Janet R. Hardy, PhD, MPH, MSc

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

In recent decades, natural products have had increased consumer attention in industrialized nations. One of the challenges is that “natural” can be more of a perception than a standard. “Herbal products” is a more frequently used and perhaps a more apt term. Herbal products come in many forms, including herbs used in food preparation, teas, infusions, caplets, dried extracts, essential oils, and tinctures.

Multiple prescription medications have pharmacologically active compounds that originated from herbal products, both historically and currently. Examples include the cardiac stimulant digoxin (foxglove plant), the antimalarial quinine (Cinchona bark), and antihypertensives (Rauwolfia serpentina). Indeed, the first pharmacologically active compound, morphine, was extracted from the seed pods of opium poppies approximately 200 years ago. This demonstrated that medications could be purified from plants and that a precise dose could be determined for administration. However, herbal products are grown and harvested in varying seasonal conditions and soil types, which, over time and geography, may contribute to variability in the levels of active compound in the final products.

The importance of active compound purification and consistent precise dosage in herbal products brings up the topic of regulation. Herbal products are considered dietary supplements and as such are Food and Drug Administration regulated as a food under the 1994 Dietary Supplement Health Education Act. Regulation as a food product does not involve the same level of scrutiny as a medication. There is no requirement that manufacturers check for purity and consistency of their product’s active compound(s). Manufacturers must ensure that the claims they make about herbal products are not false or misleading. They must also support their claims with evidence. However, there is no requirement for the manufacturers to submit this evidence to the FDA. This can translate into a discrepancy between the claim on the product label and scientific evidence that the product does what it claims to do. In other words, the product may not be effective.

With uncertain efficacy, the safety of herbal products comes into focus. Very few herbal products (or their specific active compounds) have been scientifically studied for safety in pregnancy and lactation. Further, herbal products may contain contaminants. Metals such as lead and mercury occur naturally. Yet, because of human activities, both may have collected in areas where herbal products are grown. From a safety perspective, both can be concerning in pregnancy or lactation. Lead and mercury are two examples of metal contaminants. Other contaminants may include pesticides, chemicals, and bacteria or other microorganisms. Some liquid herbal products such as tinctures contain alcohol, which should be avoided in pregnancy. An additional consideration would be the potential for herbal products, including any of their known or unknown product contents, to interact with prescribed medications or anesthesia.
 

Select examples of herbal products

Astragalus is the root of an herb and it is used for reasons of boosting immunity, energy, and other functions. These and its purported promotion of breast milk flow (galactagogue) are unsupported. Safety concerns include irregular heartbeat and dizziness, rendering it unsafe for use in pregnancy and of unknown efficacy and safety in lactation.

Kombucha is an herbal product made from leaves (tea), sugar, a culture, and other varying products. Like many herbal products, it is both manufactured and home brewed. It is used for probiotic and antioxidant reasons. As a fermented product, kombucha may contain 0.2%-0.5% alcohol. There is no known safe level of alcohol and no known safe type of alcohol for use in pregnancy. Alcohol exposure in pregnancy can result in fetal alcohol spectrum disorders, involving a range of birth defects and life-long intellectual, learning and behavioral disorders. Alcohol found in breast milk approximates the level of alcohol found in the maternal bloodstream. Alcohol-containing products should be avoided in pregnancy and lactation.

Nux vomica is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. It comes from the raw seeds (toxic) of an evergreen tree. It has serious safety concerns and yet it is still in use. It contains strychnine, which can harm both the pregnant individual and the developing fetus. It is not recommended in lactation.

Red raspberry leaf is a leaf, brewed and ingested as a tea. It is used for reasons of preventing miscarriage, relieving nausea and stomach discomfort, toning the uterus, reducing labor pain, increasing breast milk production, and other functions. In low doses, it appears to be safe. In high doses, it can induce smooth muscle relaxation. Efficacy has not been demonstrated with labor and delivery or in increasing breast milk production.

Tabacum is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. Its full name is Nicotiana tabacum (tobacco) and it contains 2%-8% nicotine, which should be avoided in pregnancy. Nicotine is a health danger for the pregnant individual and can damage a developing fetus’ brain and lungs.

Unless otherwise scientifically demonstrated, herbal products should be considered medications with pharmacologic activity, potential adverse effects, and potential toxicity in pregnancy and lactation. It’s easy for a patient to forget about reporting any nonprescription medications during a patient-provider visit. As a provider, purposefully asking about all over-the-counter and herbal products during each visit can prompt the patient to provide this important information. Further, it may facilitate discussion about the continuation/discontinuation of products of unknown safety and unknown benefit, culminating in the serious reflection: “Is it really worth the risk?”

