Kristina E. Ward and Barbara M. O’Brien
KEY CONCEPTS
Complex physiology surrounds the process of fertilization and pregnancy progression.
Drug characteristics and physiologic changes modify drug pharmacokinetics during pregnancy, including changes in absorption, protein binding, distribution, and elimination, requiring individualized drug selection and dosing.
Although drug-induced teratogenicity is a serious concern during pregnancy, most drugs required by pregnant women can be used safely. Informed selection of drug therapy is essential.
Healthcare practitioners must know where to find and how to evaluate evidence related to the safety of drugs used during pregnancy and lactation.
Health issues influenced by pregnancy, such as nausea and vomiting, can be treated safely and effectively with nonpharmacologic treatment or carefully selected drug therapy.
Some acute and chronic illnesses pose additional risks during pregnancy, requiring treatment with appropriately selected and monitored drug therapies to avoid harm to the woman and the fetus.
Management of the pregnant woman during the peripartum period can encompass uncomplicated pregnancies/deliveries, but can also include a wide variety of potential complications that require use of evidence-based treatments to maximize positive maternal and neonatal outcomes.
Understanding the physiology of lactation and pharmacokinetic factors affecting drug distribution, metabolism, and elimination can assist the clinician in selecting safe and effective medications during lactation.
A controversial and emotionally charged subject because of medicolegal and ethical implications, drug use in pregnancy and lactation is a topic often underemphasized in the education of health professionals. Clinicians are responsible for ensuring safe and effective therapy before conception, during pregnancy and parturition, and after delivery. Active patient participation is essential. Optimal treatments of illnesses during pregnancy sometimes differ from those used in the nonpregnant patient.
In many cases, medication dosing recommendations for acute or chronic illnesses in pregnant women are the same as for the general population. However, some cases require different dosing and selection of medications. Principles of drug use during lactation, although similar, are not the same as those applicable during pregnancy.
PHYSIOLOGY OF PREGNANCY
Fertilization and progression of pregnancy are complex, resulting in survival of only approximately 50% of embryos.1 Because most losses occur early, usually in the first 2 weeks after fertilization, many women do not realize they were pregnant. Spontaneous loss of pregnancy later in gestation occurs in about 15% of pregnancies that survive the first 2 weeks after fertilization.2
Fertilization occurs when a sperm attaches to the outer protein layer of the egg, the zona pellucida, and renders the egg non-responsive to other sperm.3 The attached sperm releases enzymes that allow the sperm to fully penetrate the zona pellucida and contact the egg’s cell membrane. The membranes of the sperm and egg then combine to create a new, single cell called a zygote. Male and female chromosomes join in the zygote, fuse to create a single nucleus, and organize for cell division.4
Fertilization usually occurs in the fallopian tube.4 The fertilized egg travels down the fallopian tube over 2 days, with cell division taking place. By day 3, the fertilized egg reaches the uterus. Cell division continues for another 2 to 3 days in the uterine cavity before implantation. Approximately 6 days after fertilization, the cell mass is termed a blastocyst. Human chorionic gonadotropin (hCG) now is produced in amounts detectable by commercial laboratories. Implantation begins with the blastocyst sloughing the zona pellucida to rest directly on the endometrium allowing initiation of growth into the endometrial wall. By day 10 postfertilization, the blastocyst is implanted under the endometrial surface and receives nutrition from maternal blood.4 Now it is called an embryo.5
After the embryonic period (between weeks 2 and 8 postfertilization), the conceptus is renamed a fetus.6 Most body structures are formed during the embryonic period, and they continue to grow and mature during the fetal period. The fetal period continues until the pregnancy reaches term, approximately 40 weeks after the last menstrual period.5
Gravidity is the number of times that a woman is pregnant.6,7 A multiple birth is counted as a single pregnancy. Parity refers to the number of pregnancies exceeding 20 weeks’ gestation and relates information regarding the outcome of each pregnancy. In sequence, the numbers reflect (a) term deliveries, (b) premature deliveries, (c) aborted and/or ectopic pregnancies, and (d) number of living children.7A woman who has been pregnant four times; has experienced two term deliveries, one premature delivery, and one ectopic pregnancy; and has three living children would be designated G4P2113.
Characteristics of Pregnancy
Pregnancy lasts approximately 280 days (about 40 weeks or 9 months); the time period is measured from the first day of the last menstrual period to birth.6,7 Gestational age refers to the age of the embryo or fetus beginning with the first day of the last menstrual period, which is about 2 weeks prior to fertilization. When calculating the estimated due date, add 7 days to the first day of the last menstrual period then subtract 3 months. Pregnancy is divided into three periods of 3 calendar months, each called a trimester.
Early symptoms of pregnancy include fatigue and increased frequency of urination. At approximately 6 weeks’ gestation, nausea and vomiting can occur. While commonly called morning sickness, it can happen at any time of the day. Nausea and vomiting usually resolve at 12 to 18 weeks’ gestation. A pregnant woman can feel fetal movement in the lower abdomen at 16 to 20 weeks of gestation. Signs of pregnancy include cessation of menses, change in cervical mucus consistency, bluish discoloration of the vaginal mucosa, increased skin pigmentation, and anatomic breast changes.6,7
Pharmacokinetic Changes During Pregnancy
Normal physiologic changes that occur during pregnancy may alter medication effects, resulting in the need to more closely monitor and, sometimes, adjust therapy. Physiologic changes begin in the first trimester and peak during the second trimester. For medications that can be monitored by blood or serum concentration measurements, monitoring should occur throughout pregnancy.
During pregnancy, maternal plasma volume, cardiac output, and glomerular filtration increase by 30% to 50% or higher, potentially lowering the concentration of renally cleared drugs.8,9 As body fat increases during pregnancy, the volume of distribution of fat-soluble drugs may increase. Plasma albumin concentration decreases, which increases the volume of distribution of drugs that are highly protein bound. However, unbound drugs are more rapidly cleared by the liver and kidney during pregnancy, resulting in little change in concentration. Hepatic perfusion increases, which could theoretically increase the hepatic extraction of drugs. Nausea and vomiting, as well as delayed gastric emptying, may alter the absorption of drugs. Likewise, a pregnancy-induced increase in gastric pH may affect the absorption of weak acids and bases. Higher levels of estrogen and progesterone alter liver enzyme activity and increase the elimination of some drugs but result in accumulation of others.8,9
Transplacental Drug Transfer
Although once thought to be a barrier to drug transfer, the placenta is the organ of exchange for a number of substances, including drugs, between the mother and fetus. Most drugs move from the maternal circulation to the fetal circulation by diffusion.10 Certain chemical properties, such as lipid solubility, electrical charge, molecular weight, and degree of protein binding of medications, may influence the rate of transfer across the placenta.
Drugs with molecular weights less than 500 Da readily cross the placenta, whereas larger molecules (600 to 1,000 Da) cross more slowly.10 Drugs with molecular weights greater than 1,000 Da, such as insulin and heparin, do not cross the placenta in significant amounts. Lipophilic drugs, such as opioids and antibiotics, cross the placenta more easily than do water-soluble drugs. Maternal plasma albumin progressively decreases, while fetal albumin increases during the course of pregnancy, which may result in higher concentrations of certain protein-bound drugs in the fetus. Fetal pH is slightly more acidic than maternal pH, permitting weak bases to more easily cross the placenta. Once in the fetal circulation, the molecule becomes more ionized and less likely to diffuse back into the maternal circulation.10
DRUG SELECTION DURING PREGNANCY
Many misconceptions exist regarding the association of medications and birth defects. Although some drugs have the potential to cause teratogenic effects, most medications required by pregnant women can be used safely.
The baseline risk for congenital malformations is approximately 3% to 6%, with approximately 3% considered severe.2 Medication exposure is estimated to account for less than 1% of all birth defects. Genetic causes are responsible for 15% to 25%, other environmental issues (e.g., maternal conditions and infections) account for 10%, and the remaining 65% to 75% of congenital malformations result from unknown causes.2
Factors such as the stage of pregnancy during exposure, route of administration, and dose can affect outcomes.2,11 In the first 2 weeks following conception, exposure to a teratogen may result in an “all-or-nothing” effect, which could either destroy the embryo or cause no problems.11 During organogenesis (18 to 60 days post-conception), organ systems are developing, and teratogenic exposures may result in structural anomalies. For the remainder of the pregnancy, exposure to teratogens may result in growth retardation, CNS abnormalities, or death. Examples of medications associated with teratogenic effects in the period of organogenesis include chemotherapy drugs (e.g., methotrexate, cyclophosphamide), sex hormones (e.g., diethylstilbestrol), lithium, retinoids, thalidomide, certain antiepileptic drugs, and coumarin derivatives. Other medications such as non-steroidal antiinflammatory drugs (NSAIDs) and tetracycline derivatives are more likely to exhibit effects in the second or third trimester.
Medications are necessary during pregnancy for treatment of acute and chronic conditions. Identifying patterns of medication use before conception, eliminating nonessential medications and discouraging self-medication, minimizing exposure to medications known to be harmful, and adjusting medication doses are all strategies to optimize the health of the mother while minimizing the risk to the fetus. In summary, a small number of medications have the potential to cause congenital malformations, and many can be avoided during pregnancy. In situations where a drug may be teratogenic but is necessary for maternal care, considerations related to route of administration, dosage form, and dosing may lessen the risk.
Methods and Resources for Determining Drug Safety in Pregnancy
When assessing the safety of using medications during pregnancy, evaluation of the quality of the evidence is important. Ideally, safety data from randomized, controlled trials are most desirable, but pregnant women are not usually eligible for participation in clinical trials. Other types of data commonly used to estimate the risk associated with medication use during pregnancy include animal studies, case reports, case–control studies, prospective cohort studies, historical cohort studies, and voluntary reporting systems.
Animal studies are a required component of drug testing, but extrapolation of the results to humans is not always valid.12 Thalidomide was found to be safe in some animal models, but proved to have teratogenic effects in human offspring. The value of case reports is limited because birth defects in the offspring of women who used medication during pregnancy may occur by chance.12 Case–control studies identify an outcome (congenital anomaly), match subjects with and without that outcome, and report how often exposure to a suspected agent occurred. Recall bias is a concern, as women with an affected pregnancy may be more likely to remember drugs used during the pregnancy than those with a normal outcome.
Cohort studies evaluate the intervention (use of a particular drug) in a group of persons and compare outcomes in a similar group of subjects without the intervention.12,13 Prospective studies eliminate some of the problems with recall bias, but require time and large numbers of participants. Despite these disadvantages, cohort studies are often used for evaluating the effects of a drug exposure on pregnancy outcomes.
Teratology information services provide pregnant women with information about potential exposures during pregnancy and follow these women throughout the pregnancy to assess the outcomes of the pregnancy.12 Services may publish pooled data to facilitate information sharing about medications used during pregnancy. Some pharmaceutical companies have organized voluntary reporting systems (also called pregnancy registries) for drugs used during pregnancy.
Computerized databases (e.g., www.motherisk.org, LactMed [www.toxnet.nlm.nih.gov]), tertiary compendia, and textbooks with information from large cohorts of treated women offer valuable assistance. New information regarding drug use in pregnancy and lactation can be obtained from searches of the primary literature for cohort and case–control studies.
The FDA developed risk categories (i.e., A, B, C, D, X, with A considered safe and X considered teratogenic) to guide clinicians regarding medication risk during pregnancy. The FDA ranks very few drugs as safe during pregnancy (category A) because a controlled trial is required to establish safety; this implies that few drugs are safe. Because of multiple limitations of the risk categories, the FDA proposed a new system in 2008 to replace the risk categories with a fetal risk summary and lactation risk summary. Each section discusses clinical considerations and summarizes available data.14
In summary, determining drug safety during pregnancy is limited by the quality of data and the types of study designs that can be used. While information from product labeling may provide a rough estimate of risks for medication-related adverse fetal outcomes, careful evaluation of other available information sources is necessary to make decisions about medication use in pregnant women.
