Breastfeeding and Medical Disease

Medical Problems in Pregnancy

0025-7125/89

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Breastfeeding and Medical Disease Ruth A. Lawrence, MD*

Since a nadir in 1970, more women are choosing to breastfeed their infants. This is in keeping with the health goals for this nation to be accomplished by 1990; 75 per cent of women will leave the hospital breastfeeding and at least 35 per cent will continue until 6 months postpartum. 36 The present statistics vary from 75 per cent women on the West Coast of the United States to less than 25 per cent of women in the Southeast. 39 The Surgeon General has said, "We must identify and reduce the barriers that keep women from beginning or continuing to breastfeed their infants. "37 Unnecessarily qiscontinuing breastfeeding or recommending it not be initiated are barriers sometimes created by the physician. For the internist, there will be women in the child-bearing years who will develop acute medical problems while breastfeeding, and a second group of women with chronic disease who will desire to breastfeed their infants and seek medical approval. The management of this patient may need modification to accommodate lactation. It is not necessary in most cases to terminate breastfeeding. The risk of breastfeeding will be exceeded by its great benefit to both infant and mother.

WHY BREASTFEEDING? An understanding of the many reasons a woman chooses to breastfeed and the reasons the pediatrician urges her to do so will explain why the casual discontinuation of breastfeeding is to be avoided. Human milk is meant for human infants; it is species-specific. 27 Nutritionally, it is exactly what the normal newborn needs for optimal growth and development. Tnere are many nutritional attributes not provided by infant formula that is manufactured from a cow milk base. The infection protection and immunologic protection are unique for the human infant and are in no way duplicated by any other feeding or treatment. The living cells including macfQphages and lympho*Professor of Pediatrics and Obstetrics/Gynecology, Division of Neonatology, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York

Medical Clinics of North America-Vo!' 73, No. 3, May 1989

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cytes are important factors in the immune defense system. There are over 100 enzymes in the milk that not only assist in digestion but stimulate the immature gut to maturation. Protection against infection and other immunologic disorders is important. In developing countries, it is a matter of life and death where the death rate in bottle-fed infants is three times that of breast-fed infants in the first year oflife. In the Western world, the protection is more subtle but no less important.!O The incidence of gastrointestinal disease, respiratory disease, otitis media, and allergies is less in breast-fed infants in the United States. 5 The increasing use of day-care facilities for young infants is sharpening this distinction. Evidence is accumulating to suggest that breastfeeding is also protective to a degree against obesity, allergy, arteriosclerosis, early onset of diabetes, cystic fibrosis, celiac disease, and other metabolic disorders. 4,5,10,14,18,19.23,24,29,30 In addition to the medical indications to breastfeed is the fact that lactation is the physiologic completion of the reproductive cycle and enhances the mother's postpartum recovery.27 Most women also return to their prepartum weight more rapidly, Ovulation is suppressed during full active lactation, The special psychological bond developed between the mother and her nursling is significantly different than that between the bottle-feeding woman and her offspring,32,33 It is recommended that any physician treating a woman in her reproductive years inquire not only whether she is pregnant but if she is lactating before prescribing treatment.

THE PHYSIOLOGY OF LACTATION Understanding the physiologic process will facilitate understanding its impact during pathologic states, The breast, the body, and the psyche are prepared for lactation during pregnancy; the newborn infant is prepared to suckle at the breast at birth,27 Growth of the mammary gland is a gradual process that starts during puberty under the influence of the sex steroids, The embryonic buds that developed initially in the fetus and have been quiescent since birth are stimulated by estrogen to proliferate and to become multilayered, Buds and papillae are formed. The lobuloalveolar development and ductal proliferation depend on the intact pituitary gland. There are three major stages of activity: (1) mammogenesis-mammary growth, that begins embryonically and culminates during pregnancy; (2) lactogenesis-the initiation of milk secretion, that begins in pregnancy and increases at delivery; and (3) galactopoiesis-maintenance of established lactation, that begins a few days postpartum and continues as long as there is a stimulus. The embryonic breast begins its preparation at puberty when the hypophyseal-ovarian-uterine cycle is established. Fifteen to 20 primitive ducts arborize extensively and form a compound tubuloalveolar gland. A relatively inactive stage continues through adult life until pregnancy initiates the proliferative stage. Spectacular ductal growth begins in response to luteal and placental hormones, There is true hyperplasia, but in an orderly fashion, as one alveolus does not overrun another (Fig, 1). The hormones-placental lactogen, prolactin, and chorionic gonadotro-

585

BREASTFEEDING AND MEDICAL DISEASE

A

B

c

D

E

Figure 1. Female breast from infancy to lactation with corresponding cross-section and duct structure. A, B, and C, Gradual development of well-differentiated ductular and peripheral lobular-alveolar system. D, Ductular sprouting and intensified peripheral lobular-alveolar development in pregnancy. Glandular luminal cells begin actively synthesizing milk fat and proteins near term; only small amounts are released into lumen. E, With postpartum withdrawal of luteal and placental sex steroids and placental lactogen, prolactin is able to induce cell secretory activity of alveolar cells and release of milk into alveolar and smaller ducts. (From Lawrence RA: Breastfeeding: A guide for the medical profession, ed 3. St. Louis, CV Mosby, 1989; with permission.)

pin--contribute to the acceleration of growth. At this stage, one can observe the complex interaction of the many hormones that function in the development of both the fetus and the breasts during pregnancy. Estrogen stimulates ductular sprouting, and progesterone stimulates lobular formation. There is a delicate balance of prolactin inhibiting factor in the hypothalamus and prolactin production in the adenohypophysis as the presecretory phase progresses in the second trimester to a secretory phase. In this phase, material resembling colostrum is seen in the alveoli stimulated by placental lactogen. 27 With the delivery of the placenta, the source of hormones is lost abruptly and the plasma levels begin to fall. Placental lactogen is gone within hours, progesterone within 2 to 3 days, estrogen reaches basal levels within 5 to 6 days, but prolactin levels depend upon the amount of suckling. In the nonnursing mother, prolactin drops to prepregnant levels in about 14 days. Observation of nursing mothers with retained placenta indicates that lac-