For further information about the safety of herbal products, consult local Poison Control Centers, MothertoBaby, MothertoBaby affiliates, and the National Institutes of Health Drugs and Lactation Database, LactMed.

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology, and represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy has worked with multiple pharmaceutical manufacturers regarding studies of medication safety in pregnancy, most recently Biohaven Pharmaceuticals, New Haven, CT.

.

In recent decades, natural products have had increased consumer attention in industrialized nations. One of the challenges is that “natural” can be more of a perception than a standard. “Herbal products” is a more frequently used and perhaps a more apt term. Herbal products come in many forms, including herbs used in food preparation, teas, infusions, caplets, dried extracts, essential oils, and tinctures.

Multiple prescription medications have pharmacologically active compounds that originated from herbal products, both historically and currently. Examples include the cardiac stimulant digoxin (foxglove plant), the antimalarial quinine (Cinchona bark), and antihypertensives (Rauwolfia serpentina). Indeed, the first pharmacologically active compound, morphine, was extracted from the seed pods of opium poppies approximately 200 years ago. This demonstrated that medications could be purified from plants and that a precise dose could be determined for administration. However, herbal products are grown and harvested in varying seasonal conditions and soil types, which, over time and geography, may contribute to variability in the levels of active compound in the final products.

The importance of active compound purification and consistent precise dosage in herbal products brings up the topic of regulation. Herbal products are considered dietary supplements and as such are Food and Drug Administration regulated as a food under the 1994 Dietary Supplement Health Education Act. Regulation as a food product does not involve the same level of scrutiny as a medication. There is no requirement that manufacturers check for purity and consistency of their product’s active compound(s). Manufacturers must ensure that the claims they make about herbal products are not false or misleading. They must also support their claims with evidence. However, there is no requirement for the manufacturers to submit this evidence to the FDA. This can translate into a discrepancy between the claim on the product label and scientific evidence that the product does what it claims to do. In other words, the product may not be effective.

With uncertain efficacy, the safety of herbal products comes into focus. Very few herbal products (or their specific active compounds) have been scientifically studied for safety in pregnancy and lactation. Further, herbal products may contain contaminants. Metals such as lead and mercury occur naturally. Yet, because of human activities, both may have collected in areas where herbal products are grown. From a safety perspective, both can be concerning in pregnancy or lactation. Lead and mercury are two examples of metal contaminants. Other contaminants may include pesticides, chemicals, and bacteria or other microorganisms. Some liquid herbal products such as tinctures contain alcohol, which should be avoided in pregnancy. An additional consideration would be the potential for herbal products, including any of their known or unknown product contents, to interact with prescribed medications or anesthesia.
 

Select examples of herbal products

Astragalus is the root of an herb and it is used for reasons of boosting immunity, energy, and other functions. These and its purported promotion of breast milk flow (galactagogue) are unsupported. Safety concerns include irregular heartbeat and dizziness, rendering it unsafe for use in pregnancy and of unknown efficacy and safety in lactation.

Kombucha is an herbal product made from leaves (tea), sugar, a culture, and other varying products. Like many herbal products, it is both manufactured and home brewed. It is used for probiotic and antioxidant reasons. As a fermented product, kombucha may contain 0.2%-0.5% alcohol. There is no known safe level of alcohol and no known safe type of alcohol for use in pregnancy. Alcohol exposure in pregnancy can result in fetal alcohol spectrum disorders, involving a range of birth defects and life-long intellectual, learning and behavioral disorders. Alcohol found in breast milk approximates the level of alcohol found in the maternal bloodstream. Alcohol-containing products should be avoided in pregnancy and lactation.

Nux vomica is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. It comes from the raw seeds (toxic) of an evergreen tree. It has serious safety concerns and yet it is still in use. It contains strychnine, which can harm both the pregnant individual and the developing fetus. It is not recommended in lactation.

Red raspberry leaf is a leaf, brewed and ingested as a tea. It is used for reasons of preventing miscarriage, relieving nausea and stomach discomfort, toning the uterus, reducing labor pain, increasing breast milk production, and other functions. In low doses, it appears to be safe. In high doses, it can induce smooth muscle relaxation. Efficacy has not been demonstrated with labor and delivery or in increasing breast milk production.

Tabacum is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. Its full name is Nicotiana tabacum (tobacco) and it contains 2%-8% nicotine, which should be avoided in pregnancy. Nicotine is a health danger for the pregnant individual and can damage a developing fetus’ brain and lungs.

Unless otherwise scientifically demonstrated, herbal products should be considered medications with pharmacologic activity, potential adverse effects, and potential toxicity in pregnancy and lactation. It’s easy for a patient to forget about reporting any nonprescription medications during a patient-provider visit. As a provider, purposefully asking about all over-the-counter and herbal products during each visit can prompt the patient to provide this important information. Further, it may facilitate discussion about the continuation/discontinuation of products of unknown safety and unknown benefit, culminating in the serious reflection: “Is it really worth the risk?”

