Pregnant and breastfeeding individuals’ involvement in clinical trials

During her second pregnancy, a ​​mother tested positive for cytomegalovirus (CMV). The CMV virus can cross through the placenta and infect a developing fetus, potentially causing birth defects or other long-term health problems. This mother was contacted and presented with the opportunity to participate in a clinical trial where she would be infused with a drug that would potentially mitigate the risks of her child developing congenital CMV.

The mother reports that because her child was already at risk, she saw participating in the trial as something she could do to avoid the risk of potential health problems.

The process of participating was relatively simple considering her work-from-home arrangement and having reliable child care for her older child.

At last, her daughter was born healthy and continues to thrive.

This mother reports that, until recently, she hadn’t considered what she would have done if something had gone wrong as a consequence of participating in the trial. She said that she’s unsure what kind of compensation might make up for a hypothetical injury to her child who was unable to consent to the trial. She emphasized that parents dedicate themselves to making the right decisions for their children, so the stress of raising a child with special needs coupled with the guilt of having made the “wrong” decision, could be shattering.

Photo by Ermias Tarekegn

The inclusion of pregnant and lactating people in clinical trials is part of an evolving national and international conversation.

Earlier this spring, the Committee on Developing a Framework to Address Legal, Ethical, Regulatory, and Policy Issues for Research Specific to Pregnant and Lactating Persons held a workshop to discuss how institutions make risk-benefit decisions regarding the inclusion and exclusion of pregnant and lactating persons in clinical research, and the role of liability, risk management, and trial insurance in those decisions as well as reviewed existing compensation schemes for research-related injuries and potential to scale these models to serve the needs of research participants.

Historically, pregnant and breastfeeding women have been excluded from clinical trials, due to concerns about the real or perceived potential risks to the fetus or child. [FDA Voices, 2021] Namely, the thalidomide crisis in the 1950s largely shaped the culture around risk aversion and clinical testing on the pregnant population.

“A 2011 study on all medications approved by the FDA from 1980 to 2010 found that 91 percent of the medications approved for use by adults did not have sufficient data on safety, efficacy and fetal risk of medication taken during pregnancy,” the authors of Fair inclusion of pregnant women in clinical trials: an integrated scientific and ethical approach write.  “At the same time, the number of pregnant women who take medications, as well as the number of medications that these pregnant women take, has increased.”

Today, health advocates are pushing for the inclusion of this population in clinical research on the basis that patients should have solid evidence in order to make informed decisions about their health.

Photo by Polina Tankilevitch

“Not having this evidence can result in unfairness in the distribution of benefits and burdens (injustice) and can curtail the autonomy in making informed choice,” Catriona Waitt writes in Clinical trials and pregnancy. “This may make it impossible to provide the best treatment, undermining the principle of beneficence, and risking increasing harm.”

Speakers at the workshop cited several roadblocks to the inclusion of pregnant and lactating people in clinical research.

Institutional Review Boards (IRBs) are charged with keeping patients safe, so they often take a very conservative approach. [White, 2021] Elisa A. Hurley, PhD, executive director of Public Responsibility in Medicine and Research (PRIM&R) explained that the current framework does not encourage or assess the risk of not doing research on this population, and that the culture needs to shift from exclusion to inclusion as the default. Dr. Hurley cited the University of Washington where there’s been a shift to require justification to exclude pregnant and lactating populations.

Lorien Urban, Ph.D., Senior Medical Director Clinical Development at Ferring Pharmaceuticals pointed out that IRBs tend not to acknowledge a distinction between pregnancy and lactation when reviewing trials. In fact, while the placental barrier can be sensitive, there are very few drugs that pass through to mothers’ milk. [InfantRisk Center]

Photo credit: United States Breastfeeding Committee

Metin Gülmezoğlu, M.D., Executive Director at the Concept Foundation argued that pregnant and lactating women should demand to be included in research, and that governments should react accordingly, assuming responsibility and taking action.

Gülmezoğlu’s project AIM responds to the created culture of risk aversion in the field. Gülmezoğlu said that risk aversion doesn’t get rid of risk; instead it shifts risk to another person: either the care provider or the pregnant person themself.

Risk is of primary concern for companies and organizations conducting research in these populations.

