Risks of Medications

The American Association of Pediatrics, in 1994, 1997, and 2001, reviewed research and clinical information about drug use in lactation with the latest statement supporting the safety of the use of the vast majority of drugs during breastfeeding. Generally, only the most toxic drugs, such as cancer chemotherapeutics and long half-life radioactive iodine compounds, are absolutely contraindicated. Known adverse events are usually associated with premature or small for gestational weight babies, and such effects often reflect the known side effects in adults. Prediction of risk includes the nature and degree of adverse effects. Certain categories of drugs, such as antidepressants, may be of concern. Although clinical use of many of these substances is widespread, despite the AAP’s concerns, most lack significant adverse effects.¹² The safety of antidepressant medications during lactation was discussed in Chapter 16.

Interestingly, synthetic hormonal substances such as the progestins are considered compatible with breastfeeding. Some experts are concerned about potential long-term effects on the infant yet no evidence of this has been found. Other hormonal preparations, such as synthetic thyroid preparations, are noncontroversial and have been used for decades. Synthetic estrogens are an exception; most practitioners report a decrease in milk supply with use of any amount of estrogen in birth control agents.

Measurement of the degree of milk entry of many types of pharmaceutical substances has led to the realization that few drugs can be expected to cause toxic effects in the infant. Animal lactation studies have been done for some, but not all drugs. Newer prescription drugs often lack studies. Yet, lack of specific lactation studies is not considered reason enough to contraindicate a drug. Indeed, many drugs lack even preliminary study of milk entry in animals or humans. The pharmacokinetic characterization of almost all pharmaceuticals does allow more precise prediction of milk entry, although few fall outside of the 1% to 10% milk entry rule predicted simply from maternal oral ingestion. The clinical evidence for use of most drugs has accumulated through publication of case studies, anecdotes, and experimental study of individuals or very small groups made up of a few mother–baby pairs (often fewer than 10). Typically, milk entry is only characterized for one stage of lactation. Very few drugs have been studied over long-term use, where the child has been exposed to the drug over weeks or months though some drugs are indeed administered in this way. Despite this narrow basis of experimental evidence or quantitative data on drugs during lactation, the increased prescription of medications during lactation has resulted in the documentation of few adverse reactions in children. It is worthy to note here that even drugs such as digoxin, a cardioactive alkaloid with a narrow therapeutic index, is considered compatible with breastfeeding, although close monitoring of mother and baby is necessary to ensure dose limitation.¹¹ As reassuring as this is to lactation experts, it is clear that the actual evidence for safety is quite limited when compared to the evidence for safety in adults. Thus, we know a lot about how a pharmaceutical is metabolized in the mother (pharmacokinetics), allowing tolerably accurate prediction of milk dose, yet have an almost nonexistent experimental base of information regarding actual milk entry or effects in large numbers of infants or over all stages of lactation. Quantification of milk entry and infant serum levels for most drugs is surprisingly limited.

In the Absence of Lactation Studies: Herbs vs. Medications

The powerful nature of pharmaceuticals that inherently generates side effects and drug interactions, as well as their use in complex medical situations results in a relatively high rate of adverse events associated with their use when compared with herbal medicines.¹⁶ When comparing the merits of medications vs. herbs, the relatively narrow basis of evidence for safe use of medications during lactation must still be balanced by the fact that most medications are more completely studied, particularly regarding their metabolism and that more elaborate pharmacovigilance systems are in place to monitor their use.¹⁷ However, information gained from traditional use cannot be ignored or discarded; traditional information is the basic study material for the scientific discipline of ethnopharmacology after all. Nor can drug data provided by the pharmaceutical industry be entirely trusted to always provide an objective measure of safety. Indeed, the PDR’s statements regarding safety during lactation are singularly useless to guide clinical practice.^12,15 Regarding efficacy, the principle of proportionality should not be overlooked.¹⁸ Are we talking about the mother having cancer or a cold? How important is efficacy in the risk–benefit analysis? The advantages of an herbal treatment that may not work as quickly or as well compared with a pharmaceutical must be balanced against the need for efficacy.