For further information about the safety of herbal products, consult local Poison Control Centers, MothertoBaby, MothertoBaby affiliates, and the National Institutes of Health Drugs and Lactation Database, LactMed.

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology, and represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy has worked with multiple pharmaceutical manufacturers regarding studies of medication safety in pregnancy, most recently Biohaven Pharmaceuticals, New Haven, CT.

.

In recent decades, natural products have had increased consumer attention in industrialized nations. One of the challenges is that “natural” can be more of a perception than a standard. “Herbal products” is a more frequently used and perhaps a more apt term. Herbal products come in many forms, including herbs used in food preparation, teas, infusions, caplets, dried extracts, essential oils, and tinctures.

Multiple prescription medications have pharmacologically active compounds that originated from herbal products, both historically and currently. Examples include the cardiac stimulant digoxin (foxglove plant), the antimalarial quinine (Cinchona bark), and antihypertensives (Rauwolfia serpentina). Indeed, the first pharmacologically active compound, morphine, was extracted from the seed pods of opium poppies approximately 200 years ago. This demonstrated that medications could be purified from plants and that a precise dose could be determined for administration. However, herbal products are grown and harvested in varying seasonal conditions and soil types, which, over time and geography, may contribute to variability in the levels of active compound in the final products.

The importance of active compound purification and consistent precise dosage in herbal products brings up the topic of regulation. Herbal products are considered dietary supplements and as such are Food and Drug Administration regulated as a food under the 1994 Dietary Supplement Health Education Act. Regulation as a food product does not involve the same level of scrutiny as a medication. There is no requirement that manufacturers check for purity and consistency of their product’s active compound(s). Manufacturers must ensure that the claims they make about herbal products are not false or misleading. They must also support their claims with evidence. However, there is no requirement for the manufacturers to submit this evidence to the FDA. This can translate into a discrepancy between the claim on the product label and scientific evidence that the product does what it claims to do. In other words, the product may not be effective.

With uncertain efficacy, the safety of herbal products comes into focus. Very few herbal products (or their specific active compounds) have been scientifically studied for safety in pregnancy and lactation. Further, herbal products may contain contaminants. Metals such as lead and mercury occur naturally. Yet, because of human activities, both may have collected in areas where herbal products are grown. From a safety perspective, both can be concerning in pregnancy or lactation. Lead and mercury are two examples of metal contaminants. Other contaminants may include pesticides, chemicals, and bacteria or other microorganisms. Some liquid herbal products such as tinctures contain alcohol, which should be avoided in pregnancy. An additional consideration would be the potential for herbal products, including any of their known or unknown product contents, to interact with prescribed medications or anesthesia.
 

Select examples of herbal products

Astragalus is the root of an herb and it is used for reasons of boosting immunity, energy, and other functions. These and its purported promotion of breast milk flow (galactagogue) are unsupported. Safety concerns include irregular heartbeat and dizziness, rendering it unsafe for use in pregnancy and of unknown efficacy and safety in lactation.

Kombucha is an herbal product made from leaves (tea), sugar, a culture, and other varying products. Like many herbal products, it is both manufactured and home brewed. It is used for probiotic and antioxidant reasons. As a fermented product, kombucha may contain 0.2%-0.5% alcohol. There is no known safe level of alcohol and no known safe type of alcohol for use in pregnancy. Alcohol exposure in pregnancy can result in fetal alcohol spectrum disorders, involving a range of birth defects and life-long intellectual, learning and behavioral disorders. Alcohol found in breast milk approximates the level of alcohol found in the maternal bloodstream. Alcohol-containing products should be avoided in pregnancy and lactation.

Nux vomica is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. It comes from the raw seeds (toxic) of an evergreen tree. It has serious safety concerns and yet it is still in use. It contains strychnine, which can harm both the pregnant individual and the developing fetus. It is not recommended in lactation.

Red raspberry leaf is a leaf, brewed and ingested as a tea. It is used for reasons of preventing miscarriage, relieving nausea and stomach discomfort, toning the uterus, reducing labor pain, increasing breast milk production, and other functions. In low doses, it appears to be safe. In high doses, it can induce smooth muscle relaxation. Efficacy has not been demonstrated with labor and delivery or in increasing breast milk production.

Tabacum is an herbal product and is used for reasons of reducing nausea or vomiting in pregnancy. Its full name is Nicotiana tabacum (tobacco) and it contains 2%-8% nicotine, which should be avoided in pregnancy. Nicotine is a health danger for the pregnant individual and can damage a developing fetus’ brain and lungs.