PRECONCEPTION PLANNING
Pregnancy outcomes are influenced by maternal health status, lifestyle, and history prior to conception. The goal of preconception care is health promotion, evidence-based screening, and intervention in all women of reproductive age to ensure optimal health and improve pregnancy outcomes.15 More than 60% of pregnancies in the United States are unintended. Of women who receive prenatal care, 18% seek it after the first trimester.16 Preconception planning is important, since some behaviors and exposures impart risk to the fetus during the first trimester, often before prenatal care is begun or even before pregnancy is detected.15 Table 61-1 lists selected preconception risk factors, the potential adverse pregnancy outcomes, and management or prevention options.
TABLE 61-1 Selected Preconception Risk Factors for Adverse Pregnancy Outcomes
The most common major congenital abnormalities are neural tube defects (NTDs), cleft palate and lip, and cardiac anomalies. Each year in the United States approximately 1 in 1,000 infants are born with NTDs.17 Folic acid supplementation of women substantially reduces the incidence of NTDs in their offspring. This is also true in women who have previously delivered babies with NTDs.16,17 NTDs occur within the first month of conception because neural tube closure occurs during the first month of pregnancy. Folic acid supplementation with between 0.4 and 0.9 mg daily is recommended throughout a woman’s reproductive years, since many pregnancies are unplanned and may not be recognized until after the first month.
Use of alcohol and recreational drugs during pregnancy is associated with birth defects.15 Of births in the United States in 2003, 10% were to mothers who smoked tobacco during pregnancy.15 Smoking can cause preterm birth, low birth weight, and other adverse outcomes. In a systematic review of 72 trials of smoking cessation and perinatal outcomes, incidences of low birth weight and preterm birth were reduced, and birth weight increased by 54 g with smoking cessation.18 Use of nicotine replacement during pregnancy is controversial, since its use is not supported by clinical trial data; however, nicotine replacement theoretically imparts less risk than exposure to the over 4,000 chemicals found in cigarettes.19
Clinical Controversy…
Smoking cessation during pregnancy is highly desirable but challenging. Smoking is known to cause spontaneous abortion, preterm birth, and increased perinatal mortality. Use of nicotine replacement therapy has been advocated by some, but nicotine does cross the placenta and has been shown to impair fetal growth in some animals.19 Clinical evidence on the use of nicotine replacement during pregnancy is limited as is evidence for other pharmacologic treatment options.
PREGNANCY-INFLUENCED ISSUES
Pregnancy causes or exacerbates conditions that pregnant women commonly experience, including constipation, gastroesophageal reflux, hemorrhoids, and nausea and vomiting. Women with pregnancy-influenced GI issues can be treated safely with lifestyle modification or medications, many of them nonprescription. Gestational diabetes, gestational hypertension, and venous thromboembolism (VTE) have the potential to cause adverse pregnancy consequences. Gestational thyrotoxicosis (GTT) is usually self-limiting.
GI Tract
Constipation during pregnancy is prevalent, affecting 25% to 40% of women and may contribute to the development or exacerbation of hemorrhoids; hemorrhoids are more prevalent in pregnant women compared with the general population.20,21 Light physical exercise and increased intake of dietary fiber and fluid should be instituted first for constipation.21 If additional treatment is needed, supplemental fiber and/or a stool softener is appropriate.22Osmotic laxatives (polyethylene glycol, lactulose, sorbitol, and magnesium and sodium salts) are acceptable for short-term, intermittent use. Some consider polyethylene glycol the ideal laxative for use in pregnancy.21,22 Senna and bisacodyl can be used occasionally. Castor oil and mineral oil should be avoided because they cause stimulation of uterine contractions and impairment of maternal fat-soluble vitamin absorption, respectively. Data supporting other management options for hemorrhoids during pregnancy are limited. Conservative treatment (i.e., high dietary fiber intake, adequate oral fluid intake, and use of sitz baths) should be tried first. Laxatives and stool softeners can be used if conservative management is inadequate for preventing or treating constipation. Topical anesthetics, skin protectants, and astringents (e.g., witch hazel) can be used for anal irritation and pain. Hydrocortisone may reduce inflammation and pruritis.20
Between 40% and 80% of pregnant women experience gastroesophageal reflux disease.21 An algorithm starting with lifestyle and dietary modifications (e.g., small, frequent meals; alcohol and tobacco avoidance; food avoidance before bedtime; elevation of the head of the bed) should be used. If symptoms are not relieved, antacids (aluminum, calcium, or magnesium preparations) or sucralfate are acceptable; however, sodium bicarbonate and magnesium trisilicate should be avoided. Histamine-2 (H2) receptor blockers can be used for patients unresponsive to lifestyle changes and antacids; evidence supports the use of ranitidine and cimetidine. Literature evaluating the use of famotidine and nizatidine is limited, but they are likely safe. Less data are available regarding the use of proton pump inhibitors (PPIs) during pregnancy. Although a recent cohort study of 5,082 live births with first trimester exposure to PPIs found no increased risk of major birth defects,23 use of PPIs should be reserved for women who do not respond to H2 antagonists.
Nausea and vomiting of pregnancy (NVP) is estimated to affect up to 90% of pregnant women. NVP usually begins during the fifth week of gestation and lasts through week 20; peak symptoms occur between weeks 10 and 16.21,24 Hyperemesis gravidarum (HG; i.e., unrelenting vomiting causing weight loss of more than 5% prepregnancy weight, dehydration, electrolyte imbalance, and ketonuria) occurs in 0.3% to 2.3% of women.25 Dietary modifications, such as eating frequent, small, bland meals and avoiding fatty foods, may be helpful. Applying pressure at acupressure point P6 on the volar aspect of the wrist may be beneficial. Pharmacotherapeutic approaches for NVP that have shown efficacy include pyridoxine (vitamin B6), and antihistamines (including doxylamine).24 Phenothiazines and metoclopramide are generally considered safe, but sedation and extrapyramidal effects, including dystonia, may limit use.24 Increasing evidence of safety and efficacy with ondansetron is emerging; ondansetron is better tolerated than older antiemetics.24 Corticosteroids are effective for HG but are associated with a small increase in the risk of oral clefts when used during the first trimester. Ginger has shown efficacy for hyperemesis in randomized, controlled trials and is probably safe.21,24
Gestational Diabetes
Gestational diabetes mellitus (GDM) is glucose intolerance of any degree identified during pregnancy, either of new onset or first recognition. It develops in about 7% of pregnant women, although the prevalence ranges from 1% to 14%.26,27 Risks of GDM are many and include fetal loss, increased risk of major malformations, and fetal macrosomia. Although the U.S. Preventative Services Task Force Independent Expert Panel found a lack of evidence proving that screening for gestational diabetes decreases adverse maternal and fetal outcomes, a consensus panel of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends universal screening of pregnant women not previously diagnosed with diabetes.26–29 At the first prenatal visit, all women considered high-risk for diabetes (e.g., obesity, glycosuria, strong family history of diabetes) should be screened for overt diabetes using either the A1C, fasting plasma glucose (FPG), or random plasma glucose (RPG).27,29 Overt diabetes occurs if the A1C is greater than or equal to 6.5% (0.065; 48 mmol/mol Hgb), FPG is greater than or equal to 126 mg/dL (7.0 mmol/L), or RPG is greater than or equal to 200 mg/dL (11.1 mmol/L; requires confirmation with A1C or FPG). If overt diabetes is not diagnosed or for women not at high-risk for diabetes, the IADPSG recommends screening for GDM at weeks 24 to 28 using a 75-g oral glucose tolerance test (OGTT).27,29 The American College of Obstetricians and Gynecologists (ACOG) recommends screening for gestational diabetes based on clinical risk factors or with the use of a 50 g, 1-hour glucose challenge test followed by a 100 g, 3-hour OGTT to diagnose GDM; this is commonly referred to as the “two-step” method.30 Screening and diagnosis of GDM using the OGTT is described in the American Diabetes Association practice guidelines.26,27
Clinical Controversy…
The most common screening test for gestational diabetes in the United States is the 50-g, 1-hour glucose challenge test, that is followed by a 100-g, 3-hour glucose challenge if found to be elevated.28,30 In 2011, the ACOG upheld this recommendation despite differing with a consensus panel from the IADPSG, with representation from the American Diabetes Association, which recommends universal screening using a 75-g, 2-hour OGTT.27,29
Dietary modification is considered first-line therapy for all women who have GDM, with additional caloric restriction for obese women.31 Daily self-monitoring of blood glucose is required. Drug therapy should be initiated if the following levels are not achieved with dietary modification: FPG concentrations below 90 to 99 mg/dL (5.0 to 5.5 mmol/L), 1-hour postprandial plasma glucose concentration less than or equal to 140 mg/dL (7.8 mmol/L), or 2-hour postprandial plasma glucose concentration below 120 to 127 mg/dL (6.7 to 7.0 mmol/L).31,32 Traditionally, insulin has been the drug of choice for diabetes management during pregnancy because it does not cross the placenta. Glyburide is an alternative because it minimally crosses the placenta. Increasing data suggest that, although it crosses the placenta, metformin appears to lack teratogenicity making it another alternative to insulin.31,32
Evidence supporting dietary modification, self-monitored blood glucose, exercise, and pharmacologic interventions for women with GDM is largely based on one randomized clinical trial that showed reductions in perinatal morbidity (composite of death, nerve palsy, bone fracture, and shoulder dystocia) with nutritional education, blood glucose monitoring, and insulin treatment.33,34
Hypertensive Disorders of Pregnancy
Hypertensive disorders of pregnancy (HDP) complicate approximately 10% of pregnancies. Four categories of HDP are established: chronic hypertension (preexisting hypertension or developing before 20 weeks’ gestation), gestational hypertension (hypertension without proteinuria developing after 20 weeks’ gestation), preeclampsia (hypertension with proteinuria), and preeclampsia superimposed on chronic hypertension.35 Hypertension in pregnancy is defined as a diastolic blood pressure (dBP) 90 mm Hg or greater based upon the average of two or more measurements from the same arm.36 Nondrug managements of HDP center on activity restriction, stress reduction, and exercise; however, no evidence indicates that any of these approaches improves pregnancy outcome, and prolonged bed rest may increase the risk of venous thromboembolic disease.36 Use of supplemental calcium 1 to 2 g/day decreases the relative risk of hypertension by 30% (range, 14% to 43%) and preeclampsia by 48% (range, 31% to 67%).37 High-risk patients (those with the lowest initial calcium intake) benefited most; however, even women with adequate calcium intake at baseline had a 38% decrease in risk of preeclampsia. Therefore, 1 g/day of supplemental calcium is appropriate for all pregnant women. Antihypertensive drug therapy is discussed under Chronic Illnesses in Pregnancy.
While preeclampsia usually develops after 20 weeks’ gestation, up to 30% of chronic and gestational hypertension are complicated by preeclampsia. Preeclampsia is a multisystem syndrome that complicates 2% to 8% of pregnancies and can cause poorer outcomes, including renal failure, maternal morbidity/mortality, preterm delivery, and intrauterine growth restriction.38,39 Risk factors for development of preeclampsia include primiparity, previous preeclampsia, prepregnancy body mass index above 30 kg/m2, tobacco use, underlying medical conditions (e.g., diabetes, antiphospholipid antibodies, autoimmune disease, renal disease), multiple gestations (i.e., twins), and ethnicity (black greater than white or Hispanic). Maternal age over 40 years is also a potential risk factor.39 Signs and symptoms of preeclampsia include blood pressure elevation; proteinuria (300 [or more] mg/24 h); persistent severe headache; persistent new epigastric pain; visual changes; vomiting; hyperreflexia; sudden and severe swelling of hands, face, or feet; HELLP (hemolysis, elevated liver enzymes, low platelets); and increased serum creatinine. Low-dose aspirin (75 to 81 mg/day) in women at risk for preeclampsia decreases the risk of its development by 17%, which corresponds to prevention of one preeclampsia case for every 72 at-risk women treated. Decreased rates of preterm birth (8% reduction) and fetal or neonatal death (14% reduction) also result from low-dose aspirin use.40 Treatment of hypertension in women with preeclampsia depends upon the blood pressure measurement and follows the same principles discussed under Chronic Illnesses in Pregnancy. The only cure for preeclampsia is delivery of the placenta.41
Preeclampsia may progress rapidly to eclampsia, which is the occurrence of seizures superimposed on preeclampsia. Eclampsia is a medical emergency. In high-risk women (i.e., previous severe preeclampsia, renal disease, autoimmune disease, diabetes, and chronic hypertension), use of low-dose aspirin prevents one case of preeclampsia for every 19 women treated.40 Magnesium sulfate decreases the risk of progression to eclampsia by almost 60%; it is recommended to prevent eclampsia as well as treat eclamptic seizures. The usual dose for magnesium sulfate is 4 to 6 g IV over 15 to 20 minutes followed by a 2 g/h continuous infusion; duration of use varies, but the usual duration is 24 hours. Diazepam and phenytoin should be avoided.42
Thyroid Abnormalities
During pregnancy, stimulation of the thyroid gland may occur because of hCG’s structural similarity to thyroid-stimulating hormone (TSH; thyrotropin).43 In 1% to 3% of pregnancies, gestational transient thyrotoxicosis (GTT) may result. Occurrence of GTT is often associated with HG. By 20 weeks’ gestation, GTT usually resolves as production of hCG declines. Treatment with antithyroid medication is not usually needed.43 Nausea and vomiting can be treated as for patients without this pseudohyperthyroid state.