Sara E. Dyson, M.P.H., C.P.C.U.,Vice President of Underwriting Operations & Risk Management at Medmarc laid out the ways in which institutions can make their trials less risky and more attractive to underwriters:

  • demonstrate for the potential risk,
  • conduct significant bench testing,
  • conduct informed consent on video,
  • ensure compensation is reasonable and cannot be construed as coercion
  • consult with reputable IRB (multiple IRBs in some cases),
  • select a trial site (for instance an institution with specialty in high risk pregnancy)

Niranjan Bhat, M.D., M.H.S., Senior Medical Officer at PATH, shared that PATH’s global umbrella policy which covers any adverse event during participation of the study is a key research enabler.

Michelle Mello, J.D., Ph.D., Professor of Law and Health Policy at Stanford University and Renée J. Gentry, Esq., one of the leading experts on vaccine injury litigation in the National Vaccine Injury Compensation Program (NVICP), laid out the ways in which tort versus private compensation programs can be successful or unsuccessful in compensating injured clinical trial participants.  In either case, proving causation tends to be the primary difficulty on the battleground for product liability.

The tort system is capacious enough to handle injury claims, Dr. Bello began. However, using Winston Churchill’s metaphor for democracy–  “Democracy is the worst form of government – except for all the others that have been tried.”– it tends to favor the wealthy, is laborious in terms of time, and presents high volatility in terms of settled amounts.

Photo by Ekaterina Bolovtsova

Perhaps not a solid alternative, a system like NVICP, is at a “breaking point”, according to Gentry. The program started with eight special masters when it began in the 1980s; today this number remains. Set up to cover six vaccines, the program now covers 16 vaccines; as such the number of complaints have quadrupled in the past decade. People are waiting two to three years to have their trials scheduled. In fact, some seniors have died waiting for their trials.

Gentry advises that when considering the creation of a compensation system, there should be flexibility built in to include the modification of staffing levels and scheme.

Photo by Parinda Shaan

In a private system, like the UW-Washington Human Subjects Compensation Program, this flexibility is a positive attribute; however, speakers pointed out that private systems do not address two major points:

  1. A private system does not get around addressing causation difficulties.
  2. A private system does not necessarily address equity and has the potential to lead to a patchwork of compensation of different solutions at different levels of generosity.

As health professionals, consumers and other individuals and organizations work to shape the legal, ethical and policy frameworks that affect research on the pregnant and lactating population, you might consider consulting the following readings and resources.

 

Further reading 

Clinical trials and pregnancy

A Comparison of FDA and EMA Pregnancy and Lactation Labeling

FDA’s Pregnancy and Lactation Labeling (Drugs) Final Rule (2014)

FDA Updates: Pregnant Women Subjects and Medical Device Investigations (2018)

 

Current resources for pregnant and lactating individuals and care providers 

The Trash the Pump and Dump (TPD) app encompasses medical conditions, medications and substances of concern during lactation.

Drugs and Lactation Database (LactMed®)

FDA Pregnancy Categories 

E-lactancia: comprehensive medication and herbal medicine database in Spain, available in English and Spanish

Organization of Teratology Information Specialists

Brigham and Women’s Hospital Drugs, Herbs, and Supplements during lactation

Breastfeeding is an opportunity to learn.

–This post is part of our 10-year anniversary series “Breastfeeding is…”

Breastfeeding is an opportunity to learn. Although breastfeeding is an ancient practice, there is still so much to learn about the lactating breast, breast function and the process of breastfeeding, especially as our modern lives continue to change.

Many current textbook depictions of the anatomy of the lactating breast are largely based on research conducted over 150 years ago, Donna T. Geddess points out in The anatomy of the lactating breast: Latest research and clinical implications.

“…Few studies have actively investigated the anatomy of the lactating breast despite the obvious importance a clear understanding of the lactating mammary gland has to both mother and infant,” Geddess writes. “Perhaps this lack of information is a part of the greater reason why many women continue to experience breastfeeding problems.”