Unless otherwise scientifically demonstrated, herbal products should be considered medications with pharmacologic activity, potential adverse effects, and potential toxicity in pregnancy and lactation. It’s easy for a patient to forget about reporting any nonprescription medications during a patient-provider visit. As a provider, purposefully asking about all over-the-counter and herbal products during each visit can prompt the patient to provide this important information. Further, it may facilitate discussion about the continuation/discontinuation of products of unknown safety and unknown benefit, culminating in the serious reflection: “Is it really worth the risk?”

For further information about the safety of herbal products, consult local Poison Control Centers, MothertoBaby, MothertoBaby affiliates, and the National Institutes of Health Drugs and Lactation Database, LactMed.

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology, and represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy has worked with multiple pharmaceutical manufacturers regarding studies of medication safety in pregnancy, most recently Biohaven Pharmaceuticals, New Haven, CT.

.

I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.

Antonio_Diaz/Thinkstock

Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.

Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.

The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.

In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.

In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.

The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
 

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at obnews@mdedge.com.

I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.

Antonio_Diaz/Thinkstock

Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.

Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.

The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.

In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.

In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.

The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
 

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at obnews@mdedge.com.

I have had friends and colleagues visibly shrink away when I say that my work involves the study of medication safety in pregnancy. “Yikes! I would never let my daughter participate in a clinical study if she was pregnant!” I hear. It’s an interesting response. Understandably protective of a loved one, except that the loved one is an adult woman who presumably can make her own choices. And the response reveals an assumption that medications are tested in all populations before approval for market. Sadly, the response is ill-informed given that pregnant women are still excluded from most if not all clinical research. My work, by the way, is focused on postapproval studies.

Antonio_Diaz/Thinkstock

Translating the above response to a larger picture, health care providers and pharmaceutical manufacturers also have their concerns about pregnant women and lactating women participating in clinical research. Along with the patient and her loved ones, all parties’ concerns are valid. However, there is a harsh reality: According to a study in the American Journal of Obstetrics & Gynecology, an estimated 50% of U.S. women take one or more prescription medications during pregnancy. Once marketed, therapies are prescribed to pregnant women, knowingly and unknowingly, and without evidence-based knowledge of their safety. If postapproval safety studies are undertaken, decades may pass as data accrue and before results become available. In general, even less is known about the safety of medications in breastmilk.

Without a path forward that includes pregnant women and lactating women in clinical research, we will remain without timely knowledge of medication safety. Further, our understanding of efficacy will be based on clinical studies of nonpregnant women. Recognizing the need for this information, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) was convened in 2017 and tasked with determining this path forward.

The PRGLAC was established by the 21st Century Cures Act, a law designed to help speed up medical product development. Managed by the National Institutes of Health, the PRGLAC is made up of representatives of all federal agencies with responsibilities for women’s health and research, as well as clinicians, industry experts, and other experts. The PRGLAC’s work has been conducted in two phases.

In Phase I, PRGLAC was charged with identifying gaps in knowledge and research regarding safe and effective therapies for pregnant women and lactating women. The Task Force conducted four public meetings in 2017 and 2018, and submitted their conclusions to Congress and the Secretary of Health & Human Services in a publicly available report. The report provides 15 specific recommendations, several of which are directly relevant to obstetricians: No. 3 recommends expanding the workforce of clinicians and research investigators with expertise in obstetric and lactation pharmacology, No. 6 recommends the development and implementation of evidence-based communication strategies with health care providers, and No. 13 recommends optimization of registries for pregnancy and lactation. Obstetricians can make a positive contribution to accruing medication safety data by being aware of pregnancy registries and indicating their availability to eligible patients.

In the spring of 2019, the PRGLAC reconvened with a 2-year mandate and a new charge for Phase II: to develop plans for implementing the recommendations laid out in the Phase I report. Four working groups (WGs) were identified to address the recommendations of the report: WG1 Research and Training, WG2 Regulatory, WG3 Communication and Registries, and WG4 Discovery. The four groups have deliberated, and a new report is being finalized. The PRGLAC’s efforts provide a fresh conversation to address long-standing issues to provide evidence-based information for the treatment of pregnant and lactating women. Once available, the final report will be posted on the PRGLAC website.

The recommendations in this report, when implemented, are directly relevant to patient care and clinician training and will provide a path forward for the inclusion of pregnant and lactating women in clinical research or a firm justification for their exclusion.
 

Dr. Hardy is a consultant on global maternal-child health and pharmacoepidemiology. She also represents the Society for Birth Defects Research and Prevention and the Organization of Teratology Information Specialists at PRGLAC meetings. Dr. Hardy disclosed she has worked with multiple pharmaceutical manufacturers regarding medication safety studies in pregnancy, most recently Biohaven. Email her at obnews@mdedge.com.