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tation is suppressed until the placental fragments are removed. This suppression is similar to the lack of milk secretion seen in mothers experiencing an intrauterine death. Evidence strongly suggests that it is loss of placental progesterone with the decline in plasma progesterone that triggers galactogenesis, or milk production. 27 The necessity for adequate levels of prolactin for lactation to begin in humans has been demonstrated. The exact role of prolactin in adequate milk production, however, continues to be investigated. Baseline prolactin levels are above normal throughout lactation and are proportionally increased to twice baseline each time the infant suckles. The role of other ho~mones such as insulin and thyroxine in mammogenesis, lactogenesis, and galactogenesis is well established, although the definition of their roles does not have universal agreement. The breast does not function in isolatioQ, but in synchrony and balance with the maternal endocrine system. The process of milk synthesis is complex. There is a marked alteration of the maternal metabolism with a redistribution of the blood supply and an increased demand for nutrients. The mammary blood flow, cardiac output, and milk secretion are suckling-dependent. These changes in turn trigger the hypo thalamus to release prolactin to act on the mammary cells. Milk is iso-osmolar with plasma in all species. Although milks of different species vary tremendously, each is physiologic for the growth demands of that species. The biosynthesis of milk involves a cellular site where the metabolic processes occur. Protein and fat are synthesized de novo; lactose is synth~­ sized from glucpse; ions and water diffuse across the membrane so that primary alveolar milk is diluted to plasma isotonicity by water extracted from extracellular fluid. 27 While the glands prepare for full lactation, so do other structures of the breast prepare. The areolae increase in prominence with the development and activity of the glands of Montgomery that provide a secretion to lubricate and protect the nipple and areolae during suckling. During pregnancy, the body stores nutrients that are intended for the manufacturing of milk in the postpartum period. Eight to 10 Ibs of added weight (neither fetus, placenta, uterus, or fluid) are carefully stored for future nutrient and energy needs. The body stores reflect the cumulative dietary intake of grepregnancy and pregnancy coupled with the short-term dietary variation to ensure daily sources of both macro- and micronutrients. Thus, the daily nourishment provided through the milk is consistent and balanced. Temporary deficiencies of diet are compensated by body stores (Fig. 2). The direct effect of the oxytocin released on stimulqs of suckling not only contracts the myoepithelial cells for milk ejection but also contracts the uterus for faster physiologic involution and increased tone (Fig. 3). In most anticipated normal pregnancies, a woman finds that the hormon~l milieu triggers latent maternal instincts leading to anticipation of holding the infant closely to the breast and providing continued nourishment. 33 Parenthood potentially provides the' opportunity for psychologic growth from the egocentricity of adolescence to an adult self-concept in which the mother cares for and nourishes this new being. In the meanwhile, the fetus is simultaneously undergoing development.

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ENERGY UTILIZATION IN LACTATION

Figure 2. Energy utilization in lactation, showing availability of body stores and dietary sources. (From Lawrence RA: Breastfeeding: A guide for the medical profession, ed 3. St. Louis, CV Mosby, 1989; with permission.)

MAINTENANCE AND ACTIVITY MILK LOSSES IN MILK PRODUCTION

Hypothalamus

t

Figure 3. Diagrammatic outline of ejection reflex arc. When infant suckles breast, he stimulates mechanoreceptors in the nipple and areola that send a stimulus along the nerve pathways to the hypothalamus, which stimulates the posterior pituitary to release oxytocin. It is carried via the bloodstream to breast and uterus. Oxytocin stimulates myoepithelial cells in the breast to contract and eject milk from the alveolus. Prolactin is responsible for milk production in the alveolus. It is secreted by the anterior pituitary gland in response to suckling. Stress such as pain and anxiety can inhibit the let-down reflex; the sight or cry of an infant can stimulate it. (From Lawrence RA: Breastfeeding: A guide for the medical profession, ed 3. St. Louis, CV Mosby, 1989; with permission.)

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The infant is prepared to suckle shortly after birth. The newborn already has been making sucking motions in utero, sucking and swallowing amniotic fluid. Part of the balance of the amount of amniotic fluid depends upon this suckling and swallowing of fluid in utero. The infant also has a rooting reflex that helps him turn to grasp the nipple. The normal newborn infant adapts to breast-feeding readily. When the infant grasps the nipple and areola, the sucking stimulates the nerve fibers in the nipple. In turn, the afferent nerve fibers send a message via the spinal cord to the mesencephalon of the hypothalamus in the maternal brain and trigger the pituitary to release two hormonesprolactin and oxytocin. The prolactin stimulates the synthesis and secretion of milk itself. Oxytocin rapidly causes the ejection of milk froin alveoli and smaller ducts into larger lactiferous ducts and sinuses by stimulating the myoepithelial cells to contract. The myoepithelial cells (or basket cells) are wrapped about the ducts and, when they contract, milk is ejected. Milk ejection involves both neural and endocrine stimulation and response. A neural afferent pathway and an endocrine efferent pathway are required, but this stimulus is triggered predominantly by touch and not by pressure of a full milk gland. This response may be inhibited by pain or stress (Fig. 3). This remarkable physiologic process provides total nutrition at the most critical and most rapid growth period of an infant's life using maternal substrates to manufacture the perfect infant food. 27

GENERAL MANAGEMENT OF MEDICAL ILLNESS IN THE LACTATING WOMAN Management of medical illness in the lactating woman has to consider both the mother and child. The key issues are: (1) the utilization of any drug or compound that may pass into the milk; (2) will the drug inhibit lactation itself? and (3) will the diagnostic procedures or treatment require separation of the mother and infant for more than a few hours? DRUGS IN LACTATION

The factors that influence the passage of a drug into the milk in humans include the size of the molecule, its solubility in lipid or water, whether it binds to protein, the pH of the compound, and the diffusion rates. 3 .5 ,43 The route of administration influences the absorption rate, the peak plasma time, and the half-life. 3H Passive diffusion is a principal factor in the passage of the drug into the milk but carrier-mediated diffusion, active transport, and pinocytosis are other mechanisms. Compounds that are large molecules (heparin and insulin) do not pass into milk. Compounds that are weak acids do not pass into the milk in large quantities because human milk is slightly acidic (pH, 6.9 to 7.0). Drugs bind more easily to plasma proteins than milk proteins. 35 The oral bioavailability of the drug or its metabolites (insulin is not

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absorbed from the gastrointestinal tract) influences the amount absorbed by the infant. 38 The effect on the nursing infant depends upon the maturity or gestational age and the chronological age of the infant. Gestational Age

+ Chronological Age = Conceptual Age

The ability of the neonatal liver to detoxify the compound and excrete it in the stool or the ability of the renal system to excrete it, influences its retention and accumulation and, therefore, its pharmacologic effect. The younger and less mature an infant, the less well he or she handles a compound. If the drug interferes with bilirubin metabolism in the glucuronyldase system in the newborn infant, bilirubin may accumulate dangerously. If the drug binds to albumin as the sulfa compounds do, the bilirubin binding may be interrupted and place the infant at theoretical risk of kernicterus. On the other hand, if the infant is several months old (conceptual age of at least 44 weeks), it should not be a problem because liver metabolism and albumin binding will have improved. The age of the infant is also a factor in the volume of milk consumed and, therefore, the amount of drug consumed. Per unit of body weight, the amount of drug is less in the older child if he or she is receiving other foods as well (6 months and older). Milk plasma ratios are often published after a single dose of a drug, but unless the time and amount of dosing are known, the figure may be difficult to interpret. The effect of multiple doses and the presence of a steady-state is closer to the clinical situation. Some investigators·3.5 prefer calculations utilizing the volume of distribution of a drug: Dose Ch = - Vd where Ch is the concentration of the drug in breast milk in g per L, Vd is the apparent volume of distribution in L per kg, and the dose is the dosage delivered to the systemic circulation in mg per kg. Utilization of the oral bioavailability of the drug with the half-life of the drug in plasma is also a useful means of estimating the risk of some drugs. 37 The drugs with zero or negligible oral bioavailability are shown in Table l. The American Academy of Pediatrics published a list of the transfer of drugs and other chemicals into human milk in 1983. 8 This list is divided into four categories: 1. 2. 3. 4.