Although not all women experience postpartum thyroiditis (PPT) similarly, the typical presentation is characterized by transient hyperthyroidism during the first 6 months postpartum, a period of transient hypothyroidism, and, finally, euthyroidism within 1 year.43 The initial hyperthyroid state usually does not require treatment; however, β-blockers (propranolol, starting at 10 to 20 mg daily as needed) can provide symptomatic relief of adrenergic symptoms. Because PTT is from a destructive inflammation process and not overproduction of thyroid hormone, antithyroid drugs are ineffective. Levothyroxine is recommended in the hypothyroid phase of PPT for severe hypothyroid symptoms, duration of hypothyroidism greater than 6 months, breast-feeding women, or if another pregnancy is attempted. Levothyroxine replacement is suggested for a total of 6 to 12 months.43 Occurrence of permanent hypothyroidism ranges from 2% to 21% of women affected by PPT.
Thromboembolism
The risk of VTE in pregnant women is increased by five- to tenfold over non-pregnant women.44 Low-molecular-weight heparin (LMWH) is recommended over unfractionated heparin (UFH) and warfarin for treatment of acute thromboembolism during pregnancy. Treatment should be continued throughout pregnancy and for 6 weeks after delivery; the minimum total duration of therapy should not be less than 3 months. Fondaparinux and injectable direct thrombin inhibitors (e.g., lepirudin, bivalirudin) should be avoided unless a severe allergy to heparin (e.g., heparin-induced thrombocytopenia) is present. Dabigatran, rivaroxaban, and apixaban are not recommended.44 Warfarin is not used because it causes nasal hypoplasia, stippled epiphyses, limb hypoplasia, and eye abnormalities; the risk period appears to be between 6 and 12 weeks’ gestation. CNS anomalies are associated with second- and third-trimester exposure.
Recurrent VTE is divided into three categories: low risk, intermediate risk, and high risk of recurrence. Antepartum monitoring is recommended for women with a single episode of VTE who have a low risk of recurrence (i.e., one transient risk factor [e.g., surgery, injury, lengthy travel, or immobility]). For intermediate risk (i.e., hormone-related, pregnancy-related, or unprovoked VTE) and high risk (i.e., more than one unprovoked VTE or continuous risk factors), antipartum prophylaxis with LMWH plus 6-week postpartum prophylaxis with either LMWH or warfarin is recommended. Specific recommendations for thrombophilias (e.g., antiphospholipid antibodies, Factor V Leiden, protein C and S deficiencies) can be found in the American College of Chest Physicians clinical practice guidelines.44
Women with prosthetic heart valves should receive LMWH (twice daily) or UFH (every 12 hours) during pregnancy. LMWH should be adjusted to achieve a peak anti-Xa level at 4 hours postsubcutaneous dose, while UFH treatment should target a midinterval aPTT at least twice the control value or an anti-Xa heparin level of 0.35 to 0.7 units/mL.44 After a discussion of potential risks, LMWH or UFH can be used until week 13 of gestation with subsequent substitution of warfarin until the middle of the third trimester when LMWH or UFH should be resumed. In women considered very high-risk for VTE (e.g., older-generation prosthetic mitral valve, history of thromboembolism), prevention of maternal complications such as valve thrombosis exceeds the risk of fetal malformation; use of warfarin is appropriate until replacement with LMWH or UFH near the end of the third trimester. High-risk women with prosthetic heart valves may also receive low-dose aspirin (75 to 100 mg/day).44
ACUTE CARE ISSUES IN PREGNANCY
In some cases, the risks associated with the acute illness are magnified during pregnancy, and early screening and treatment become critical. In other cases, such as during treatment of certain sexually transmitted diseases, the urgency regarding treatment comes from an increased likelihood of infection leading to preterm labor. Occasionally, common acute care issues, such as migraine headache, improve during pregnancy.
Urinary Tract Infection
The most common infections in pregnant and nonpregnant women are urinary tract infections (UTIs). Typically, UTIs are characterized as asymptomatic (e.g., asymptomatic bacteriuria) or symptomatic (e.g., lower [cystitis] or upper [pyelonephritis]).45,46 Escherichia coli is the primary cause of infection in 75% to 90% of cases.46 Other gram-negative rods, such as Proteus and Klebsiella, as well as Group B Streptococcus (GBS) account for some infections. The presence of GBS in the urine indicates heavy colonization of the genitourinary tract, increasing the risk for GBS infection in the newborn.47
The incidence of asymptomatic bacteriuria ranges from 2% to 10%. Untreated, bacteriuria progresses to pyelonephritis in approximately 30% of pregnant women.46,47 While no consensus regarding screening for asymptomatic bacteriuria exists, a urine culture obtained at the first prenatal visit is appropriate; some advocate a urine culture in each trimester. Use of rapid screening tests, such as dipsticks, should be avoided because of poor performance in pregnant women.47 Acute cystitis occurs in about 1% to 3% of pregnant women. Signs and symptoms of acute cystitis include urgency, frequency, hematuria, pyuria, and dysuria.46,47
Treatment of asymptomatic bacteriuria is necessary to prevent pyelonephritis. For asymptomatic bacteriuria, the agents of choice and treatment duration are not well defined. Treatment of acute cystitis is similar to that of asymptomatic bacteriuria. Using outcomes of cure rates, recurrent infection, incidence of preterm delivery or rupture of membranes, admission to neonatal intensive care, need for change of antibiotic, or incidence of prolonged fever, antibiotic treatment has demonstrated effectiveness in treating symptomatic UTIs (including pyelonephritis) in pregnancy. No specific treatment appeared superior to other commonly used treatments.45,47 Treatment courses for asymptomatic bacteriuria and cystitis of 7 to 14 days are common, but shorter courses of therapy may be sufficient.
The most commonly used antibiotics to treat asymptomatic bacteriuria and cystitis are the β-lactams (including penicillins and cephalosporins) and nitrofurantoin.45,47 β-Lactams are not known teratogens; however, the incidence of E. coli resistance to ampicillin and amoxicillin limits their use as single agents. Nitrofurantoin is not active against Proteus species and should not be used after week 37 in patients with glucose-6-phosphate dehydrogenase deficiency because of a theoretical risk for hemolytic anemia in the neonate. Sulfa-containing drugs can contribute to the development of newborn kernicterus; use should be avoided during the last weeks of gestation. Trimethoprim is a folate antagonist and is relatively contraindicated during the first trimester because of associations with cardiovascular malformations. Regionally, increased rates of E. coli resistance to trimethoprim-sulfa may limit its use. Fluoroquinolones and tetracyclines are contraindicated because of potential associations with impaired cartilage development and deciduous teeth discoloration (if given after 5 months’ gestation), respectively.47
Patients with pyelonephritis usually present with bacteriuria and systemic symptoms of costovertebral angle tenderness, dysuria, fever, flank pain, nausea, and vomiting.46,47 Complications of pyelonephritis include premature delivery, low infant birth weight, hypertension, anemia, bacteremia, and transient renal failure. Hospitalization is the standard of care for pregnant women.47 Inpatient therapy has included parenteral administration of cephalosporins (e.g., cefazolin, ceftriaxone), ampicillin plus gentamicin, or ampicillin–sulbactam. Switching to oral antibiotics can occur after the woman is afebrile for 48 hours; however, nitrofurantoin should be avoided because it does not achieve therapeutic levels outside of the urine. Outpatient antibiotic therapy can be considered after initial inpatient observation in women who are afebrile and less than 24 weeks’ gestation. The total duration of antibiotic therapy for acute pyelonephritis is 10 to 14 days.47 Suppression therapy with nitrofurantoin can be considered for the remainder of gestation.46
Sexually Transmitted Infections
Sexually transmitted infections (STIs) in pregnant women range from infections that may be transmitted across the placenta and infect the infant prenatally (e.g., syphilis) to organisms that may be transmitted during birth and cause neonatal infection (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, or herpes simplex virus [HSV]) to infections that pose a threat for preterm labor (e.g., bacterial vaginosis [BV]). Initial screening during the first prenatal visit is recommended for HIV, C. trachomatis, and syphilis. Women at high risk for gonorrhea or who live in an area of high prevalence as well as women at high risk for hepatitis C should also be screened during the first prenatal visit. Screening for hepatitis B using the surface antigen should occur during the first trimester. Treatment for selected STIs is summarized in Table 61-2.
TABLE 61-2 Management of Sexually Transmitted Diseases in Pregnancy
Syphilis
Syphilis is caused by Treponema pallidum; complications are many (e.g., mucocutaneous lesions, altered mental status, visual and auditory abnormalities, gumma, cranial nerve palsies). For women who live in areas with a high prevalence of syphilis, are at high risk, have not been previously tested, or had positive serology in the first trimester, additional serologic testing twice during the third trimester (28 to 32 weeks) and at delivery is recommended.48With the exception of neurosyphilis, which is treated with aqueous penicillin G, the drug of choice for all stages of syphilis is benzathine penicillin G. Penicillin effectively prevents transmission to the fetus and treats the fetus, if already infected. Treatment during the second half of pregnancy may increase the risk for preterm labor and fetal distress because a Jarisch-Herxheimer reaction may occur; however, treatment should not be withheld or delayed.48
Chlamydia and Gonorrhea
Chlamydia is the most commonly reported STI in the United States; complications of C. trachomatis include pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. C. trachomatis infects the newborn through exposure to the infected cervix during delivery. Perinatal infection most commonly causes conjunctivitis that develops 5 to 12 days postpartum. A subacute, afebrile pneumonia with an onset at ages 1 to 3 months may occur.48
Gonorrhea, an STI caused by N. gonorrhoeae, is the second-most commonly reported notifiable infection in the United States.49 In women, recognizable symptoms may be absent initially, but gonorrheal infection can cause PID, a known risk for infertility. Perinatal gonococcal infection results from exposure to the infected cervix during birth. Symptoms usually manifest within 2 to 5 days after delivery. Milder manifestations include rhinitis, vaginitis, and urethritis. More severe presentations include ophthalmia neonatorum and sepsis.48 Identification and treatment of the infection in neonates is crucial as permanent sequelae such as blindness can occur.
Concerningly, antimicrobial resistance rates among N. gonorrhoeae are increasing which has prompted the Centers for Disease Control to remove oral cephalosporins as a preferred treatment option.49Coinfection with C. trachomatis is common; treatment of most N. gonorrhoeae infections includes treatment for C. trachomatis.48,49
Bacterial Vaginosis and Trichomoniasis
Bacterial vaginosis and trichomoniasis are STIs characterized by vaginal discharge. BV results from the lack of normal vaginal flora (i.e., Lactobacillus species) and replacement with anaerobic bacteria, mycoplasmas, and Gardnerella vaginalis.48 It is a risk factor for premature rupture of membranes, preterm labor, preterm birth, intraamniotic infection, and postpartum endometritis. In women at high risk for preterm delivery, data to support routine screening for asymptomatic BV at the first prenatal visit are equivocal.48 Conflicting data exist with regard to treating women at low risk for preterm labor.