Herb Risks: Herbs with Pharmacokinetic Information

De Smet and Brouwers provide a systematic review of the state of herbal pharmacokinetics, evaluating the complexities of phytoconstituent bioavailability and pharmacokinetics, and providing a short list of plant constituents where serum levels have been measured.¹⁸ The authors advocate pharmacokinetic study of herbs with narrow safety margins or those commonly used for life-threatening disorders, but point out that for herbs with wide safety margins, available in high-quality preparations and used for minor health disorders, the need for such characterization is unnecessary. Yet, bioavailability and serum levels are two measures that are of great utility in assessing herb safety during lactation, if for no other reason than to reassure the doubtful health practitioner. Assessment of herb risk during lactation is hindered by the fact that useful information such as serum levels, half-life, and protein binding are not yet characterized for many phytochemicals. Dose information for any one constituent, usually the “active” constituent, is often available for most controversial or well-researched herbs, and the simple application of the 1% rule to estimate maternal serum levels from oral dose will yield a ballpark estimate of milk entry for the chemical of toxicologic interest. Even if you assume a worse-case scenario and use 10% as the rule, this number is still likely to be very small. Hypericin and soy isoflavones are two examples where serum levels have been measured. Hypericin is a constituent of St. John’s wort (Hypericum perforatum) that has been considered active, even though more recent studies indicate a number of other constituents may actually be responsible for the antidepressant activity. In any event, hypericin serum levels have been measured at 8.5 ng/mL following a dose of 900 mg/day of the dried herb.¹⁹ This amount represents a very small dose available to diffuse into the milk. The soy isoflavone, genistein, was recently measured in breast milk at concentrations of 0.2 μmol/L in breast milk following ingestion of soy nuts containing a 20 mg of genistein.²⁰ Genistein entry into breast milk appears extremely limited in this study as serum levels were measured at 2.0 μmol/L plasma, representing a 1:10 milk:plasma ratio. This amount is tiny compared to what babies receive when fed soy formula.²¹

Another class of relatively well-studied herbs is the stimulant laxatives that breastfeeding women are cautioned about for good reason; diarrhea can result from local activity of constituents within the GI tract (compartmental effect). In a study described in Hale, sennosides A and B could not be detected in milk in one study of 20 breastfeeding women using Senokot tablets containing a dose of 8.6 mg sennosides/day.¹² Most (15/23) women in the study reported loose stool, of these, two had babies also had loose stools. In another study rhein, an active laxative metabolite of sennosides, was measured in 100 milk samples drawn from 20 women.²² A daily dose of 15 mg sennosides were consumed for 3 days before sampling; 0 to 27 ng/mL was found, with over 90% of the milk samples containing less than 10 ng/mL of rhein. None of the infants had loose stools. However, the senna was combined with the bulking agent, Plantago ovata, which may have slowed or lowered absorption of the laxative constituents into the mothers’ bloodstreams. In contrast to the German Commission E, senna and cascara are considered compatible with breastfeeding; this statement assumes the necessary short-term use of a standardized product in appropriate doses; occasional diarrhea has been noted in neonates but not older children.¹¹