Drugs that are contraindicated during breastfeeding. Drugs that require temporary cessation of breastfeeding. Drugs that are usually compatible with breastfeeding. Food and environmental agents: effect on breastfeeding.

Only compounds about which there was information in 1983 are listed. Most compounds are in category 3 although some of these are controversial. There are some other resources for determining the relative risks of a given drug. The drugs with the least risk to the infant will be provided in each disease category.

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Table 1.

A. LAWRENCE

Drugs with Zero or Negligible Oral Bioavailability

ANTl\IlCROBIAI.S

OTHERS

Amikacin Amphotericin B Carbenicillin Cefamandole Cefazolin Cefonicid Cefoperazone Cefoxitin Ceftizoxime Cephalothin Cisplatin Doxorubicin Gentamycin Kanamycin Methicillin Moxalactam Neomycin Streptomycin Tricarcillin

ACTH Epinephrine Heparin Insulin Trimethaphan Vasopressin

Some of these drugs were documented to be excreted into breast milk, but should not pose any risk to the infant because of lack of oral bioavailability. From Rivera-Calimlin L: The significance of drugs in breast milk. Clin Perinatol 14:51, 1987. SEPARATION OF MOTHER AND INFANT

If diagnosis or treatment will require separation of the mother and infant for more than a few hours, arrangements need to be made to nourish the infant and pump the mother's breasts. If the situation permits, the best solution may be to allow the infant to room-in with the mother if she is hospitalized if another adult is available to care for the infant's other needs. The increase in ambulatory care and home care programs have actually enhanced the maintenance of lactation and decreased mother-infant separation whether breast- or bottle-fed since mothers return home promptly. However, there is a certain danger of expecting mother to continue to care for her infant totally if she is recovering at home. The physician should ensure appropriate home care and homemaker assistance is provided either by the family or an agency. If the nursing couplet must be separated, a regular schedule of pumping the breasts should be implemented not only to provide the milk for the infant but to maintain the milk supply for the postrecovery phase and resumption of breast-feeding. 1.27 A fully lactating woman who abruptly stops lactating will become febrile and develop a flu-like syndrome, which will also confuse the primary medical picture. Furthermore, it may predispose to mastitis and/or loss of milk supply. If the mother is receiving a drug contraindicated for the baby, she should pump her milk to maintain her supply until the medication is discontinued and discard the contaminated milk. The infant will have to have temporary feedings of formula or banked human milk. Most medical supply stores and home health aid supply companies rent electric breast pumps and sell the disposable personal tubing,

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flange, and bottles. (White River, Inc., Medela, Inc., and Egnell, Inc. also have hand pumps and equipment that permits pumping both breasts simultaneously. ) Medications that may suppress lactation in general include those that inhibit prolactin release or those that affect the secretory gland directly or inhibit let-down by suppressing oxytocin. Prolactin inhibitors affect the production or release of prolactin and include androgens, clomiphene citrate, levodopa, excessive pyridoxine (200 mg), monoamine oxidase inhibitors, ergot derivatives, metergoline, and prostaglandins E and F 2".35 Some of these compounds are used therapeutically postpartum to suppress lactation in women choosing to bottle-feed. Diuretics have been used to suppress lactation and have been described to decrease milk production in some women. On the other hand, less diuretic may be necessary in a woman who establishes lactation and produces 500 to 1000 ml per day. Drugs that enhance lactation or, more commonly, cause galactorrhea (milk secretion without pregnancy and in males) include phenothiazines, thioxanthines, butyrophenones, and reserpine and its derivatives. 35

MINIMIZING THE EFFECT OF MATERNAL MEDICATION

If it is necessary to medicate a nursing woman and the hazard to the infant is minimal, the following important adjustments can be made to minimize the effects 27 : Do not use a long-acting form of the drug because the infant will have more trouble excreting it. Accumulation in infants is a concern. 2. Schedule the doses so that the least amount possible is in the milk. Check peak milk and peak blood level times and avoid feeding at peak times. 3. When possible, choose drug with least amount in milk. 4. Watch infant for unusual signs or symptoms such as change in feeding pattern, sleeping habits, fussiness, or rash. 1.

MANAGEMENT OF SPECIFIC DISEASES INFECTIOUS DISEASE

The most common medical complication during lactation is acute or chronic infection. An acute infection which is self-limited and not life-threatening can be treated with appropriate antibiotics without discontinuing or interrupting breastfeeding. An appropriate antibiotic is one that can safely be given to the infant. All antibiotics get into the milk to some degree, some more than others. There are a few antibiotics that are contraindicated in the neonate (Table 2), unless the infant has an infection that responds to no other chemical. These drugs should be avoided especially when the conceptual age is less than 44 weeks. Infections (trichomonas, amebiasis, and certain parasites such as Giardia) that respond to no other treatment and require metronidazole (Flagyl) can be given as effectively in one large (2 g) dose instead of a prolonged 10-

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Table 2.

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LAWRENCE

Antibiotics Contraindicated in Newborns ORAL BIOAVAILABILITY

PLAS~A

FEATURES

(PER CENT)

HALF-LIFE

Accumulates in infant causing grey syndrome Stains unerupted teeth Competes with bilirubin for binding Higher in milk Sulfa derivative Not used in infants

75-90

4.0±2

77 96-100

1O.6± 1.5

35-25

1.6±0.7

99

8.5±2.9

Al\TIBIOTICS

Chloramphenicol Tetracycline Sulfas Erythromycin Metronidazole (Flagyl)

day course. The highest level is obtained in the first few hours and clears in 24 hours. The mother is instructed to pump to maintain her supply but discard her milk for 24 hours. She may then resume breast-feeding. Metronidazole appears in milk in levels equal to serum: symptoms of the drug effect in the young infant include poor feeding, vomiting, and occasionally blood dyscrasia. 2 Table 1 lists antibiotics that are not orally bioavailable. The value of continued breast-feeding outweighs the minimal risk of antibiotic sensitization via the milk. 38 From the contagious standpoint, maternal antibodies appear in the milk within hours and thus the infant is exposed prior to the maternal diagnosis; discontinuing breast-feeding to "protect" the infant against the infectious disease is therefore ineffective. Mastitis Infections of the breast are best treated by continuing to breast-feed while draining the infected breast well by suckling. 27 Unless there is an abscess that ruptures into a duct, the milk is not contaminated. An appropriately treated mastitis does not become an abscess. Antibiotic therapy must be continued for a minimum of 10 days while maintaining full lactation. Local therapy of hot or cold compresses are used for comfort. Maternal rest is mandatory as mastitis is often the result of excessive fatigue of the mother.

