DOI: 10.31038/AWHC.2023613

Abstract

This review identifies and summarizes the current state of the literature on the reproductive health of women firefighters. Several alarming exposures were noted including chemical, biological, and non-chemical occupational risk factors. The existing literature supports an association between firefighting and higher rates of miscarriage, birth defects, labor and delivery difficulties, fetal mortality, possible fertility issues, and newborn health complications (e.g., jaundice, low birth weight). A significant gap in the literature was identified despite the growing concern among women firefighters regarding reproductive health, signaling the crucial need for further research. Consequently, the lack of research has precipitated uncertainty concerning appropriate firefighting duties during pregnancy and safe return to work post-partum, leading to an absence of effective policy and, in some cases, no policy within fire departments.

Introduction

The fire service is, by nature, an extremely dangerous job. Though touted as an exceptionally close-knit brotherhood, this ‘brotherhood’ employs the fewest women of all tactical occupations (including law enforcement and the military). Even the Marine Corps, where all members must be combat certified, outnumbers the fire service with its prevalence of women (9%) [1]. Women represent 11% of the volunteer fire service and only 5% of the career fire service [2]. With such a relatively small proportion of women, there is little evidence-based information detailing how the dangerous nature of the job impacts them specifically. More explicitly, there is a dearth of data regarding women-specific injury rates, mental health, substance use, cancer, and reproductive health.

As firefighter health research has expanded, there has been emerging interest in the health of women firefighters. Jahnke and colleagues [3] published data from a population-based epidemiologic cohort study that found that overall, women firefighters (n=31) were relatively healthy compared to their male counterparts. For instance, women evidenced a lower rate of overweight and obesity than men firefighters and were less likely to be obese when compared to women in the general population (civilians). Most women firefighters also exhibited good or excellent flexibility (66.6% career and 53.9% volunteer) and were in the “high” range of strength (70.6% career, 69.2% volunteer) on standardized tests of flexibility and torso strength, although the sample size was small, limiting generalizability [3]. Calls for additional research specific to the health of women firefighters and the unique, gender-specific impacts of occupational exposures are noted as critical research needs in the most recent National Fire Service Research Agenda [4].

Concerns about the impact of firefighting on reproductive issues among women were raised in the 1980-90s [5-8], but with little scientific follow-up. Potential reproductive health risks identified as possibly contributing to increased maternal complications include chemical, biological, and radiologic exposures from responding to incidents [5,7-9], as well as non-exposure related risks, such as the unique shift schedules common in the fire service, the extreme physiologic strain of emergency responses, and working in situations with high ambient temperatures and noise volumes [7]. Reproductive health is an emerging area of concern for firefighters, both men and women [10-13].

Currently, no guidelines for physicians and other health care providers outline the dangers of firefighting with specific considerations for pregnant firefighters. As a result, there is widespread confusion among women firefighters regarding when to limit or restrict firefighting duties when pregnant and when it is appropriate to return to work after giving birth. Recent research found that nearly 30% of fire departments do not have a policy for pregnant firefighters [10,12]. Potential injuries to firefighters and their offspring may occur due to insufficient information and guidance. In addition, the lack of literature may impact recruitment and retention in the fire service, further confounding finding reliable workers to fill open positions. The purpose of this project was to conduct a state of the science review of the current research available on women’s reproductive health and occupational exposures to serve as a foundation for additional work and as a reference for firefighters, departmental leadership, health and wellness personnel, occupational medical physicians, and obstetrics/gynecologists.

Methods

Researchers synthesized current literature in a systematic review. PubMed, a free resource containing more than 35 million citations and abstracts of biomedical literature, was used to search the below combinations of key terms (Table 1) in April-May 2022. All fields of publications were searched with any of the key fire terms and any of the reproductive keywords [e.g.: (fire) AND (reproductive health)]; (Table 1). Inclusion criteria included: English version of the abstract available; peer-reviewed article; contains research on firefighter-specific exposures; and included a reproductive health outcome. If more than one article with overlapping populations was retrieved, preference was given to the article with more comprehensive information. Review articles were included. Letters to the editor, commentaries, reports, theses/dissertations, and conference presentations/abstracts were excluded. Articles that did not explicitly include firefighters as their population were not included, though a table was added with several relevant articles as comparisons for discussion and as a source of additional information.