Trichomoniasis is caused by the protozoa, Trichomonas vaginalis. Infection with T. vaginalis is associated with an increased risk of premature rupture of the membranes, preterm delivery, and low birth weight. Treatment may prevent respiratory or genital infection in the neonate.
Genital Herpes
Genital herpes is a chronic disease most frequently caused by herpes simplex virus-2 (HSV-2), although the number of anogenital herpes infections caused by HSV-1 is increasing. Neonatal herpes often occurs in infants born to women lacking histories of genital herpes. The risk of neonatal transmission is under 1% for women with a history of recurrent herpes at term or those who acquire herpes in the first half of pregnancy, but is 30% to 50% for women who initially acquire genital herpes near term.48 However, because recurrent herpes occurs more commonly than new acquisition during pregnancy, it remains the cause for most cases of neonatal transmission. Prevention strategies include counseling uninfected women to avoid intercourse during the third trimester with partners having known or suspected genital herpes infection. Women with no history of orolabial herpes should avoid receptive oral sex during the third trimester with partners who have orolabial herpes. Prevention of genital herpes transmission to pregnant women using antiviral agents has not been studied.48
All women should be asked about symptoms of genital herpes at the time of delivery and should be examined for lesions. Women who have no symptoms (including prodromal symptoms) or lesions proceed with vaginal childbirth; however, those with evidence of an outbreak undergo cesarean section to decrease the risk of neonatal transmission.48
Maternal use of acyclovir during the first trimester has not demonstrated an increased risk for birth defects. Valacyclovir is an alternative, but is more expensive.50 Safety data with famciclovir are limited. For initial or recurrent episodes, most women receive oral acyclovir therapy; IV acyclovir is reserved for severe infections. In women seropositive for HSV but who have not experienced an outbreak, no data suggest a treatment benefit.48
Headache
Primary headaches (e.g., tension, migraine) in pregnant and nonpregnant women are the most common types of headache. Secondary headaches can also occur and include those caused by eclampsia, stroke, postdural puncture, cerebral angiopathy, and cerebral venous thrombosis.51
Migraine headaches are associated with estrogen fluctuations in women of childbearing age. Between 60% and 70% of pregnant women with a history of migraine headaches experience symptom improvement during pregnancy; 20% experience complete cessation. Improvement is more likely in women who have migraine without aura and in women with a history of menstrual migraine. Women with menstrual migraine are more likely to have postpartum recurrence.51 Tension headaches are less studied. Most women report no change in the frequency or intensity of tension headaches, and remission is possible.
Relaxation, stress management, and biofeedback are all effective nonpharmacologic treatment methods that should be attempted in pregnant women with migraines and tension headaches because these interventions pose a minimal risk. For tension headache, acetaminophen or ibuprofen can be used if nonpharmacologic treatments fail. While ibuprofen is considered safe, all NSAIDs are contraindicated in the third trimester because of the potential for premature closure of the ductus arteriosus. Aspirin should be avoided in the third trimester because, in addition to its effects on the ductus arteriosis, it can cause maternal and fetal bleeding as well as decreased uterine contractility (hence, prolonged labor). Opioids are rarely used.51
Pharmacologic treatment for migraines involves use of analgesics (i.e., acetaminophen, ibuprofen). Opioids have been used, but may contribute to migraine-associated nausea; long-term use near term can cause neonatal withdrawal. For migraines that are not responsive to other treatments, triptans may be used; sumatriptan is the triptan of choice, because other triptans have relatively little information about use in pregnancy. Ergotamine and dihydroergotamine are contraindicated because of effects on uterine tone. Promethazine, prochlorperazine, and metoclopramide can be used for patients who have migraine-associated nausea.51
Tension-type headaches do not usually require prophylaxis. Chronic, preventive treatment is reserved for women with severe headaches (usually migraines) that are not responsive to other treatments. The agent of choice is propranolol given at the lowest effective dose. Alternatives include tricyclic antidepressants. Amitriptyline and nortriptyline (each dosed 10 to 25 mg by mouth daily) are preferred over the selective serotonin reuptake inhibitors (SSRI) or serotonin–norepinephrine reuptake inhibitors (SNRI) because data on safe use of these agents during pregnancy are conflicting.51
CHRONIC ILLNESSES IN PREGNANCY
For the majority of women and their healthcare providers, pregnancy is a new consideration for a previously diagnosed health condition. Medications used to treat the chronic illness can often be used throughout the pregnancy and during breast-feeding.
Allergic Rhinitis and Asthma
Asthma and rhinitis are common chronic illnesses in pregnancy. Asthma affects approximately 8% of pregnancies.52 During pregnancy, almost equal proportions of patients have symptoms that worsen, improve, or remain unchanged. Diagnosis and staging of asthma during pregnancy is the same as in nonpregnant women, although more frequent follow-up is necessary because of changes in disease severity.53,54 Health consequences of untreated or poorly treated asthma include preterm labor, preeclampsia, intrauterine growth restriction, premature birth, low birth weight, and stillbirth; therefore, the treatment goal is to achieve and maintain control. Asthma is controlled when there are no daytime symptoms, limitations of activities, nocturnal symptoms, short-acting β2-agonist use, or exacerbations, and there is normal pulmonary function.53,54
The risks of medication use to the fetus are lower than the risks of untreated asthma; therefore, use of medications to achieve and maintain control is warranted. Treatment recommendations are divided into six steps based on symptom control and follow a stepwise approach. Once control is achieved, the goal is maintenance of control at the lowest controlling step. A short-acting β2-agonist is recommended for all patients with asthma for quick relief of symptoms and is the sole drug therapy recommended for Step 1 (intermittent); albuterol is preferred during pregnancy.52–54 For persistent asthma (Step 2 and higher), step-appropriate doses (low, medium, high) of inhaled corticosteroids form the foundation of the controller medication regimen. Budesonide is preferred during pregnancy, although other inhaled corticosteroids that were effective before pregnancy can be continued. Long-acting β2-agonists are considered safe to use during pregnancy because of the similar pharmacologic and safety profiles compared with short-acting agents. Cromolyn, leukotriene receptor antagonists, and theophylline are considered alternative treatments but are not preferred because they are less effective (cromolyn), there is less experience with them (leukotriene receptor antagonists), and there is more potential toxicity (theophylline) than with inhaled corticosteroids. For patients with the most severe disease, addition of systemic corticosteroids is recommended to gain control of symptoms.52–54
Approximately 20% of all pregnancies are impacted by allergic rhinitis. Notably, nasal congestion can be caused by pregnancy because of vascular engorgement in the nasal passages and hormonal effects on mucus secretion. Treatment strategies for allergic rhinitis during pregnancy are similar to those used in nonpregnant women and include avoidance of allergens, immunotherapy, and pharmacotherapy. Immunotherapy is not contraindicated in pregnancy, but dose increases during pregnancy are not advised in order to lessen the risk for anaphylaxis.55
First-line medications to treat allergic rhinitis during pregnancy include intranasal corticosteroids, nasal cromolyn, and first-generation antihistamines (e.g., chlorpheniramine, hydroxyzine).56 Intranasal corticosteroids are the most effective treatment and have a low risk of systemic effect; beclomethasone and budesonide have been most widely studied. Second-generation antihistamines (i.e., loratadine and cetirizine) do not appear to increase fetal risk, but are less extensively studied than first-generation products.55,56 Oral decongestants, such as pseudoephedrine, may be associated with an increased risk for the rare birth defect gastroschisis. Use of an external nasal dilator, short-term topical oxymetazoline, or inhaled corticosteroids may be preferable to use of oral decongestants, especially during early pregnancy.56
Diabetes
Poorly controlled diabetes can cause fetal malformations, fetal loss, and maternal morbidity. Women with diabetes should use effective contraception until optimal glycemic control is achieved before attempting pregnancy. Additionally, diabetic retinopathy may worsen, hypertension may develop, and renal function may deteriorate during pregnancy, requiring enhanced monitoring for these target-organ problems.27,57
Glycemic control can change dramatically during pregnancy; frequent adjustment to management may be needed. Medical nutrition therapy and supervised physical activity programs should continue. Self-monitored blood glucose should occur before and after meals, with occasional early morning (i.e., 2 to 4 am) measurement.57 For patients with type 1 and type 2 diabetes, insulin is the drug treatment of choice.57 Women receiving insulin glargine or detemir should be switched to NPH insulin. Glyburide and metformin may be alternatives, but are not recommended by the American Diabetes Association.31,32,57
Epilepsy
Seizure frequency does not change for most pregnant women with epilepsy. Studies have demonstrated no frequency change in 54% to 80% of women with epilepsy, while decreased frequency ranges between 3% and 24% and increased frequency ranges from 14% to 32%.58,59 Seizures may become more frequent because of changes in maternal hormones, sleep deprivation, and medication adherence problems (because of perceived teratogenic risk). Another potential cause is changes in free serum concentrations of antiepileptic drugs resulting from increased maternal volume of distribution, decreased protein binding from hypoalbuminemia, increased hepatic drug metabolism, and increased renal drug clearance. A woman’s clinical condition and her free serum concentrations of antiepileptic drug should be the basis for dose adjustments.
The risks of untreated epilepsy to the fetus are considered to be greater than those associated with the antiepileptic drugs.59 Major malformations are two to three times more likely to occur in children born to women taking antiepileptic drugs than to those who do not. Major malformations with valproic acid are dose related and range from 6.2% to 10.7%; use of valproic acid should be avoided if possible during pregnancy to minimize the risk of NTDs (e.g., spina bifida), facial clefts, and cognitive teratogenicity.60,61 Rates of major malformation for monotherapy with antiepileptic drugs other than valproic acid range between 2.9% and 3.6%. Carbamazepine and lamotrigine appear to be safest based on available data. However, individual antiepileptic drugs are associated with malformations. Phenytoin, lamotrigine, and carbamazepine may cause cleft palate, while phenobarbital is associated with cardiac malformations. Polytherapy with antiepileptic drugs is associated with a greater rate of major malformation than monotherapy.60,61
When possible, antiepileptic drug monotherapy is recommended with medication regimen optimization occurring before conception.60 Medication change solely to minimize teratogenic risk is not recommended. If drug withdrawal is planned, it should be attempted at least 6 months before attempting to conceive.60 While vitamin K administration during the last month of gestation was previously recommended to decrease the risk of hemorrhagic complications in newborns, evidence to support this practice is lacking. The American Academy of Pediatrics recommends that all neonates receive vitamin K at delivery. All women taking antiepileptic drugs should receive folic acid supplementation: 4 to 5 mg daily starting before pregnancy and continuing through at least the first trimester.59
Human Immunodeficiency Virus Infection
Pregnant women should receive counseling about HIV, and those infected with the virus should receive treatment with antiretroviral (ARV) therapy to decrease the risk of perinatal transmission of HIV. The treatment regimen should be selected from those suggested for nonpregnant adults, with special consideration given to the teratogenic profile of each drug. Women currently receiving ARV treatment should be continued on their regimen when possible. In a change from past recommendations, women receiving efavirenz as part of ARV therapy should continue treatment since NTDs usually occur through weeks 5 to 6 of gestation, and pregnancy often is not recognized until 4 to 6 weeks’ gestation.62
For ARV-naïve women, use of a three-drug combination regimen is recommended and usually contains two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with high transplacental passage (preferred: zidovudine, lamivudine; alternatives: emtricitabine, tenofovir, abacavir) along with a protease inhibitor (preferred: atazanavir in combination plus low-dose ritonavir, lopinavir/ritonavir; alternative: darunavir or saquinavir, both with low-dose ritonavir).62 Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), can be used as an alternative to a protease inhibitor but is associated with severe rash that can lead to life-threatening or fatal hepatotoxicity. After discussion of risks and benefits, some women who do not require immediate therapy may choose to delay ARV therapy until after the first trimester to avoid potential teratogenic complications.62
For women with HIV, cesarean section before the onset of labor (usually at 39 weeks’ gestation) is recommended to reduce the risk of perinatal HIV transmission. If maternal viral load is greater than or equal to 400 copies/mL (400 × 103/L or greater) or not known, IV zidovudine should be initiated with a 1-hour loading dose (2 mg/kg) followed by a continuous infusion (1 mg/kg) for 2 hours (cesarean) or until delivery (for vaginal delivery).62 Zidovudine IV should still be administered in the presence of resistance to oral zidovudine. Women with a viral load below 400 copies/mL (400 × 103/L or less) near delivery do not require zidovudine IV, but should continue their ARV regimen. Specific recommendations for different clinical scenarios during antepartum, intrapartum, and postpartum are provided in the clinical guidelines.62
Hypertension
Hypertension occurring before 20 weeks’ gestation, the use of antihypertensive medications before pregnancy, or the persistence of hypertension beyond 12 weeks postpartum define chronic hypertension in pregnancy. It is classified as mild/nonsevere (systolic blood pressure [sBP] 140 to 159 mm Hg or dBP 90 to 109 mm Hg) or severe (sBP 160 mm Hg or greater, or dBP 110 mm Hg or greater).63 Typically, a physiologic decrease in blood pressure occurs during the first part of pregnancy, reaching its lowest point between 16 and 18 weeks’ gestation; this decrease may mask undiagnosed hypertension. By the third trimester, blood pressure usually returns to prepregnancy levels.
