FDA plans to phase out the use of letter categories, and replace them with detailed information about the effects of drugs during pregnancy. The format employed will have three sections

• Fetal Risk Summary: This section will describe what we know about drug effects on the fetus, and will offer a conclusion, such as, "Human data indicate this drug increases the risk of cardiac abnormalities." • Clinical Considerations: This section will describe the likely effects if a drug is taken before a patient knows she is pregnant. The section will also discuss the risks to the pregnant patient and the fetus of the disease being treated, along with dosing information and ways to deal with complications. • Data: This section will give detailed evidence from human and animal studies regarding the information presented in the Fetal Risk Summary. At the time of publication, the new guidance was not yet available.

Identification of Teratogens For the following reasons, human teratogens are extremely difficult to identify:

• The incidence of congenital anomalies is generally low. • Animal tests may not be applicable to humans. • Prolonged drug exposure may be required. • Teratogenic effects may be delayed. • Behavioral effects are difficult to document. • Controlled experiments can't be done in humans.