Herb Risk to the Child

Herbs that present a well-documented risk to adults [i.e., those containing aristolochic acid (AA) or toxic pyrrolizidine alkaloids (PAs)] logically can be expected to present some degree of risk to the breastfeeding child. However, most herbs of commerce lack serious side effects when used appropriately, and thus would not be expected to be able to produce them in infants in the tiny doses of phytoconstituents received in breast milk. Synthetic hormones such as progesterones, estrogens, thyroid replacements, and insulins are compatible with breastfeeding at least infant safety.¹¹ Thus, regarding, the proportional risk posed to the child by the relatively much weaker phytohormones would seem slight. This is not to say that adverse effects cannot occur. Herbs that do have adverse side effects when used appropriately or with narrow therapeutic safety range would be predicted to be much more likely to cause similar problems in the breastfeeding child. These herbs must be used with caution when breastfeeding, even in standardized or OTC forms. Yet, documented infant effects are rarely seen even in the more vulnerable neonates. And, in those instances where the infant has received the plant chemicals through breast milk alone, the adverse effects have been reversible. Appropriate use of herbs by mothers of nursing toddlers is not expected to pose a risk to the child. Still, the mother needs counseling on what appropriate use is, and what potential side effects should be watched for in the child. The strategy of using the medicinal and watching the child for expected side effects is advocated by lactation experts.^12,14 If side effects should appear in the infant, the dose is lowered or a different medicinal is used. Obviously, use of questionable herbs during lactation always needs a close look: Alternative approaches that may or may not include the use of other herbs need to be explored or recommended to the mother. A questionable herbal product should not be used by the nursing mother, regardless of the herb. This pragmatic aspect of herb safety cannot be ignored. Education on product selection should be part of any guidance provided to a mother.

The Pregnancy and Lactation Confusion

When reading herbal literature, it is important to determine whether precautions distinguish between pregnancy and lactation. Numerous authors do not make this distinction. To further complicate matters, many authors do not differentiate between self-directed use and supervised use of herbs; thus, it is not at all clear under what use conditions such contraindications are thought necessary.

A prime example of confusing pregnancy and lactation precautions is seen in herbs where many authors contraindicate their use during “pregnancy and lactation due to hormonal influences.”⁶ For oxytocic or uterotonic herbs, this confounding of pregnancy and lactation is unfortunate as the following discussion shows. Note that “oxytocic” describes an agent capable of causing uterine contractions leading to the delivery of the fetus or placenta. Not all uterotonics are oxytocic, or capable of inducing true labor. “Oxytocin” is the hormone mainly responsible for labor resulting in birth; it is absolutely required for the milk ejection reflex (MER) to occur. Without oxytocin, there is no milk production. (It is worth noting here that women with a healthy pregnancy, who continue to nurse their child do not run an increased risk of premature labor.) Agents that are called oxytocic do not necessarily replace oxytocin, although many probably interact in some way at the oxytocin receptor. A synthetic form (Pitocin) is used to promote labor as well as trigger the MER after birth; it can act at peripheral receptor sites but cannot access the receptor sites within the CNS. At present, there is no information available on plant constituent interactions with oxytocin or its receptors in the brain or at peripheral sites. Although oxytocic herbs are properly contraindicated for self-use during pregnancy, there is a wealth of data on their usefulness in lactation. Galactagogues are herbs used with the intent of increasing milk production. Most herbal galactagogues common in clinical practice in Western countries have some degree of uterotonic or even oxytocin activity. Indeed, many of the hundreds of herbs traditionally used as oxytocics, i.e., speeding labor and delivery of both infant and placenta, are also traditionally used as galactogogues. 23 24 25 Recent lactation research has verified that frequent adequate milk removal is the primary mechanism by which milk production can be increased or maintained.²⁶ Adequate removal of milk immediately increases the rate of milk synthesis in that breast for the next several hours. Oxytocin is needed to remove milk and it is known that increasing the activity of the oxytocin system results in an increased milk flow from the breast, an immediate galactogogue effect. This boost in milk production can stimulate a flagging synthesis rate for a sustained galactogogue effect. Herbs with noted oxytocic effects have been noted to help trigger the MER as well as to increase milk flow. Both these actions can indeed aid lactation. However, a mother needing help with milk production is best served by consulting with a lactation specialist; judicious use of oxytocic herbs can play an important but complementary role.