Severe hypertension (as defined above) can cause maternal complications, hospital admission, and potential premature delivery. Drug therapy is indicated for women with blood pressure of 160/110 mm Hg and above.63 Blood pressure, as measured by mean arterial pressure, should be lowered by a maximum of 25% in the first minutes to 1 hour with further reduction to below 160/100 mm Hg over a period of hours.35,38 Initial choice of pharmacologic agent varies, but the most commonly used agents are parenteral labetalol and hydralazine; however, hydralazine is associated with more maternal and fetal adverse effects. Oral nifedipine may also be used.36,38 Although still commonly used, limited evidence supports the use of magnesium sulfate to lower blood pressure except when being used concomitantly for preeclampsia. Nitroprusside, diazoxide, and nitroglycerin should be reserved for refractory hypertension in an appropriately monitored environment.36,38
Treatment of nonsevere hypertension (defined as sBP 140 to 159 mm Hg or dBP 90 to 109 mm Hg) reduces the risk of severe hypertension by 50%, but does not substantially affect fetal outcomes.35,38 Studies of antihypertensive drug therapy for non-severe hypertension in pregnancy have not conclusively shown a decrease in the risk of preeclampsia, neonatal death, preterm birth, or small-for-gestational-age babies.35 No consensus exists on when to initiate treatment of non-severe hypertension and treatment goals vary. In the United States, recommendations for treatment initiation include blood pressures of 150 to 160/100 to 110 mm Hg, with the goal of treatment to lower blood pressure below 150/100 mm Hg.63 Treatment of women with blood pressure below 150/100 mm Hg can be withheld and lowering doses or discontinuing therapy can be considered for women already treated for hypertension who achieve blood pressure below 150/100 mm Hg.63 However, in Canada and the United Kingdom, treatment is suggested for nonsevere hypertension; sBP targets range from 110 to 140 mm Hg while dBP targets range from 80 to 105 mm Hg.38
No evidence supports selection of one pharmacologic agent as first-line therapy. Labetalol is increasingly being used to manage hypertension during pregnancy. Other commonly used drugs include methyldopa and calcium channel blockers. With the exception of atenolol, β-adrenoreceptor antagonists can also be used. Atenolol has been associated with fetal growth restriction. Thiazide diuretics, while theoretically lowering the increase in plasma volume during pregnancy, have been successfully used in women who were treated with them before pregnancy. Agents affecting the renin–angiotensin pathway (i.e., angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and renin inhibitors) are contraindicated throughout pregnancy.35,36,38,63
Mental Health Conditions
Psychiatric illness affects approximately 500,000 pregnancies each year.64 Anxiety disorders, including panic disorder, obsessive–compulsive disorder, generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, and phobias, can cause adverse maternal and fetal outcomes such as spontaneous abortion, preterm delivery, prolonged labor, and fetal distress.64
Depression occurs in 10% to 16% of pregnant women. Maternal depression is associated with greater risk for premature birth, low birth weight, and fetal growth restriction. In addition to the potential impact of maternal depression on obstetric complications, untreated depression may have long-term implications for normal infant development.64 Up to 6.4% of Americans have bipolar disorder, with men and women equally affected; the incidence in pregnancy is unclear although perinatal episodes tend toward depressive manifestations.64 Schizophrenia occurs in 1% to 2% of women; however, the incidence in pregnancy is unknown.64 Maternal schizophrenia is associated with increased risk of perinatal death, low birth weight, small-for-gestational-age infants, cardiovascular malformations, preterm delivery, stillbirth, and infant death.64
Up to 70% of women with mental health conditions discontinue or refuse treatment because of concerns about teratogenicity, or because of paranoid or delusional thinking.65 Therefore, the risks and benefits of psychotropic medication use during pregnancy must be discussed with the patient. Because most psychotropic medications are used to treat more than one condition, the reader should refer to other sources for information about treatment of specific mental health diagnoses. In general, monotherapy is preferred over polytherapy even if higher doses are required.64
Through 2005, the use of SSRIs was considered relatively safe. However, paroxetine may cause a 1.5- to twofold increased risk of cardiac malformations when used during the first trimester use; conflicting data exist regarding first trimester use of other SSRIs.64,65 Despite this association, SSRIs are not considered major teratogens, as their absolute risk for congenital effects is less than 2 per 1,000 births. Risks with SNRIs are less defined. Use of SSRIs and SNRIs in the latter part of pregnancy is associated with persistent pulmonary hypertension of the newborn and Prenatal Antidepressant Exposure Syndrome (encompasses cardiac, respiratory, neurological, GI, and metabolic complications from drug toxicity or withdrawal of drug therapy).65 Tricyclic antidepressants were commonly used in pregnancy before the introduction of SSRIs and are not considered major teratogens, although they have also been associated with a neonatal withdrawal syndrome when used late in pregnancy.64,65 Importantly, women who stop taking antidepressants are more likely to relapse, which can also have implications for the well-being of the infant.
Studies completed over 30 years ago showed an increased risk of oral clefts with diazepam use during pregnancy; these findings were not confirmed in a meta-analysis that found the absolute risk of oral cleft changed from six cases to seven cases per 10,000 exposures (0.01%).64 Benzodiazepine use in the third trimester can cause infant sedation and withdrawal symptoms (e.g., restlessness, hypertonia, hyperreflexia, tremulousness, apnea, diarrhea, vomiting). “Floppy baby syndrome,” consisting of low Apgar scores, hypothermia, poor muscle tone, feeding difficulties, and poor temperature adaptation, has also been described.64
Mood stabilizers, such as lithium, lamotrigine, carbamazepine, and valproic acid, are often used to treat bipolar disorder.64 The reader can find information related to the use of the seizure medications used for mood stabilization in the section on epilepsy. Lithium’s place in the treatment of bipolar disorder during pregnancy is controversial because of concerns about cardiovascular anomalies, especially Ebstein’s anomaly, in exposed infants.64 A meta-analysis calculated that the relative risk for cardiac malformations was between 1.2 and 7.7 and for all congenital malformations was between 1.5 and 3. Stated differently, the risk for Ebstein’s anomaly after prenatal lithium exposure would rise from 1:20,000 to 1:1,000; it is no longer considered a major human teratogen.65,66 Other reported neonatal side effects include floppy baby syndrome, nephrogenic diabetes insipidus, hypoglycemia, cardiac arrhythmias, thyroid dysfunction, polyhydramnios, and premature delivery. Lithium may cause lethargy, hypotonia, hypothermia, cyanosis, and changes in electrocardiogram in infants exposed through breast-feeding. If breast-feeding, the infant’s lithium levels, thyroid function, and complete blood count should be monitored.64
The typical antipsychotics are considered to have minimum toxic or teratogenic potential. Chlorpromazine, haloperidol, and perphenazine have long histories of use during pregnancy, with no reported significant teratogenic effect.64 Atypical antipsychotics are considered first-line treatment for schizophrenia because of their more favorable side-effect profiles and potential increased efficacy for treating negative symptoms compared with the older agents. However, use of atypical antipsychotics in pregnant women is controversial because of the limited data regarding teratogenic potential. One study found a higher rate (10% vs. 2%) of low-birth-weight infants with olanzapine, clozapine, quetiapine, and risperidone compared with nonexposed infants.64 Olanzapine is the most commonly used atypical agent during pregnancy; however, olanzapine as well as clozapine and quetiapine can cause weight gain and metabolic syndrome which have implications for poorer obstetric outcomes.66,67 At present, atypical antipsychotics do not appear to be safer than the typical agents.
Thyroid Disorders
Universal screening for thyroid disorders during pregnancy is controversial; some advocate targeted screening of women considered high risk. Hypothyroidism is present in 2% to 3% of pregnancies. Untreated hypothyroidism increases the risk of preeclampsia, premature birth, miscarriage, and growth restriction; impaired neurological development in the fetus may also occur. Causes of hypothyroidism include autoimmune diseases (e.g., Hashimoto’s thyroiditis), iodine deficiency (uncommon in the United States), and thyroid dysfunction following surgery or ablative therapy for previous hyperthyroidism. If hypothyroidism is present, thyroid replacement should occur with levothyroxine to attain a TSH of 0.1 to 2.5, 0.2 to 3, and 0.3 to 3 milli-international units per liter in the first, second, and third trimesters, respectively.43 A reasonable starting dose of levothyroxine is 0.1 mg/day. Women receiving thyroid replacement therapy before pregnancy may have an increased dosage requirement during pregnancy. Laboratory follow-up of TSH should occur every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks of pregnancy to allow for dose titration according to TSH levels.43
Hyperthyroidism affects approximately 0.4% to 1.7% of pregnancies and is associated with fetal death, low birth weight, intrauterine growth restriction, and preeclampsia. Graves’ disease accounts for 85% to 90% of hyperthyroidism in pregnancy.43 Therapy includes the thioamides (i.e., methimazole, propylthiouracil [PTU]). Dose reductions are possible after becoming euthyroid. Surgery is reserved for the most severe cases. The risks of uncontrolled hyperthyroidism outweigh the risks of the thioamides. However, some support a switch to PTU during the first trimester because of potential risks with methimazole followed by a subsequent switch to methimazole for the second and third trimesters to prevent hepatoxicity from PTU. Iodine-131 is contraindicated because of the risk of thyroid damage in the fetus. The goal of therapy is to attain free thyroxine concentrations near the upper limit of normal to allow for dose minimization and to limit fetal or neonatal hypothyroidism.43
LABOR AND DELIVERY
Management of the pregnant woman during the perinatal period often requires drug therapy for pain and for potential complications.
Preterm Labor
Preterm labor occurs when there are cervical changes and uterine contractions between 20 and 37 weeks’ gestation.68,69 Preterm birth is the leading cause of infant morbidity and mortality in the world and in the United States, with an incidence of 11% to 18% worldwide and 12% in the United States.70 Risk factors for preterm delivery include previous preterm delivery, infections, multiple gestation, poverty, nonwhite race, maternal complication factors (e.g., smoking and use of illicit drugs or alcohol), and uterine functional causes (e.g., incompetent cervix); previous history and prior second trimester loss confer a higher risk.68,69
No adequate tests are available for monitoring and preventing preterm labor. Monitoring of uterine activity along with intensive surveillance does not minimize risk.69 The presence of fetal fibronectin, a glycoprotein found in cervicovaginal secretions, indicates a high risk of preterm birth. Cervical shortening is also associated with preterm delivery. Fetal fibronectin determinations and cervical ultrasound have not helped to prevent preterm labor but have been useful for their negative predictive value.69
Tocolytic Therapy
The purposes of tocolytic therapy are threefold: (a) postpone delivery long enough to allow for the maximum effect of antenatal steroid administration; (b) allow for transportation of the mother to a facility equipped to deal with high-risk deliveries; and (c) prolongation of pregnancy when there are underlying, self-limited conditions that can cause labor, such as pyelonephritis or abdominal surgery, that are unlikely to cause recurrent preterm labor.69,71,72Tocolytics have not reduced the number of premature deliveries. The criteria for starting tocolysis are regular uterine contractions with cervical change. Tocolytic therapy should not be used in cases of intrauterine fetal demise, a lethal fetal anomaly, intrauterine infection, fetal distress, severe preeclampsia, vaginal bleeding, or maternal hemodynamic instability.