Toxic Shock Syndrome Toxic shock syndrome is a medical emergency and requires immediate aggressive therapy. Staphylococcal enterotoxin has been found in milk of a woman with toxic shock syndrome postpartum at days 5, 8, and 11 postinfection. 4o The mother and infant lacked significant antibody in their sera.

Tuberculosis Mothers who are identified as tuberculin-positive and bacteriologically positive while breast-feeding must be started on therapy, as well as the infant after appropriate testing. Breast-feeding should be discontinued if the infant has access to good alternative nutrition. 8 Mothers who are identified as tuberculin-positive but radiographically and bacteriologically negative may continue to breast-feed; both mother and

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infant are given antituberculin drugs while contacts are investigated. Drugs recommended are isoniazid and rifampin (which may turn the milk redorange). Both of these drugs appear in the milk. However, the infant cannot be medicated via the milk alone and must receive direct dosing. If it is safe for the mother to be in contact with her infant, it is safe for her to breastfeed. 8 Hepatitis B Infection with hepatitis B virus (HBV) may present in the postpartum period as a subacute illness with jaundice and anorexia, nausea, and malaise. It may also have occurred during pregnancy. Women who give birth who are HB,Ag-positive should be identified before delivery by history or screening of high-risk groups. Their infants are given hepatitis B immune globulin (HBIG) 0.5 ml, intramuscularly immediately at birth in the delivery room. If the diagnosis was overlooked, the infant would still receive HBIG immediately. The infant is also given 0.5 (10 fLg) human hepatitis vaccine intramuscularly in the delivery room with a different syringe at a different site, or at least within 7 days. This is repeated at 1 and 6 months. With this protection, the infant can be breast-fed not only in developing countries but in the United States according to the Committee on Infectious Disease of the American Academy of Pediatrics. 8 Although the virus has been isolated in some cases in the breast milk, studies in Taiwan and England do not show that breastfeeding by mothers who are HB,Ag-positive increases the risk of HBV infection in their infants. If the disease is diagnosed weeks or months postpartum, the same treatment regime of HBIG and human hepatitis B vaccine should be used for the infant after diagnostic tests. Breastfeeding can continue. The treatment for the mother is unchanged. Women with Hepatitis A and Associated Jaundice at Delivery. There is no special treatment of the neonate (the efficacy of immune globulin is not established) and breastfeeding is not withheld. 8 Acquired Immune Deficiency (AIDS) Syndrome and HTLV-I1I/LAV Infections In the United States in infants whose prognosis for survival would be close to 100 per cent if it were not for being born to a human immunodeficiency virus (HIV)-positive mother, breastfeeding is strongly discouraged whether the mother is symptomatic or not. The virus has been isolated from the milk in some cases (not all). In developing countries, however, where the survival to 1 year of age for any infant is less than 50 per cent if not breast-fed, the recommendation is usually to permit breastfeeding. 27 (Infants are breast-fed by mothers with Hansen's disease under treatment in Leprosariums, too. 8 ) In certain circumstances in this country, breastfeeding may be permitted on a case-by-case basis. Herpes Simplex In the newborn infant, herpes simplex virus (HSV) infection is a serious life-threatening disease with Significant mortality and neurologic impairment of the survivors. It is usually transmitted during passage through the birth canal or occasionally in utero due to ascending infection through the cervix.

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Rarely, infection occurs postnatally from nongenital infections of mouth, hands, or breasts. The infant is not isolated from the mother but from her lesions. Breast-feeding, therefore, is appropriate in a mother whose lesions can be protected. An il1fant should never be breast-fed when there are lesions on the breast. If suspicious lesions occur, breast-feeding should be interrupted until the diagnosis can be made, or the lesions completely clear. Reports in the literature of older infants surviving breast-feeding when lesions were present are misleading. The lesions were not cultured or confirmed to be herpes, and the infants were over 6 months of age. There are reports of death in infants under 1 month who suckled a breast with confirmed herpetic lesions. These infants should be assumed to be infected and treated vigorously immediately. 27 Chicken Pox (Varicella-Zoster, VZV) Chicken pox remains the one common childhood disease for which there is no general vaccination available (limited resources of vaccine are being tested in high-risk groups with childhood leukemia). Adults who develop the disease are often quite ill, especiaiIy during pregnancy. Infants born to women who develop the onset of chickeri pox within 5 days before delivery or within 48 hours after delivery are given varicella-zoster immune globulin (VZIG), 125 units. 8 Antibodies appear in the milk within 48 hours of diseaseonset, so that the infant can be breast-fed as soon as it is appropriate for the mother and infant to be together. NONINFECTIOUS DISEASES

Diabetes Mellitus Diabetes mellitus is a medical disease in which lactation has a Significant impact beyond the matter of maternal medication. l While interest in lactation among diabetics increases, clinical research on the topic is lean. The breast is known to be a target organ for insulin and there are insulin receptors in the acini of the mammary gland itself. As an insulin-sensitive tissue, acute changes in insulin concentration result in rapid alteration in the rate of lipogenesis and the utilization of glucose to produce milk. Cultures of mammalian breast tissue serve as models for explorations of insulin activity. The breast synthesizes lactose from the glucose substrate in normal galactogenesis. Thus, the natural question is: Can the diabetic produce lactose and a milk comparable to the nondiabetic woman? The composition of the milk of diabetics has been studied by Butte et aP in a group of moderately wellcontrolled insulin-dependent (classes B, C, and D) women (insulin-dependent diabetes mellitus, lOOM) at 3 months postpartum. There were no significant differences in the values of lactose, total nitrogen, fat, or calories. Sodium content averaged slightly higher than normal-140 f,Lg per g compared to 100 f,Lg per g. The mean glucose value was higher; however, glucose makes up only about 0.4 per cent of the total energy content of milk, so this was not significant. During the collections, some of the diabetics were slightly hyperglycemic. Measurements of glycosylated hemoglobin were noted to be 8.1 ± 0.6 per cent (normal range, 4.0 to 7.6 per cent). All the infants grew