Katherine Lee writes in Katie Hinde Championing the Fun Side of Science Through Virtual Animal Games, Thunderdome Style about Hinde’s hope to change the perception about breastmilk and quotes her saying “‘Still to this day, there is no integration between breastfeeding and milk composition and volume,’ noted Hinde. ‘In Pubmed, there are more articles about tomatoes than human breast milk.’ When they listed the human microbiome project, they didn’t include breastmilk…”

This week we present several  recent (in the last 5 years) publications that are helping to shape our understanding of infant feeding. We have also included studies that relate specifically to pregnancy as pregnancy, birth and breastfeeding are all part of a continuum.

It is important to note that research published in medical journals is not the only way to capture and develop an understanding of infant feeding experiences. For instance, Camie Jae Goldhammer,  MSW, LICSW, IBCLC, (Sisseton-Wahpeton), founder of  Hummingbird Indigenous Doula Services says that their program is proudly not rooted in “evidence”; instead, it’s a community designed program. Anecdotal evidence and indigenous knowledge and wisdom should be honored. Moreover, as with any research, we must always consider how the research is funded, who is or is not being represented, and how the research is presented. For more on equity in science, check out Increasing equity in data science and the work being done at the Urban Indian Health Institute.

 

Lactation duration and stroke risk 

In February 2022, Ziyang Ren, MD, et al released Lactation Duration and the Risk of Subtypes of Stroke Among Parous Postmenopausal Women From the China Kadoorie Biobank.

Stroke is a growing global health problem. It is the third leading cause of disability adjusted–life years (DALYs) worldwide and the first leading cause of DALYs in China, Ren, et al point out. Stroke  imposes a financial burden on patients, families, and society. The cohort study found that lactation duration significantly lowers the risk of stroke.

Up until now, most research has focused on the association between lactation and cardiovascular diseases (CVDs), but this piece lays out the association between lactation and stroke subtypes.

Specifically, the study found that parous postmenopausal women with lifetime lactation duration of at least 7 months had lower risks of ischemic stroke and intracerebral hemorrhage (ICH) compared with women who never lactated. For subarachnoid hemorrhage (SAH) though, such associations were found only in participants with lifetime lactation duration of longer than 24 months. In addition, the authors found that those with an average lactation duration per child or lactation duration for the first child of at least 7 months were less likely to develop stroke and its subtypes.

 

Marijuana exposure in utero 

Birth Outcomes of Neonates Exposed to Marijuana in Utero: A Systematic Review and Meta-analysis by Greg Marchand, et al, the largest meta-analyses on prenatal cannabis use to date, the authors  found significant increases in seven adverse neonatal outcomes among women who were exposed to marijuana during pregnancy versus those who were not exposed during pregnancy.

Photo by Solen Feyissa on Unsplash

The systematic review and meta-analysis demonstrated higher rates of low birth weight (<2500 g) and small for gestational age (<fifth percentile), lower mean birth weight, preterm delivery (<37 weeks’ gestation), higher rate of admission to the neonatal intensive care unit, poorer Apgar scores at 1 minute, and smaller head circumference in those exposed to marijuana.

The prevalence of marijuana use during pregnancy is significant, and many people cite the belief that marijuana use is relatively safe during

pregnancy. This work may help to raise awareness and be used to educate patients about adverse outcomes with the hope of improving neonatal health.

With increased marijuana legalization in mind, Kara R. Skelton, PhD and  Sara E. Benjamin-Neelon, PhD, JD, MPH in Reexamining Risks of Prenatal Cannabis Use—Mounting Evidence and a Call to Action urge states that have legalized and commercialized cannabis to retroactively prioritize protection of neonatal health.

More on cannabis during the perinatal period here.

 

Childhood obesity 

The authors of Childhood Obesity and Breastfeeding Rates in Pennsylvania Counties-Spatial Analysis of the Lactation Support Landscape examined the relationship between childhood obesity and breastfeeding rates in Pennsylvania (PA) counties, the relationship between geographic access to professional lactation support providers  (LSPs) in PA counties and breastfeeding rates, and  the relationship between geographic access to professional LSPs and childhood obesity in PA counties. They found a significant, inverse relationship between breastfeeding rates and childhood obesity prevalence at the county level and a significant, inverse relationship between the number of CLCs and the number of all professional LSPs and childhood obesity rates at the county level. Thus,  the authors conclude, the availability of breastfeeding support is significantly related to breastfeeding rates and inversely related to childhood obesity rates across Pennsylvania.