Four classes of tocolytics are available in the United States: β-agonists, magnesium, calcium channel blockers, and NSAIDs.73 All four therapies have similar effectiveness in prolonging pregnancy from 48 hours to 1 week. However, this prolongation of pregnancy was not associated with a statistically significant reduction in overall rates of respiratory distress syndrome or neonatal death.
The β-agonists terbutaline and ritodrine have been used for tocolytic therapy.71 Ritodrine is no longer available in the United States. Relative to other agents, β-agonists have a higher incidence of maternal side effects, including hyperkalemia, arrhythmias, hyperglycemia, hypotension, and pulmonary edema. Recommended terbutaline doses range from 250 to 500 mcg subcutaneously every 3 to 4 hours.72
IV magnesium sulfate has been used for tocolysis; however, a Cochrane review does not support its effectiveness.74 Heterogeneity of study designs and results along with small treatment arms in the included studies may partially explain this finding; however, its use remains controversial.71 The incidence of cerebral palsy is increased in premature infants. In one study, IV magnesium use (6 g load followed by 2 g/h continuous infusion) decreased the occurrence of moderate or severe cerebral palsy.75 Although not the primary end point, the study suggests that women at risk for imminent delivery (up to 34 weeks’ gestation) should receive IV magnesium. Maternal side effects are rare but can include pulmonary edema. At toxic levels, hypotension, muscle paralysis, tetany, cardiac arrest, and respiratory depression may occur.72 Magnesium undergoes renal excretion; dose adjustment is required in women with impaired renal function.
Nifedipine is associated with fewer side effects than magnesium or β-agonist therapy.71 Several studies have suggested that calcium channel blockers are superior to β-agonists for prolonging labor. One concern with the use of nifedipine is its hypotensive effect and corresponding change in uteroplacental blood flow. However, a meta-analysis showed reduced neonatal morbidity with calcium channel blocker use. With the initial diagnosis of preterm labor, 5 to 10 mg nifedipine can be administered sublingually every 15 to 20 minutes for three doses. After patient stabilization, if no evidence of continuing cervical dilation is seen, 10 to 20 mg nifedipine can be administered orally every 4 to 6 hours for preterm contractions.72
NSAIDs such as indomethacin have been used for tocolysis.71,72 Oral or rectal doses of 50 to 100 mg, followed by an oral dose of 25 to 50 mg every 6 hours, have been used. An increased rate of premature constriction of the ductus arteriosus has been noted in infants with indomethacin use after 32 weeks’ gestation and with use exceeding 48 hours.71 Indomethacin may be used when tocolysis is needed despite treatment with magnesium for neuroprotection because other agents, such as calcium channel blockers, can cause hypotension when administered concurrently with magnesium.
Other Drug Therapies for Preterm Labor Prevention
Infection is a potential cause of preterm labor. Antibiotics have been used, in addition to tocolytics and corticosteroids, to improve the outcome of preterm labor; however, a Cochrane review showed no reduction in the incidence of preterm delivery but a trend toward increased neonatal mortality. Therefore, routine use of antibiotics is not recommended. However, if a patient experiences preterm premature rupture of membranes (PPROM) before 34 weeks’ gestation, prophylactic antibiotics should be initiated because a reduction in major morbidities (i.e., death, respiratory distress syndrome, early sepsis, severe intraventricular hemorrhage, and necrotizing enterocolitis) was demonstrated.76 A 7-day course of antibiotics with reasonable activity against gram negative and anaerobic bacteria should be used with the intent to prolong latency, which is the time from ruptured membranes to delivery. Ampicillin 2 g IV every 6 hours for 48 hours, followed by amoxicillin (500 mg orally three times daily or 875 mg orally twice daily) for 5 days is preferred instead of multiple courses of erythromycin.76 Cefazolin (1 g every 8 hours) for 48 hours, followed by cephalexin (500 mg four times daily for 5 days) should be used for patients with a penicillin allergy who have a low risk for anaphylaxis to provide coverage for GBS and E. coli, the two major causes of neonatal infection. For patients at high risk for anaphylaxis to penicillin, clindamycin 900 mg IV every eight hours for 48 hours plus gentamicin 7 mg/kg (dosed on ideal body weight) for two doses given 24 hours apart, followed by oral clindamycin 300 mg every 8 hours for 5 days is the regimen of choice. For each regimen, one dose of azithromycin (1 g orally) upon admission and a second dose 5 days later also provides coverage for C. trachomatis, which can cause neonatal conjunctivitis and pneumonitis.48
Progesterone administration in the setting of prior preterm birth is much debated. Two large randomized, controlled trials produced significant findings. First, the administration of intramuscular 17-α-hydroxyprogesterone weekly (250 mg) starting between weeks 16 and 20 and continued through week 36 in high-risk women decreased the incidence of recurrent preterm birth.77 The second study replicated the findings using vaginal progesterone suppositories (100 mg).78 However, progesterone supplementation in women whose previous preterm birth occurred beyond 34 weeks produced similar rates of preterm delivery compared with placebo.79 Currently, ACOG recommends that progesterone supplementation be limited to women with a singleton pregnancy and a previous history of spontaneous preterm birth.80
Clinical Controversy…
Hydroxyprogesterone (Makena®) was approved in February 2011 for prevention of preterm birth in women with a singleton pregnancy and a history of preterm birth. Prior to its approval, compounding pharmacies were supplying hydroxyprogesterone for this use. The FDA has recommended that when an FDA-approved drug is commercially available, that the commercially available product be used instead of a compounded form. The pricing difference for the FDA-approved product is substantial; many patients continue to use the compounded product.
Antenatal Corticosteroids
Use of antenatal corticosteroids for fetal lung maturation to prevent respiratory distress syndrome, intraventricular hemorrhage, and death in infants delivered prematurely is supported by a Cochrane review.81The current clinical recommendation is to administer betamethasone 12 mg intramuscularly every 24 hours for two doses or dexamethasone 6 mg intramuscularly every 12 hours for four doses to pregnant women between 26 and 34 weeks’ gestation who are at risk for preterm delivery within the next 7 days. Benefits from antenatal corticosteroids are believed to begin within 24 hours.
Salvage (“rescue”) treatment is administered to women who are at risk of delivering within 7 days but who have received a previous course of therapy. The incidence of respiratory distress syndrome was lower with the administration of rescue steroids compared with placebo (41.4% with betamethasone vs. 61.6% with placebo).82
Group B Streptococcus Infection
Maternal infection with GBS is associated with invasive disease in the newborn.83,84 Women colonized with GBS have an increased risk for pregnancy loss, premature delivery, and transmission of the bacteria to the infant during delivery. Between 10% and 30% of pregnant women are colonized with GBS. The rate of invasive infection (defined as isolation of GBS from blood or other sterile body site excluding urine) in pregnant women is 0.12 per 1,000 live births (range, 0.11 to 0.14 per 1,000 births). The incidence of early-onset disease in neonates, although higher than in pregnant women, has declined steadily from 1.5 per 1,000 live births in 1993 to approximately 0.24 cases per 1,000 live births in 2010. The consequences of neonatal infections include bacteremia, pneumonia, meningitis, and fatality in the newborn.84 The case-fatality rate is approximately 4%.
Recommendations for prevention of GBS infection were updated in 2010.84 Universal prenatal screening for GBS colonization is recommended. Antibiotics are given if the woman previously gave birth to an infant with invasive GBS disease or in the presence of GBS bacteriuria. All other pregnant women should have a vaginal/rectal culture at 35 to 37 weeks’ gestation. If negative, antibiotics are not indicated. If a woman presents in labor and no screening information is available, antibiotics are given for fever greater than 100.4°F (38°C), membrane rupture at least 18 hours prior, or gestation under 37 weeks.
Penicillin G 5 million units given IV, followed by 2.5 million units given every 4 hours until delivery is the recommended treatment regimen.84 Alternatively, ampicillin 2 g can be given IV, followed by 1 g every 4 hours. For women with penicillin allergy but not at risk for anaphylaxis, cefazolin 2 g IV, followed by 1 g every 8 hours, is recommended. In women at high risk for anaphylaxis, clindamycin 900 mg IV every 8 hours or erythromycin 500 mg IV every 6 hours is recommended. For penicillin-allergic women, GBS cultures should be sent for sensitivities. If resistant to clindamycin or erythromycin, vancomycin 1 g IV every 12 hours until delivery is appropriate.
Cervical Ripening and Labor Induction
Throughout gestation, the cervix is closed and firm. During the last few weeks of pregnancy, the cervix softens and thins to facilitate labor.85,86 This process is mediated by hormonal changes, including final mediation by prostaglandins E2 and F2α, which increase collagenase activity in the cervix leading to thinning and dilation.
The rate of pregnancy induction ranges from 9.5% to 33.5%; the most common indications for induction are postdatism (beyond 42 weeks) and pregnancy-induced hypertension, which account for 80% of inductions.85,86 Other reasons for induction include suspected fetal growth retardation, maternal hypertension, premature rupture of membranes with no active onset of labor, and social factors. Contraindications include placenta previa, oblique or transverse lie, pelvic structure abnormality, prolapsed umbilical cord, and active herpes. Concerns with induction of labor are ineffective labor and side effects, such as uterine hyperstimulation, that may adversely affect the infant and increase the likelihood of cesarean section.
Scoring systems have been used to determine the likelihood of successful labor induction. The Bishop scoring system is most commonly used and is based on five parameters: cervical dilation, cervical effacement (thinning), station of the baby’s head, consistency of the cervix, and position of the cervix.85,86 A Bishop score under six indicates the need for cervical ripening while a score above eight corresponds to a likely successful vaginal delivery.
A number of nonpharmacologic methods are used for cervical ripening. Castor oil, hot baths, sexual intercourse, and nipple stimulation all have been suggested for labor induction.85 Minimal evidence supports the efficacy of these methods. Use of a Foley catheter placed in an unfavorable cervix for ripening has been found as effective as prostaglandin E2. Membrane stripping is safe and inexpensive.85,86
Prostaglandin E2 analogs (e.g., dinoprostone [Prepidil gel, Cervidil vaginal insert]) are commonly used for cervical ripening. Prepidil 500 mcg is administered intracervically.86 The dose may be repeated after 6 hours to a maximum of three doses in 24 hours. After administration, the patient remains supine for 30 minutes. Cervidil contains 10 mg dinoprostone with a slower, more constant release of medication than the gel. The insert is removed when labor begins or after 12 hours. Patients must be attached to a fetal heart rate monitor for the duration of Cervidil use and for 15 minutes after its removal.85
Misoprostol, a prostaglandin E1 analog, is an effective and inexpensive drug for cervical ripening and labor induction.86 Intravaginal administration of misoprostol is more effective than other prostaglandin agents and results in a shorter time to delivery. Oral misoprostol has been used successfully for cervical ripening and labor induction, but the evidence of safety is more extensive with intravaginal use. The most commonly encountered side effects are uterine hyperstimulation and meconium-stained amniotic fluid. Use of misoprostol is contraindicated in women with a previous uterine scar because of its association with uterine rupture, a catastrophic medical event.
Progesterone inhibits uterine contractions. Preliminary studies show that mifepristone, an antiprogesterone agent, compared with placebo results in a shorter time to delivery and fewer cesarean sections.87Limited information on fetal and maternal outcomes is available because of the small sample sizes.