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and gained weight appropriately as they have in other studies of infants of diabetic mothers (IDMs) who are breast-fed. Although diabetic, a mother should be offered the same opportunity to breastfeed as other women unless her disease has so incapacitated her that any stress is out of the question. l Many lactating diabetics have a sense of well-being and have markedly diminished insulin needs while increasing dietary allowances. When the IDM's neonatal period is uneventful, there is no contraindication to breastfeeding. The major interferences are an operative delivery for the mother or separation of mother and baby due to the infant's admission to an intensive care nursery. During the last weeks of pregnancy, spilling of lactose in the urine of all women is not uncommon as the breast prepares for full milk production. l Lactose in the urine occurs in both breast- and bottle-feeders in the first days postpartum; thus the reducing substance in the urine may be lactose because lactose reabsorbed from the milk is excreted in the urine. Diabetics, therefore, cannot be followed by testing reducing substance in the urine. Diet for the Lactating Diabetic. All lactating women have an increased dietary energy requirement, and utilize the nutritional reserves accumulated as body stores in the last weeks of pregnancy as substrate for the production of milk (see Fig. 2); the diabetic does this also. She must add 500 to 800 additional kcal above prepregnant requirements, and consider that the body energy store that will be mobilized as substrate for the mammary gland is predominantly fat. When a diabetic increases fat metabolism, there is always increased risk ofketonemia and ketonuria. This indicates a need for increased kcal in both the diabetic and the nondiabetic. A group of IDDM women were followed by Ferris et aPS to analyze their dietary intake and the outcome oflactation. Sixteen women breast-fed and 14 women bottle-fed their infants. The IDDM women who successfully sustained lactation had been prescribed diets of 31 kcal per kg per day based on their weights 3 days postpartum, or 35 kcal per kg per day based on preconceptual weights. On the other hand, women who stopped nursing for lack of adequate milk were prescribed only 25 kcal per kg per day on postpartum weight, or 31 kcal per kg per day on preconception weight that was actually similar to the prescription for nonlactators. Normal women (nondiabetic) were given 2000 and 500 kcal during lactation. The successful study mothers consumed more than they thought whereas those who discontinued breastfeeding had actually consumed less. Those women who stopped lactating had lost more weight than the successfullactators, the bottle-feeders, and the normal controls. Fasting blood sugars were lower (60 mg per dl) in the successful lactators without an increase in insulin dosage. Insulin dosages required during lactation are reported in several studies. The subjects in the study by Butte et aP received less insulin (35 ± 10 units per day) compared to the requirement during pregnancy (63 ± 14 units per day). In a report by Whichelow and Doddridge,42 insulin requirements at 3 months postpartum among breastfeeders were 43 units per day average compared to 50 units per day in bottle-feeders. Ferris et aPS reported that insulin doses were not different between breast- and bottle-feeders; however, the dosages were not reported. A significant negative factor in the ultimate success ofiactation in IDDM

596 Table 3.

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Comparison of Findings of Engorgement, Plugged Duct, and Mastitis

CHARACTERISTICS

EI\CORGEylENT

PLUGCED DUCT

ylASTlTlS

Gradual, immediately Gradual, after feedings Sudden. after 10 days postpartum Unilateral Usually unilateral Bilateral Site May shift/little or no heat Localized, red, hot, Swelling and heat Generalized and swollen Intense but localized Mild but localized Pain Generalized >38.4°C <38.4°C Body temperature <38.4°C Feels well Flulike symptoms Systemic symptoms Feels well

Onset

From Lawrence RA: Breastfeeding: A guide for the medical profession, ed 3. St Louis, CV Mosby, 1989; with permission.

is the separation of the mother and infant because the infant is in the neonatal intensive care unit. Ferris '6 reported that the first breast-feeding for IDDMs took place at 35 ± 5 hours (normal newborns are put to breast in the delivery room and at least by 4 hours). This not only delays breast-feeding but increases the amount of formula and number of rubber nipples and bottles given to the infant. All mothers in the Ferris study who stopped breastfeeding early had infants who received 9 oz or more formula by bottle. Lapsed time to initiate breast-feeding is significant to ultimate success. If the infant cannot be put to the breast, the mother should be assisted to pump her breast four to six times a day until the infant can suckle in order to establish lactation. 16 Management of the Lactating Diabetic. The medical needs of the diabetic should be managed as they would be in the nonlactator with the proviso that any drugs deemed necessary be selected (where possible) from those that minimally pass into breast milk and are "safe" during lactation. Insulin dosage should be adjusted to match diet, lactation, and the energy required to produce milk which is usually less than during pregnancy and may be lower than that needed prepregnancy.16 During lactation, increased acetone usually indicates a need for increased calories, not increased insulin. Attention to the increased need for nutrition including 500 extra calories over baseline is critical to lactation success. Pumping the breasts with an electric pump should be initiated as soon as possible (within hours) if the infant is unable to go to breast because of neonatal problems such as respiratory distress syndrome. Since infection is a prime concern of the diabetic and milk is an excellent culture media, particular attention should be paid to any signs of mastitis. In the first few days postpartum, the breasts become physiologically engorged bilaterally with the increased vascular supply and the adaptation to full milk production; some women become excessively engorged and may run a low grade fever. The treatment for this is more frequent feeding or pumping of the breasts and attention to manual expression and massage of the peripherallobules. Warm compresses may assist with flow. This phenomenon is not infection. Mastitis usually does not occur until after the first week, is unilateral, and there may be a small, warm lump or wedge of tissue in one quadrant of the breast (Table 3). The important steps to successful treatment of mastitis include 1.27 :

BREASTFEEJ)]NG A'lD ,\,lEDICAL DISEASE

1.

2. 3. 4. 5.

597

Continue breastfeeding including the affected breast, being sure the drainage is complete. Antibiotics fill' at least 10 days, choosing one that is safe for the baby. Rest-fatigue is usually an important factor in infection. Local treatment to affected breast including prefeeding massage, warm or cold packs for comfort. Analgesics for pain and fever (Acetaminophen).