 

Measuring optimal skin-to-skin practice 

The authors of Mapping, Measuring, and Analyzing the Process of Skin-to-Skin Contact and Early Breastfeeding in the First Hour After Birth show how process mapping of optimal skin-to-skin practice in the first hour after birth using the algorithm, HCP-S2S-IA, produced an accurate and useful measurement, illuminating how work is conducted and providing patterns for analysis and opportunities for improvement with targeted interventions.

More specifically, the algorithm provides a tool to help reduce delays or decrease interruptions during skin-to-skin contact (SSC). The authors note, “Not suckling in the first hour after birth places newborns at higher risk for neonatal morbidities and mortality. Examining patterns and developing strategies for change optimizes patient outcomes.”

 

Acknowledging the social determinants of health

Pregnancy and the origins of illness (2022) by Anne Drapkin Lyerly begins by acknowledging that the COVID-19 pandemic has induced a collective trauma that is expected to be felt for generations after the virus is contained. The study of epigenetics has shown that children gestated or born during times of great tragedy, carry a genetically coded and inherited imprint of their mother’s experience with lifelong consequences to their health.

Recognizing the “maternal-fetal interface” as the “nexus of inter-generational trauma” raises the question of how we should think about this implication of maternal bodies, especially in light of the current pandemic.

The author explores the growing field of developmental origins of health and disease (DOHaD) and its use of epigenetics. Thinking about the tools of history, philosophy, and gender studies of science, the author advises we proceed with caution as we consider maternal effect science which raises several concerns that can impact practice and the well-being of mothers and consequently their children.

Namely,  there may be a tendency to ascribe blame on pregnant people for the health outcomes of their offspring that are well beyond their control. This approach doesn’t adequately weigh the effects of paternal, postanal, and other social and environmental factors that also influence the long-term health of children.

Analyzing epigenetics can eventually contribute to the erasure of the mother as a person, and further, characterizing the maternal body as an environment may excuse women from being appropriately considered in public health policies, clinical care and health research.

The author considers DOHaD research a corrective approach to near-sighted fetal origins science and urges that we expand our understanding of the gestational environment from not simply the womb, but to the broader environment in which a person gestates, marking the importance of acknowledging the social determinants of health. To best direct our efforts during the current pandemic, the author suggests shifting the focus off of maternal behavior and choices and instead focus on limiting the harm of climate change, racism, and other structural inequities.

 

Can’t get enough? 

Check out the Breastfeeding Medicine Podcat’s episode Review of a Potpourri of Research Topics with co Hosts Anne Eglash MD, IBCLC and Karen Bodnar MD, IBCLC. You can find a full list of their podcast episodes here.

Subscribe to SPLASH! Milk Science Update

Check out The International Society for Research in Human Milk and Lactation

 

——–

As part of our celebration, we are giving away an online learning module with contact hours each week. Here’s how to enter into the drawings:

Email info@ourmilkyway.org with your name and “OMW is 10” in the subject line.

This week, in the body of the email, tell us: What fascinates you about breastfeeding and/or what do you wonder about breastfeeding?

Subsequent weeks will have a different prompt in the blog post.

We will conduct a new drawing each week over the 10-week period.  Please email separately each week to be entered in the drawing. You may only win once. If your name is drawn, we will email a link with access to the learning module. The winner of the final week will score a grand finale swag bag.

Graduate student explores complexities of nutrition and health from cradle to grave

Originally from New Orleans, Erin Bannister, lab instructor and dietetic intern at Northern Illinois University, says that food is tied to her identity.  Bannister was ten when she first learned to make a roux. Those early skills prepared her for her later work as a chef, which she describes as a kind of manual labor with long, hot hours. 

Bannister shares with a laugh, that she started to wonder how she could work with food and continue to nourish people with weekends and holidays off. Eventually, she discovered the field of dietetics.

Photo by ja ma on Unsplash

Currently in the thick of her Master’s thesis, Bannister is exploring the metabolic energy needs in adults and determining whether the default equations we use are accurate in the populations they’re used in. 

For instance, it is widely accepted that an average allowance for a roughly 170 pound man is  2,300 kcal/day; for women, it is 1,900 kcal/day. We expect that pregnant and lactating people will have higher metabolic energy needs. 