Oxytocic activity is but one of many hormonal influences in which pregnancy cautions do not apply during lactation; indeed, hormonal activity risks during pregnancy may be what makes that herb helpful as a galactogogue. Although consumers should be able to easily identify such herbs, and thus avoid their unintentional use during lactation, health care providers should not mistake general consumer warnings as indicative of the need for all breastfeeding women to avoid supervised use when warranted.

Maternal Plant Use and Risks to the Infant

A study done in Minnesota examined the dietary habits of experienced breastfeeding mothers to determine what foods might be associated with colic symptoms in infants.²⁷ Researchers found a strong association between the consumption of cruciferous vegetables and the degree of crying and other colic symptoms. Clearly, constituents from the mother’s diet are able to enter breast milk in sufficient quantity to cause the baby discomfort. It is worth noting that vegetables (foods) are consumed in much larger doses than most medicinal plants. No other systematic studies looking at food and adverse reactions in babies have apparently been done, although mothers are routinely told to avoid hot peppers, garlic, and onions by their doctors and others.

Capsaicin, the “hot” constituent in hot peppers, has been noted to cause problems with episodic consumption by the mother, including fussiness, diarrhea, and a red bottom in the baby. However, many mothers who eat hot peppers daily report no such problems. Additionally, infants accustomed to drinking “spicy” milk will readily eat spicy foods when introduced later in the first year. In the Botanical Safety Handbook, the authors classify garlic as an herb to use with caution, and cite references where infant ingestion of garlic resulted in death.¹⁰ Clearly, the authors underestimated the dose difference between direct ingestion of a substance, and indirect ingestion of phytochemical constituents through breast milk. Although direct exposure of infants to large quantities of raw garlic may be potentially dangerous, the daily diet of many countries contains medicinal quantities of garlic, yet there are no documented adverse effects of garlic on nursing infants. Garlic is even used as a galactogogue in India. In one human trial, neither efficacy nor harm was demonstrated.²⁵ New lactation studies of garlic have been done, yielding no adverse effects.²⁸ Hale infers it is not known whether garlic constituents enter milk, which overlooks the pioneering work of Julie Mennella et al. who studied the effect of garlic on breastfeeding infants.¹² In an earlier study, these authors demonstrated greater interest and longer nursing times in infants whose mothers had ingested a dose of garlic. In a 1993 follow-up study in which mothers ingested garlic daily, the novelty wore off, and the infants went back to their usual nursing patterns. None of the infants suffered adverse effects during these tests. Given the widespread use of garlic as a food, and the existence of studies of garlic and breastfeeding infants, the maternal use of garlic to prevent or treat maternal breast candidiasis (thrush) should be considered a relatively safe and inexpensive alternative to certain medications, such as fluconazole, a powerful antifungal with potential serious adverse effects on the liver.

Allergy and Associated Risks of Direct Feeding on the Baby and Breastfeeding

The risk of allergic reaction to plant chemicals is real and most likely in the first months of life, yet significantly reduced when exposure is restricted through breastfeeding. Not only are the range of plant chemicals reaching the bloodstream reduced but the dose received by the child is very small. Mothers with allergies or atopic and autoimmune diseases will need guidance with allergenic plants, for both her and the baby’s protection. It is also important to determine the father’s allergy history. When possible, initial use of simple rather than combination remedies will assist identification of the culprit if an allergy should occur in a mother or baby. Allergy, atopic, and autoimmune diseases are rampant in modern society, now in this third generation of widespread formula feeding experimentation. Besides being proved as a major preventative of allergenic and atopic disease,¹⁵ exclusive breastfeeding in the first 6 months of life is also preventative against an enormous range of diseases of both childhood and adulthood;¹ direct feeding of substances (whether these are considered food, herbs, or drugs) other than breast milk is clearly an introduced risk.^1,29 The young baby’s GI tract is not mature and is still quite “leaky” or permeable to ingested substances, even proteins. Early exposure of the GI tract and flora to foreign substances is thought to set the child up for subtle and frank infections as well as allergy. These effects may have permanent consequences.¹⁴