Prevention of mastitis is more appropriate and should include avoidance of fatigue and care to fully empty the breasts at each feeding. 1 Monilial infections are more common in diabetics because of the glucose-rich vaginal secretions.](j Infections of the nipples can also occur due to Candida albicans either because the infant was infected during vaginal delivery or there is a post-antibiotics therapy surge in fungal organisms. Treatment must include both mother and baby simultaneously. Mycostatin rubbed into the nipple and aerola post-feeding usually is effective therapy. The diabetic may be especially interested in breastfeeding and should be able to do so successfully with attention to the details of diet, insulin, and infection. Thyroid Disease Maternal hypothyroidism is not a contraindication to breastfeeding and, if the mother achieved pregnancy, she should also be able to lactate. Hypothyroidism in pregnancy does not affect the fetus whose thyroid works independently if there is sufficient iodine available. The use of desiccated thyroid in lactation is not a contraindication. Normally in a euthyroid woman, a small amount of active thyroxine is present in the milk. It is appropriate to screen the newborn for normal thyroid activity in all cases. This is done routinely on all newborns by state law in many states. If the diagnosis of hypothyroidism is made in the mother postpartum, it should not alter the decision to breastfeed. Maternal hyperthyroidism itself is not a contraindication to breastfeeding; however, the medication utilized in its management may be if it occurs in the milk in a form that could suppress the newborn thyroid. Only a few infants born to mothers with Graves' disease show frank manifestations of the transient-transferred form of the disease. Recognition of thyroid disease as immunologic in nature is providing greater understanding of the effect on the newborn. Graves' disease, Hashimoto's disease, and primary myxedema are different facets of a spectrum of immunologically mediated thyroid disease according to Scott. 40 N eonatal thyrotoxicoSis, a rare entity seen in 10 per cent of infants born to women with Graves' disease due to transplacental passage of thyroid stimulating immunoglobulins, is important because it does not depend upon maternal thyroid status. These antibodies are IgG antibodies that do not appear in the milk in any amount and are not absorbed by the gastrointestinal tract. The medication selected for medical management of the mother should not pass to the fetus or postpartum into the breast milk. Thiouracil appears in the milk in amounts higher than in the plasma and is contraindicated. 9 Methimazole (Tapazole) appears in the milk with a milk:plasma ratio of 1. A 40-mg dose of methimazole yields 70 j..Lg in 1 L of milk. When 12 lactating

598

RCTH

Table 4.

The

lIalj~lives

of Various Antiepileptic Drugs

Phenobarbital Primidone Phenytoin

40-500 hours 7-60 hours

Ethosuximide Valproie acid Diazepam

40 hours 14-88 hours 40-400 hours

Carb~mazepine

A. LAWRENCE

1.5-10.5 hours 8-28 hours

women were treated with carbimazole, a methimazole derivative, in doses ranging from 5 to 15 mg daily (equal to 3.3 to 10 mg methimazole), all the infants maintained normal thyroid function studies through 21 days.26 Two children followed to 3 to 4 months remained normal. Propylthiouracil appears in the milk in only minimal amounts (0.025 to 0.077 per cent of dose), and has been demonstrated to be safe for the breast -fed infant. 20 The infant's T 3 , T 4 , and thyroid-stimulating hormone should be monitored while fully breast-fed by a mother receiving these medications. Iodine should not be given to the lactating woman for hyperthyroidism or in expectorants for asthma or pulmonary disease, since the breast is a major pathway of excretion of iodine. Iodides have been noted to be goitrogenic and to sensitize the thyroid gland to other drugs such as lithium, chlorpromazine, and methylxanthines. 2 Radioactive iodine is contraindicated as a treatment during lactation. A single therapeutic dose is excreted in 1 to 3 weeks. Milk could be pumped and discarded until it is clear of radioactivity, and the breast-feeding then resumed. As a diagnostic tool, pll will actively reach the milk at 5 per cent of the dose. The half-life of p31 in the milk is 24 hours. It is possible to suspend breast-feeding but maintain lactation by pumping and discarding the contaminated milk and then resuming lactation after the milk is no longer radioactive (24 hours in most cases but definitely by 48 hours). 27 Epilepsy A seizure in a mother with a young infant is of concern whether the infant is breast- or bottle-fed, since the infant might easily be injured during the event. Seizure control, therefore, is the first concern. 21 Breast-feeding an infant poses a problem in terms of the medication itself and the amount that appears in the milk. Antiepileptic drugs (AED) that will be considered here are phenobarbital, primidone, phenytoin, carbamazepine, ethosuximide, valproic acid, and diazepam. The drug level in the infant's serum at birth is important and breast-feeding may provide a means of gradually withdrawing the infant from maternal medication and avoiding a "withdrawal syndrome"21 (hyperirritability, tremor, vomiting, poor sucking, hyperventilation, and sleep disturbances). The half-life of various AEDs are shown in Table 4. Because these compounds have a sedating effect, they may prevent the infant from suckling adequately in the first few days. The nutritional intake of the infant needs to be monitored as does the maternal need for adequate stimulus to initiate milk production. The infant may need a supplement for

BREASTn:EDlNG AND MEDICAL DISEASE

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nutrition but it will also dilute the medication effect. The mother will need a pump to increase production. 21 Forty-two infants of epileptic mothers were studied by Kaneko et al. 21 Poor sucking was correlated with the drug and the dosage. The authors recommended mixed feeds of breast with some formula early in the postpartum period to reduce medication supplied to the infant via the milk until the levels in the serum taper and the infant's liver and kidneys mature to metabolize and excrete drug more effectively. Full breastfeeding then proceeded if care had been taken to establish a good milk supply with supplementary pumping. Phenobarbital is considered compatible with breastfeeding by the Committee of Drugs of the Academy of Pediatrics 7 if maternal doses are modest. Levels can be obtained on the infant in earlv weeks as a check, and the infant should be observed for unusual sleepine~s or poor suckling. Phenytoin (Dilantin) also appears in the milk, but little (milk:plasma levels 0.18 to 0.54) reaches the infant if the mother's levels are in the therapeutic range. Although the Academy of Pediatrics 7 also considers this drug compatible with breastfeeding, the infant should be monitored for adverse effects (poor feedings, sleepiness). Primidone, a structural analogue of phenobarbital, appears in breast milk. 31 A milk:plasma ratio of 0.8 and milk concentrations of 2.3 f-Lg per ml is reported by Kaneko et al. 21 This is also considered compatible with breastfeeding on the American Academy of Pediatrics (AAP) list. 7 Carbamazepine, a tricyclic antidepressant used since the 1960s, is excreted in breast milk; infant serum levels have been recorded at 0.4 to 1. 8 f-Lg per ml. 21 Accumulation has not been reported and the AAP considers it compatible. 7 Ethosuximide, a succinimide anticonvulsant used in the treatment of petit mal epilepsy, freely enters the milk so that levels of serum and milk are comparable. 22 The milk:plasma ratio has been reported at 0.78 to 1. O. No effects in the nursling have been reported. 2 AAp7 considers its use compatible with breastfeedi~g. Valproic acid has been of concern as a teratogen although its levels in milk are low, 0.17 to 1. 0 f-Lg per ml that corresponds to milk: plasma ratio of 0.01 to 0.07. 2 AAp7 lists this drug as compatible with breastfeeding; no reports of untoward effects on the nursling have been published to date. Diazepam and its metabolite, n-demethyl diazepam, freely cross into breast milk. The milk:plasma ratios vary but have been reported as high as 2.7. 6 ,34 In addition, diazepam tends to aecumulate in the newborn causing lethargy and weight loss; it is therefore not recommended for chronic use during lactation. 21 Acute seizure control with one or two doses is not sufficient reason to terminate breastfeeding. If necessary, in the first post-dose 24-to 48-hour period, milk could be pumped and discarded. The half-life of diazepam is 43 ± 13 hours.