Oxytocin is the most commonly used agent for labor induction after cervical ripening. By the end of pregnancy, the number of oxytocin receptors has increased by 300-fold.85,86 A solution of 10 milliunits/mL is used for infusion. Oxytocin is effective in both low-dose (physiologic) and high-dose (pharmacologic) regimens.
Labor Analgesia
In the first phase of labor, women perceive visceral pain caused by uterine contractions. Pain in the second phase of labor is associated with perineal stretching.88
Nonpharmacologic Approaches to Analgesia
Women who receive continuous support from nurses, midwives, childbirth educators, or doulas [lay women trained in labor support], have fewer operative vaginal deliveries, cesarean deliveries, and requests for pain medication.89Warm water baths provide temporary pain relief but have not been shown to decrease the use of pharmacologic pain treatments. Intradermal injections of sterile water in the sacral area decrease back pain during labor for 45 to 120 minutes. However, requests for pain medication did not decrease in studies. Acupuncture has also been used for pain relief. Three randomized, controlled trials have shown that acupuncture decreases the need for analgesia, but more methodologically sound studies are needed. Use of audioanalgesia (music or white noise), relaxation and breathing techniques, application of heat and cold, aromatherapy, acupressure, and hypnosis have little to no evidence of effectiveness derived from randomized, controlled trials.
Pharmacologic Approaches to Labor Pain Management
Maternal request alone is a sufficient medical indication for labor analgesia.90 The two main types of pharmacologic approaches in the United States are parenteral opioids and epidural analgesia.
Parenteral opioids are commonly used to alleviate labor pain.91 In comparison with epidural analgesia, parenteral opioids have lower rates of oxytocin augmentation, result in shorter stages of labor, and require fewer instrumental deliveries.
Approximately 60% of women in the United States choose an epidural for pain relief during labor and report better pain relief than with other analgesic modalities.91 With epidural analgesia, a catheter is introduced into the epidural space and an opioid and/or an anesthetic (e.g., fentanyl and/or bupivacaine) is administered. Combined spinal–epidural analgesia consists of injecting a single opioid bolus into the subarachnoid space to provide instant pain relief with additional use of a local anesthetic epidural. Patient-controlled epidural analgesia allows the patient to control the amount and timing of the anesthetic; it results in a lower total dose of local anesthetics used over the course of labor compared with continuous epidural infusions.92
Side effects of the regional anesthesia include hypotension, pruritus, and inability to void.91 Epidural analgesia is associated with prolongation of the first and second stages of labor, higher numbers of instrumental deliveries, and maternal fever. A rare complication of epidural anesthesia is puncture of the subarachnoid space leading to a severe headache, which occurs in approximately 1% of women. Other complications include hypotension, nausea, vomiting, itching, and urinary retention. Low back pain has not been associated with the use of epidural analgesia.
Postpartum Hemorrhage
The placenta is delivered after the delivery of the baby and is referred to as the third stage of labor. Postpartum hemorrhage is an obstetrical emergency and is a major cause of morbidity and mortality.93In the United States, the postpartum hemorrhage rate is approximately 1% to 5% for vaginal deliveries.94 The traditional definition of postpartum hemorrhage is more than 500 mL of blood within 24 hours of a vaginal delivery or 1,000 mL after a cesarean section; however, other definitions have also been suggested. Risk factors include retained placenta, failure to progress during the second stage of labor, placenta previa, placenta accreta, lacerations, instrumental delivery, large for gestational age newborn, hypertensive disorders, labor induction, augmentation of labor with oxytocin, prior history, obesity, and high parity.95
A stepwise approach to the treatment of postpartum hemorrhage is advised. After the exclusion of retained products of conception and cervical and vaginal lacerations, attention should be turned to the management of uterine atony if present. The most common cause of postpartum hemorrhage is uterine atony.93,94 Initial management should include oxytocin. Early clamping and cutting of the umbilical cord as well as controlled traction of the cord also decrease the incidence.93 Administration of a uterotonic medication (intramuscular oxytocin, ergotamine, or combination) before placental delivery and instituting active management of labor after all uncomplicated vaginal deliveries result in reduced maternal blood loss, fewer cases of postpartum hemorrhage, and less prolongation of the third stage of labor. Other uterotonic agents should be used if an inadequate response is attained with oxytocin alone. Methylergonovine, carboprost, misoprostol, and dinoprostone have all been used; less evidence is available for misoprostol and dinoprostone. If uterotonic drug therapies fail to control the bleeding, uterine artery embolization, intrauterine balloon catheters, or a variety of different surgical techniques can be used.
POSTPARTUM ISSUES
Drug Use During Lactation
A wide variety of benefits (health, nutritional, immunologic, psychological, economic, developmental, and social) are imparted by breast-feeding to infants, mothers, and the family. Women should breastfeed exclusively for 6 months and continue until at least 12 months of age while other foods are introduced.96 Healthy People 2020 increased targets for breast-feeding to 81.9% of neonates at the time of birth and to 60.5% for infants being breast-fed at 6 months.96
Adequate milk removal from the breast by breast-feeding or pumping is necessary to maintain or increase milk production.97 Relactation is the process of increasing the breast milk supply for women whose milk has not “come in,” who have inadequate milk production despite appropriate breast-feeding frequency or pumping, or who have weaned or never breast-fed after delivery. Metoclopramide can be used if nonpharmacologic measures are ineffective because of its stimulation of prolactin secretion. The most common dose is 10 mg orally three times daily for 7 to 14 days.97 Breast milk production may decrease after metoclopramide therapy is stopped, but production will continue if lactation has been established successfully.
Most drugs transfer into breast milk, but breast-feeding may be continued in most circumstances. Healthcare providers should encourage breast-feeding women who require medications to continue breast-feeding whenever possible. Passive diffusion is the primary mechanism for drug transfer into breast milk, but other drug-related factors influence drug transfer from maternal circulation into breast milk, including (a) degree of protein binding in maternal plasma, (b) molecular weight, (c) lipid solubility (and corresponding fat content of milk), (d) maternal plasma concentration, (e) drug half-life, and (f) drug pH.98,99 The degree of protein binding to maternal plasma proteins is one of the most significant factors affecting drug transfer to breast milk; highly bound medications transfer in low amounts. Low-molecular-weight drugs passively diffuse into breast milk, but larger molecules are not likely to transfer in large amounts. Higher lipid solubility of drugs also increases the likelihood of transfer. Colostrum is secreted in the first couple of days after birth and has high quantities of immunoglobulins, maternal lymphocytes, and maternal macrophages. Compared with mature milk, colostrum is lower in fat content, so highly lipid-soluble drugs achieve higher concentrations in mature milk. The higher the concentration of drug in the mother’s serum, the higher the concentration will be in the breast milk. As the drug is metabolized and excreted by the mother, the mother’s serum concentration drops, and the drug in the breast milk may redistribute back into the mother’s bloodstream. Maternal plasma pH is 7.4, while the pH of breast milk ranges between 6.8 and 7. Weak bases are not ionized in the maternal circulation and easily transfer to breast milk.99 In the lower pH of breast milk, molecules become ionized and are less likely to diffuse back into maternal circulation (“ion trapping”). Likewise, drugs with longer half-lives are more likely to maintain higher levels in breast milk, resulting in greater exposure to the infant.
Infant-related factors may also influence the amount of drug ingested through breast-feeding.98 Both the frequency of feedings and the amount of milk ingested are important considerations. Exclusively breast-fed infants are more likely to ingest larger amounts of drugs than older infants who receive other foods. Drugs unstable in gastric acid (aminoglycosides, omeprazole, heparin, insulin) are less likely to be absorbed by infants. Finally, infants may vary in their ability to metabolize and excrete ingested medication. Premature and full-term infants may not have full renal and liver function.
Strategies for reducing the risk to the infant include selection of medications that would be considered safe for use in the infant.98 Drugs with shorter half-lives accumulate less, and those that are more protein bound do not cross into breast milk as well as those that are less protein bound. Drugs with lower oral bioavailability and lower lipid solubility are good choices. If the mother is using a once-daily medication, administration before the infant’s longest sleep period may be advised to increase the interval to the next feeding. For medications taken multiple times per day, administration immediately after breast-feeding provides the longest interval for back diffusion of drug from the breast milk to the mother’s serum. During short-term drug therapy, the mother can pump and discard milk to preserve her milk-producing capability if the medication is not considered compatible with breast-feeding.99
Information regarding drug use during breast-feeding is available from expert committees (e.g., American Academy of Pediatrics Committee on Drugs) and evidence-based textbooks or databases (e.g., LactMed [www.toxnet.nlm.nih.gov]). All may be of assistance in determining safe and appropriate medications to use during breast-feeding.
Mastitis
Mastitis is inflammation in one breast.100 It can be infectious or noninfectious; the most common cause is milk stasis. About 10% of women in the United States experience mastitis during the first 3 months postpartum. Signs and symptoms include breast tenderness, redness, warmth, and flulike symptoms.101 Risk factors for developing mastitis include breast engorgement, plugged milk ducts, and cracked nipples.
Staphylococcus aureus is the most common bacterial cause of mastitis; E. coli and Streptococcus have also been implicated.100,101 A 10- to 14-day course of antibiotics is usually given for treatment of mastitis; penicillinase-resistant penicillins (e.g., dicloxacillin, oxacillin) and cephalosporins (e.g., cephalexin) are frequently prescribed. Antiinflammatory drugs, such as ibuprofen, may provide some pain relief. Application of heat may also be helpful. Affected women should be counseled to continue breast-feeding from both breasts throughout treatment and to pump if breasts are not emptied completely with feedings.
Postpartum Depression
Mood disorders in the postpartum period may include postpartum blues, postpartum depression, and postpartum psychosis.102 Postpartum blues is common, usually affecting 15% to 85% of new mothers within the first 10 days of delivery, and generally does not require treatment. Symptoms include anxiety, anger, and sadness. Postpartum psychosis is more severe but is rare, affecting less than 1% of new mothers.
Postpartum depression affects up to 15% of women.102 Symptoms may develop during pregnancy or up to 6 months after delivery, although the strict definition for major depressive disorder after delivery specifies symptom occurrence within 1 month. Psychotherapy, including interpersonal psychotherapy, cognitive behavioral therapy, and group/family therapy, has been shown effective for treatment of postpartum depression.
In cases where pharmacotherapy is warranted, selection of medication with low transfer to breast milk is desirable. Sertraline is generally considered a first-line treatment because of its minimal transfer into breast milk and lack of reported adverse events in infants.98,102 Paroxetine and nortriptyline are considered second-line.
ABBREVIATIONS
REFERENCES
1. Ord T. The scourge: Moral implications of natural embryo loss. Am J Bioeth 2008;8:12–19.
2. Brent RL. Environmental causes of human congenital malformations: The pediatrician’s role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics 2004; 113(4 Suppl):957–968.
3. Gupta SK, Bansal P, Ganguly A, Bhandari B, Chakrabarti K. Human zona pellucida glycoproteins: Functional relevance during fertilization. J Reprod Immunol 2009;83:50–55.
4. Cunningham FG, Leveno KJ, Bloom SL, et al. Chap. 3. Implantation, embryogenesis, and placental development. In: Cunningham FG, Leveno KJ, Bloom SL, et al. eds. Williams Obstetrics. 23rd ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content/aspx?aID=6030341. Accessed June 14, 2013.
5. Cunningham FG, Leveno KJ, Bloom SL, et al. Chap. 4. Fetal growth and development. In: Cunningham FG, Leveno KJ, Bloom SL, et al. eds. Williams Obstetrics. 23rd ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content/aspx?aID=6037835. Accessed June 14, 2013.
6. Bernstein HB, VanBuren G. Chap. 6. Normal pregnancy and prenatal care. In: DeCherney AH, Nathan L, Laufer N, et al. eds. Current Diagnosis and Treatment Obstetrics and Gynecology. 11th ed. New York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=5694326. Accessed June 14, 2013.