As Bannister spends a swath of her days compiling and extracting data, she says she’s discovering that some of the accepted equations need to be delineated. 

“The real root of my thesis and the root of most of my studies and the goals that I have, is to use accurate evidence-based interventions in the populations that they are meant to be used in and to not remove ourselves from that evidence,” Bannister begins. “… Often times, things are taught and then they are believed because the person that taught it is an expert and the evidence gets lost on the way; don’t forget to review the evidence.” 

As Bannister continues to pursue this idea that we can do better than sludging through the status quo, she sought out the Lactation Counselor Training Course (LCTC). Although Bannister has great interest in the complexities of nutrition and health from cradle to grave, she says that there is a solid argument that the health of a population is highly correlated with the health of its mothers. 

Source: United States Breastfeeding Committee (USBC)

“[I want] to be as helpful and effective as possible… to have the knowledge to be able to contribute meaningfully, and the certification adds credibility,” she explains. “The training was quite eye-opening, almost embarrassing to say how little I knew about breastfeeding.” 

Bannister goes on that ultimately, she would like to work with nutrition intervention in low and middle income countries where the burden of improper nutrition is most severe. Currently, many countries worldwide face the double burden of malnutrition – characterized by the coexistence of undernutrition along with overweight, obesity or diet-related noncommunicable diseases (NCDs). In fact, nearly one in three people globally suffers from at least one form of malnutrition: wasting, stunting, vitamin and mineral deficiency, overweight or obesity and diet-related NCDs. (WHO 2017)

As Bannister buckles down at the end of the semester, she says, “I want to make sure I am utilizing all the forks I’ve got in the fire.” 

You can learn more about Bannister’s work by exploring the various topics she has presented on, ranging from potatoes to prison to poop. Connect with Bannister on Linkedin and Instagram @calibrating_palates.

Suggested Covid-19 resources for pregnancy and lactation

Lactation care and breastfeeding support are always essential, but perhaps even more so during crises like the one we’re facing today, dazed by social isolation.

Photo by Sasha Freemind on Unsplash

Like many states responding to the Covid-19 pandemic, The Academy of Lactation Policy and Practice (ALPP) is required to comply with Massachusetts Governor Baker’s emergency order and stop in-person operations. Healthy Children Project, Inc. has also been required to halt in-person operations, including the Lactation Counselor Training Courses (LCTC) for the time being. ALPP is continuing to process Certified Lactation Counselor (CLC) recertification requests remotely.  

Despite the current situation, the spirit of CLCs shines. In the CLC Facebook Group, lactation care providers are engaging in conversations about telemedicine, HIPAA compliance, and protective equipment and how to best serve families amidst the unknown. 

ALPP Executive Director Ellie MacGregor, MPH, CLC mentions that there are other important exchanges happening in  ALPP’s Community of Practice portal like current research and practice recommendations.

“We’re doing our best to share all of the evidence-based information although it’s changing every day,” MacGregor says.  

Photo by Luiza Braun on Unsplash

Healthy Children Project’s Cindy Turner-Maffei, MA, ALC, IBCLC has compiled resources for maternal child health care providers to reference when helping their clients navigate life during a pandemic. 

General Statements and Resources

For formula-feeding families

For expectant parents 

  •  Ready Set Baby curriculum produced by The Connecticut Department of Public Health (CT-DPH) in partnership with the Carolina Global Breastfeeding Institute (CGBI)

For personal sanity 

  • The meditation app, Ten Percent Happier, has made a set of meditations entitled “Coronavirus Sanity Guide” available to the general public.  In addition, they are making their full app available at no charge to healthcare workers who are responding to the virus outbreak. They invite health workers to email them for instructions at care@tenpercent.com. 
  • Yale’s Dr. Laurie Santos will host a Coursera Live Q&A event featuring ways to cope and process our emotions during the Covid-19 pandemic.
Photo by Greg Rakozy on Unsplash

Going forward, the United States Breastfeeding Committee (USBC) and MomsRising are inviting health care providers, pregnant and breastfeeding families, and all public health stakeholders to share how the pandemic is impacting the infant feeding experience. MomsRising points out that with the situation constantly evolving, personal experiences can make an impact on decision-making and help elected leaders understand how to best meet the needs of families.