Hypertension/Heart Disease The concerns surrounding the issue of breastfeeding by hypertensive women or women with significant cardiovascular disease are centered on the medication required for control. There are no data to suggest that the

600

RUTH

A. LAWRENCE

cardiac output is compromised during lactation. 43 \Vhether the elevated levels of prolactin associated with lactation have a tranquilizing effect upon the hypertensive patient has not been demonstrated in humans. 27 Animal data show behavior changes in nonpregnant or male animals perfused with lactational hormones. It is known, however, that lactation decreases the need for diuretics. Since the breast secretes 1 L or so of fluid a day, depending upon infant intake, it is a pathway for fluid excretion. Milk also contains a small amount of sodium that is controlled by a sodium pump and does not alter maternal sodium levels (the level is lower in milk than in plasma). Sodium levels are not abnormal in milk if abnormal in maternal serum. Sodium levels in milk in the affected breast may be elevated during mastitis, however, which is probably due to an alteration in passive diffusion. Certain diuretics have been used in large amounts to suppress lactation in women who did not choose to breast-feed and, therefore, had no suckling stimulus to the breast. In dehydrated women, the breast continues to secrete although urine production may be decreased. Diuretics. Chlorothiazide, hydrochlorothiazides, and chlorthalidone are minimally excreted in milk as is spironolactone and its metabolite canrenone according to single-dose kinetics. 2 No data are available about excretion of furosemide into breast milk nor its effect on milk production. 41 Chlorothiazide, ethacrynic acid, and furosemide have a risk for interfering with bilirubin metabolism; thus, caution is advised in a jaundiced newborn. Beta-adrenergic Blocking Agents. The beta-adrenergic blocking agents are weak bases and should, therefore, theoretically appear in milk with a milk:plasma ratio greater than 1. Propranolol has been widely studied and is considered the safest of the beta-blockers during lactation. 27 The halflife of propranolol is 3.9 ± 0.4 hours, and it is less than 50 per cent orally bioavailable. Propranolol has been used safely in infants and children and is considered compatible with breast-feeding by the AAP. Methyldopa appears in low amounts in the milk but its direct action on the pituitary to suppress prolactin release presents a theoretical risk of suppressing milk production. Reserpine is a recognized risk to the infant during delivery and postpartum as it crosses the placenta and appears in the breast milk causing nasal congestion, tachypnea, and bradycardia. The antihypertensive drugs atenolol (Tenormin), metoprolol (Lopressor), and nadolol (Corgard, Corzide) all appear in the milk but at very different milk:plasma ratios. 25 ,28 Atenolol, a cardioselective beta-adrenergic blocking agent, is a weak base and appears to accumulate in milk at levels greater than in plasma (25 to 100 mg per day; regimens resulted in a milk:plasma ratio of 2. 9 to 3.6), Atenolol has been found in serum and urine of breast-fed infants in some studies and not in others. After a 100-mg dose with a milk level of 1500 ng per ml, ate nolo I was measured in infant serum at 4 hours, 28 To date, no symptoms have been reported, although bradycardia and beta-blockade symptoms should be watched for, AAP lists the drug as compatible with breast-feeding. 7 Metoprolol, also a cardioselective beta-blocking agent, is secreted into milk at concentrations 2.0 to 3,7 times that of the maternal serum. 2 No untoward symptoms have been observed in the neonate. The half-life of metoprolol is 3.2 ± 1.2 hours and the oral bioavailability is less than 50 per

BlmASTFEEDlNG AND MEDICAL DISEASE

601

cent. Maternal peak serum level of 713 ng per 100 ml occurred at 1.1 hours post-ingestion and peak milk level of 4.7 ng per 100 ml occurred at 3.8 hours. Avoiding peak levels for breastfeeding is appropriate. It is considered the safest of this group for breast-fed infants. The AAP lists it as compatible. 7 Nadolol, a nonselective beta-adrenergic blocking agent used for both hypertension and angina pectoris, is found in milk in levels 4.6 times the maternal serum levels. A study of 12 women ingesting 80 mg per day for 5 days to achieve a steady-state had levels of 357 f-Lg per ml in their milk that would provide a 5-kg infant with 2 to 7 per cent of the adult dose.1 2 The plasma half-life is 16 ± 2 hours, and it is less than 50 per cent orally bioavailable. 38 The AAP considers this drug compatible with breastfeeding. Timolol, a nonselective beta-adrenergic blocking agent, is excreted into breast milk with a milk:plasma ratio of 0.83 at doses of 5 mg and 10 mg three times daily.l7 Milk levels were dose-dependent. The plasma half-life is 4.1 ± 1.1 hours, and there is 50 per cent oral bioavailability. No reports of problems with infants breast-fed by mothers taking timolol have been published. It is appropriate to avoid nursing at peak plasma times. Timolol is not listed by the AAP. Captopril is excreted in breast milk in low concentrations when mothers received 100 mg three times a day. Levels peaked in their milk at 3.8 hours at 4.7 ng per ml; the milk:plasma ratio is 0.012.13 No effects have been seen in infants breast-fed by these mothers. The AAP considers the drug compatible with nursing, and investigators consider it one of the safest in its class of drugs. Digitalis, in the form of digoxin, does appear in breast milk. Milk:plasma ratios vary from 0.6 to 0.9, but because of protein binding, represent little of the maternal dose. If one calculates the predicted level using the volume of distribution, which is high (7.5 L per kg), the infant would receive 1.1 ng per ml in the milk when a 60-kg mother takes a 0.5-mg dose. 35 Sufficient experience has accumulated to conclude that it is safe to breastfeed under these conditions, and the AAP concurs. Digoxin and digitoxin are readily bioavailable and have long half-lives (39 hours and 6.7 days). With the careful selection of medications, breastfeeding can be compatible with successful pharmacologic treatment of cardiovascular disease. 43 REFERENCES 1. Asselin BL, Lawrence RA: Maternal disease as a consideration in lactation management. Clin Perinatol 14:71, 1987 2. Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation, ed 2. Baltimore, Williams & Wilkins, 1986 3. Butte NF, Garza C, Burr R, et al: Milk composition of insulin-dependent diabetic women. J Pediatr Gastr Nutr 6:936, 1987 4. Chandra HK: Prospective studies of the effect of breast feeding on incidence of infection and allergy. Acta Paediatr Scand 68:691, 1979 5. Chen Y, Yu S, Li WX: Artificial feeding and hospitalization in the first 18 months of life. Pediatrics 81:52, 1988 6. Cole AP, Hailey DM: Diazepam and active metabolite in breast milk and their transfer to the neonate. Arch Dis Child 50:741, 1975 7. Committee on Drugs, American Academy of Pediatrics: The transfer of drugs and other chemicals into human breast milk. Pediatrics 72:375, 1983