7. Cunningham FG, Leveno KJ, Bloom SL, et al. Chap. 8. Prenatal care. In: Cunningham FG, Leveno KJ, Bloom SL, et al. Williams Obstetrics. 23rd ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content/aspx? aID=6052072. Accessed June 14, 2013.
8. Feghali MN, Mattison DR. Clinical therapeutics in pregnancy. J Biomed Biotechnol 2011;2011:783528. doi: 10.1155/2011/783528.
9. Flick AA, Kahn DA. Chap. 8. Maternal physiology during pregnancy and fetal and early neonatal physiology. In: DeCherney AH, Nathan L, Laufer N, et al. eds. Current Diagnosis and Treatment Obstetrics and Gynecology. 11th ed. New York: McGraw-Hill; 2013. http://www.accessmedicine.com/content.aspx?aID=56964738.
10. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet 2004;43:487–514.
11. Polifka JE, Friedman JM. Medical genetics: 1. Clinical teratology in the age of genomics. CMAJ 2002;167:265–273.
12. Kallen BA. Methodological issues in the epidemiological study of the teratogenicity of drugs. Congenit Anom (Kyoto) 2005;45:44–51.
13. Schaefer C, Ornoy A, Clementi M, et al. Using observational cohort data for studying drug effects on pregnancy outcome—Methodological considerations. Reprod Toxicol 2008;26:36–41.
14. Food and Drug Administration. Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling (Proposed Rules). Federal Register 73:104 (May 29, 2008):30831–30868.
15. Johnson K, Posner SF, Biermann J, et al. Recommendations to improve preconception health and health care—United States. A report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. MMWR Recomm Rep 2006;55(RR-6):1–23.
16. Korenbrot CC, Steinberg A, Bender C, et al. Preconception care: A systematic review. Matern Child Health J 2002;6:75–88.
17. U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150:626–631.
18. Lumley J, Chamberlain C, Dowswell T, et al. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2009(3):CD001055.
19. Rore C, Brace V, Danielian P, et al. Smoking cessation in pregnancy. Expert Opin Drug Saf 2008;7:727–737.
20. Avsar AF, Keskin HL. Haemorrhoids during pregnancy. J Obstet Gynaecol 2010;30:231–237.
21. Keller J, Frederking D, Layer P. The spectrum and treatment of gastrointestinal disorders during pregnancy. Nat Clin Pract Gastroenterol Hepatol 2008;5:430–443.
22. Mahadevan U, Kane S. American Gastroenterological Association Institute Technical Review on the use of gastrointestinal medications in pregnancy. Gastroenterology 2006;131:283–311.
23. Pasternak B, Hviid A. Use of proton–pump inhibitors in early pregnancy and the risk of birth defects. N Engl J Med 2010;363:2114–2123.
24. Lee NM, Saha S. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am 2011;40:309–334.
25. Wegrzyniak LJ, Repke JT, Ural SH. Treatment of hyperemesis gravidarum. Rev Obstet Gynecol 2012;5:78–84.
26. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(Suppl 1):S64–S71.
27. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care 2012;35(Suppl 1):S11–S63.
28. U.S. Preventive Services Task Force. Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008;148:759–765.
29. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682.
30. Committee Opinion No. 504: Screening and diagnosis of gestational diabetes mellitus. Obstet Gynecol 2011;118:751–753.
31. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl 2):S251–S260.
32. Ballas J, Moore TR, Ramos GA. Management of diabetes in pregnancy. Curr Diab Rep 2012;12:33–42.
33. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477–2486.
34. Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database Syst Rev 2009;(3):CD003395.
35. Mustafa R, Ahmed S, Gupta A, et al. A comprehensive review of hypertension in pregnancy. J Pregnancy 2012; 2012:105918. doi: 10.1155/2012/105918.
36. Magee LA, Helewa M, Moutquin JM, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. J Obstet Gynaecol Can 2008;30:S1–S48.
37. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: A systematic review and commentary. BJOG 2007;114:933–943.
38. Magee LA, Abalos E, von Dadelszen P, et al. How to manage hypertension in pregnancy effectively. Br J Clin Pharmacol 2011;72:394–401.
39. Trogstad L, Magnus P, Stoltenberg C. Pre-eclampsia: Risk factors and causal models. Best Pract Res Clin Obstet Gynaecol 2011;25:329–342.
40. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007;(2):CD004659.
41. Payne B, Magee LA, von Dadelszen P. Assessment, surveillance and prognosis in pre-eclampsia. Best Pract Res Clin Obstet Gynaecol 2011;25:449–462.
42. Duley L, Gulmezoglu AM, Henderson-Smart DJ, et al. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2010;(11):CD000025.
43. Yazbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin North Am 2012;96:235–256.
44. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S–e736S.
45. Vazquez JC, Abalos E. Treatments for symptomatic urinary tract infections during pregnancy. Cochrane Database Syst Rev 2011;(1):CD002256.
46. Law H, Fiadjoe P. Urogynaecological problems in pregnancy. J Obstet Gynaecol 2012;32:109–112.
47. Schnarr J, Smaill F. Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy. Eur J Clin Invest 2008;38(Suppl 2):50–57.
48. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59(RR-12):1–110.
49. Centers for Disease Control and Prevention (CDC). Update to CDC’s Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. Morb Mortal Wkly Rep 2012;61:590–594.
50. Su CW, McKay B. Treatment of HSV infection in late pregnancy. Am Fam Physician 2012;85:390–393.
51. Macgregor EA. Headache in pregnancy. Neurol Clin 2012;30:835–866.
52. Vatti RR, Teuber SS. Asthma and pregnancy. Clin Rev Allergy Immunol 2012;43:45–56.
53. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma—Summary Report 2007. J Allergy Clin Immunol 2007;120(5 Suppl):S94–S138.
54. Global Strategy for Asthma Management and Prevention (updated 2011): Global Initiative for Asthma (GINA). http://www.ginasthma.org, 2011..
55. Piette V, Daures JP, Demoly P. Treating allergic rhinitis in pregnancy. Curr Allergy Asthma Rep 2006;6:232–238.
56. Gilbert C, Mazzotta P, Loebstein R, et al. Fetal safety of drugs used in the treatment of allergic rhinitis: A critical review. Drug Saf 2005;28:707–719.
57. Kitzmiller JL, Block JM, Brown FM, et al. Managing preexisting diabetes for pregnancy: Summary of evidence and consensus recommendations for care. Diabetes Care 2008;31:1060–1079.
58. Harden CL, Hopp J, Ting TY, et al. Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009;50:1229–1236.
59. Tomson T, Battino D. Pregnancy and epilepsy: What should we tell our patients? J Neurol 2009;256:856–862.
60. Harden CL, Sethi NK. Epileptic disorders in pregnancy: An overview. Curr Opin Obstet Gynecol 2008;20:557–562.
61. Harden CL, Meador KJ, Pennell PB, et al. Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009;50:1237–1246.
62. Panel on treatment of HIV-infected pregnant women and prevention of perinatal transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health andinterventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
63. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 125: Chronic hypertension in pregnancy. Obstet Gynecol 2012;119:396–407.
64. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists No. 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol 2008;111:1001–1020.
65. Gentile S. Drug treatment for mood disorders in pregnancy. Curr Opin Psychiatry 2011;24:34–40.
66. Levey L, Ragan K, Hower-Hartley A, et al. Psychiatric disorders in pregnancy. Neurol Clin 2004;22:863–893.
67. McCauley-Elsom K, Gurvich C, Elsom SJ, et al. Antipsychotics in pregnancy. J Psychiatr Ment Health Nurs 2010;17:97–104.
68. Damus K. Prevention of preterm birth: A renewed national priority. Curr Opin Obstet Gynecol 2008;20:590–596.
69. Chandiramani M, Shennan A. Preterm labour: Update on prediction and prevention strategies. Curr Opin Obstet Gynecol 2006;18:618–624.
70. Hamilton BE, Martin JA, Ventura SJ. Births: Preliminary data for 2010. Natl Vital Stat Rep 2011;60(2):1–6.
71. Giles W, Bisits A. Preterm labour. The present and future of tocolysis. Best Pract Res Clin Obstet Gynaecol 2007;21:857–868.
72. Weismiller DG. Preterm labor. Am Fam Physician 1999;59:593–602.
73. Haas DM, Imperiale TF, Kirkpatrick PR, et al. Tocolytic therapy: A meta-analysis and decision analysis. Obstet Gynecol 2009;113:585–594.
74. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2002(4):CD001060.
75. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.
76. ACOG Committee Opinion No. 445. Antibiotics for preterm labor. Obstet Gynecol 2009;114:1159–1160.
77. Meis PJ, Connors N. Progesterone treatment to prevent preterm birth. Clin Obstet Gynecol 2004;47:784–795.
78. da Fonseca EB, Bittar RE, Carvalho MH, et al. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419–424.
79. Spong CY, Meis PJ, Thom EA, et al. Progesterone for prevention of recurrent preterm birth: Impact of gestational age at previous delivery. Am J Obstet Gynecol 2005;193:1127–1131.
80. ACOG Committee Opinion No. 419, October 2008 (replaces no. 291, November 2003). Use of progesterone to reduce preterm birth. Obstet Gynecol 2008;112:963–965.
81. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006(3);3: CD004454.
82. Garite TJ, Kurtzman J, Maurel K, et al. Impact of a ‘rescue course’ of antenatal corticosteroids: A multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009;200:248 e1–e9.
83. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005. JAMA 2008;299:2056–2065.
84. Verani JR, McGee L, Schrag SJ, et al. Prevention of perinatal group B streptococcal disease—Revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–36.
85. Tenore JL. Methods for cervical ripening and induction of labor. Am Fam Physician 2003;67:2123–2128.
86. Sanchez-Ramos L. Induction of labor. Obstet Gynecol Clin North Am 2005;32:181–200.
87. Hapangama D, Neilson JP. Mifepristone for induction of labour. Cochrane Database Syst Rev 2009;(3): CD002865.
88. Kuczkowski KM. Labor pain and its management with the combined spinal-epidural analgesia: What does an obstetrician need to know? Arch Gynecol Obstet 2007; 275:183–185.
89. Simkin P, Bolding A. Update on nonpharmacologic approaches to relieve labor pain and prevent suffering. J Midwifery Womens Health 2004;49:489–504.
90. ACOG Committee Opinion No. 295: Pain relief during labor. Obstet Gynecol 2004;104:213.
91. Anim-Somuah M, Smyth R, Howell C. Epidural versus non-epidural or no analgesia in labour. Cochrane Database Syst Rev 2005;(4):CD000331.
92. van der Vyver M, Halpern S, Joseph G. Patient-controlled epidural analgesia versus continuous infusion for labour analgesia: A meta-analysis. Br J Anaesth 2002;89:459–465.
93. Chong YS, Su LL, Arulkumaran S. Current strategies for the prevention of postpartum haemorrhage in the third stage of labour. Curr Opin Obstet Gynecol 2004;16:143–150.
94. Mousa HA, Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev 2007;(1): CD003249.
95. Sheiner E, Sarid L, Levy A, et al. Obstetric risk factors and outcome of pregnancies complicated with early postpartum hemorrhage: A population-based study. J Matern Fetal Neonatal Med 2005;18:149–154.
96. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827–841.
97. Academy Of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol #9: Use of galactogogues in initiating or augmenting the rate of maternal milk secretion (First Revision January 2011). Breastfeed Med 2011;6:41–49.
98. Ilett KF, Kristensen JH. Drug use and breastfeeding. Expert Opin Drug Saf 2005;4:745–768.
99. Della-Giustina K, Chow G. Medications in pregnancy and lactation. Emerg Med Clin North Am 2003;21:585–613.
100. Jahanfar S, Ng CJ, Teng CL. Antibiotics for mastitis in breastfeeding women. Cochrane Database Syst Rev 2009;(1):CD005458.
101. Walker M. Conquering common breast-feeding problems. J Perinat Neonatal Nurs 2008;22:267–274.
102. Pearlstein T, Howard M, Salisbury A, et al. Postpartum depression. Am J Obstet Gynecol 2009;200:357–364.