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LAWRENCE

8. Committee on Infectious Disease Report, ed 20. Elk Crove Village, lL, American Academy of Pediatrics, 1986 9. Cooper DS: Antithyroid drugs: To breastfeed or not to breastfeed. Am J Obstet Cynccol 157:234, 1987 10. Cunningham AS: Morbidity in breastfed and artificially fed infants. n. J Pediatr 95:685, 1979 11. Davis MK: Infant feeding and childhood cancer. Lancet 2:365, 1988 12. Devlin HC, Duchin KL, Fleiss PM: Nadolol in human serum and breast milk. Br J Clin Pharmacol 12:393, 1981 13. Devlin RC, Fleiss PM: Captopril in human blood and breast milk. J Clin PharmacoI2l:1I0, 1981 14. Duffy LC, Heipenhoff-Talty M, Byers TE, et al: The effects of infant fecding on rotavirusinduced gastroenteritis: A prospective study. Am J Dis Child 140:1164, 1986 15. Ferris AM, Dalidowitz CK, Ingardia CM, et al: Lactation outcome in insulin-dependent diabetic women. Am Diet Assoc 88:317, 1988 16. Ferris AM, Reece EA: Postpartum management and lactation. In Reece EA, Coustan DR (eds): Diabetes Mellitus in Pregnancy. New York, Churchill Livingstone, 1988, pp 623-633 17. Fidler J, Smith V, DeSwiet M: Excretion of oxprenolol and timolol in breast milk. Br J Ob stet Cynaecol 90:961, 1985 18. Clatthaar C, Whittall DE, Welborn TA, et al: Diabetes in western Australian children: Descriptive epidemiology. Med J Aust 148:117, 1988 19. Hanson LA, Ahlstedt S, Andersson B, et al: Protective factors in milk and the development of the immune system. Pediatrics 75(suppl):172, 1984 20. Kampmann JP, Johansen K, Hansen JM, et al: Propylthiouracil in human milk. Lancet 1:736, 1980 21. Kaneko S, Suzuki K, Sato T, et al: The problems of antiepileptic medication during the neonatal period: Is breastfeeding advisable? In Janz D, Dam M, Hichens A, et al (eds): Epilepsy, Pregnancy, and the Child. New York, Haven Press, 1982, pp 343-348 22. Koup JH, Rose JQ, Cohen ME: Ethosuximide pharmacokinetics in pregnant patient and her newborn. Epilepsia 19:535, 1978 23. Kramer MS, Barr RC, Leduc DC, et al: Determinants of weight and adiposity in the first year of life. J Pediatr 106: 10, 1985 24. Kovar MC, Serdula MK, Marks JS, et al: Review of the epidemiologic evidence for an association between infant feeding and infant health. Pediatrics 74(suppl):619, 1984 25. Kulas J, Lunell NO, Hosing V, et al: Atenolol and metoprolol: A comparison of their excretion into human breast milk. Acta Obstet Cynecol Scand 118(suppl):65, 1984 26. Lamberg BA, Ikonen E, Osterlund K, et al: Antithyroid treatment of maternal hyperthyroidism during lactation. Clin Endocrinol 21:81, 1984 27. Lawrence HA: Breastfeeding: A guide for the medical profession, ed 3. St. Louis, CV 'vIosby, 1989 28. Liedholm H, Melander FA, Bitzen PO, et al: Accumulation of atenolol and metoprolol in human breast milk. Eur J Clin Pharmacol 20:229, 1981 29. Mayer EJ, Hamman HF, Cay EC, et al: Reduced risk of insulin-dependent diabetes mellitus (IDDM) among breast fed children: A case-control study. Diabetes, 37:1625, 1988 30. McKinney PA, Cartwright HA, Saiu JMT, et al: The inter-regional epidemiological study of childhood cancer (IRESCC): A case-control study of aetiological fuctors in leukaemia and lymphoma. Arch Dis Child 62:279, 1987 31. Nau H, Rating D, Hauser I, et al: Placental transfer at birth and postnatal elimination of primidone and metabolites in neonates of epileptic mothers. In Janz D, Dam M, Richens A, et al (eds): Epilepsy, Pregnancy, and the Child. New York, Haven Press, 1982, pp 361-366 32. Newton N: Psychologic differences between breast and bottle feeding. Am J Clin Nutr 24:993, 1971 33. Newton N, Newton 'vi: Psychologic aspects ofiactation. N Engl J Med 277:1179, 1967 34. Patrick MJ, Ti-Istone WJ, Heavey P: Diazepam and breast feeding. Lancet 1:542, 1972 35. Peterson HC, Bowes WAJ: Drugs, toxins, and environmental agents in breast milk. In Neville MC, Neifert MH (eds): Lactation Physiology, Nutrition, and Breast Feeding. New York, Plenum Press, 1983, pp .367-403

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36. Public Health Service: Promoting health, preventing disease; Objectives for the nation. US Department of Health and Human Scrvices, Washington, DC, 1980, pp 73-77 37. Report of the Surgeon General's Workshop on Hreastfeeding and Human Lactation: DHHS Publication :>io. HRS-D-MC 84-2, pp 3-7. Rockvillc, MD, Government Printing OfRce, 1984 38. Rivera-Calimlin L: The significance of drugs in breast milk. Clin Perinatol 14:51, 1987 39. Ryan AS, Martinez GA: Breastfeeding and the working mother: A profile. Pediatrics, in press 40. Scott JS: Immunological disorders. In Brudenell M, Wilds PL (eds): Medical and Surgical Problems in Obstetrics. Bristol, England, John Wright, 1984 41. Vergerom JM: Recovery of staphylococcal enterotoxin F from the breast milk of a woman with toxic-shock syndrome. J Infcct Dis 146:456, 1982 42. Whichelow MJ, Doddridge ~IC: Lactation in diabetic women. Br Med J 287:649, 1983 43. White WB: ~1anagement of hypertension during lactation. Iiypertension 6:297, 1984 44. Wilson JT, Brown RD, Hinson JL, et al: Pharmacokinetic pitfalls in the estimation of the breast milk/plasma ratio for drugs. Annu Rev Pharmacol Toxicol 2.5:667, 1985 Division of Neonatology Box 777 Department of Pediatrics University of Rochester Medical Center Rochester, NY 14642