Table 1: Keywords

Results

A total of 1,254 records were returned from the search of PubMed. Duplicate records (n=176) were removed prior to screening (See Figure 1, Prisma Diagram). A total of 1,078 article titles were screened for relevance; 1,056 were excluded (not relevant or did not include firefighters). Twenty-two articles were sought for retrieval, one was not available (there was no abstract or article, only a title/citation). The remaining 21 articles were assessed for eligibility. One report was excluded as it was a letter to the editor and not a peer-reviewed article, and five reports were removed due to relevance (not firefighter specific). A total of 15 articles are included in the review. Additionally, the references (n=44) from an unpublished literature review from Dr. Jahnke, a known expert in the field of firefighter health, were searched. Six reports were sought for retrieval and assessed for eligibility. Six articles were duplicates from the present literature search, and one was not firefighter specific. The remaining article was added to the list of eligible firefighter articles for this review (n=16; Table 2). An additional six studies that were not specific to firefighters are included in a separate table (Table 3) as they provide relevant exposure information related to pregnancy outcomes.

Table 2: Firefighter Studies Included in Review

Table Notes: FF: firefighter. Vol: Volunteer. PFOA: Perfluorooctanoic Acid. PFOS: Perfluorooctane sulfonic acid. Car: Career. AMH: Anti-Müllerian Hormone. WHO: World Health Organization. WL/WUI: wildland/wildland urban interface. BDCPP: bis(1,3-dichloro-2-propyl)phosphate, a flame retardant metabolite. PFAS: per-and polyfluoroalkyl substances.

Table 3: Non-Firefighter or Non-Reproductive Studies Included in Review

Table Notes: FFs: Firefighters. PM_2.5: fine particulate matter. PAH: polycyclic aromatic hydrocarbons. WTC: World Trade Center.

Figure 1: Prisma flow diagram.
*Citations examined from previous unpublished literature review (Jahnke, 2014)
**Records excluded did not meet inclusion criteria (not relevant [non-firefighter related, did not mention reproductive outcomes]; was not a peer-reviewed article; etc.)
From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. doi: 10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/

Current research suggests significant reproductive dangers associated with firefighting can injure firefighters and harm their offspring. McDiarmid and colleagues [8] identified numerous male and female-mediated reproductive health effects due to firefighting, including various chemical and non-chemical hazards. The International Federation of Gynecology and Obstetrics has identified chemical exposures during pregnancy and breastfeeding as a threat to healthy human reproduction and development with implications for fertility, pregnancy, neurodevelopment, and cancer later in life [14]. Firefighters are potentially exposed to a plethora of toxic chemicals, both during active firefighting and while on-scene conducting overhaul activities after the fire is extinguished [15]. Chemicals present on the fireground include allergens and irritants (e.g., ammonia, hydrogen chloride, sulfur dioxide, phenol), asphyxiants (e.g., carbon monoxide, hydrogen sulfide, and carbon dioxide), and known carcinogens (e.g., polycyclic aromatic hydrocarbons and chromium) [5,9,15]. Recent research suggests that sub-micron sized chemical particles are still present during overhaul even when firefighters cannot see visible smoke [15]. In addition to the inhaled chemicals, firefighters face risks associated with exposure to residues of the products of combustion that become embedded in their personal protective equipment and are absorbed on their skin post-incident [15].

Several of the chemicals identified as key risks to pregnant women are the same as those found to be present on the fireground. For instance, preliminary data from the 1980s indicated that exposure to carbon monoxide increases the risk of birth defects among pregnant women firefighters [8,16]. McDiarmid et al. [16] and Evanoff and Rosenstock [5] cited several known products of combustion that are believed to impact reproductive health in either animal or human models including: aldehydes (e.g., acetaldehyde, formaldehyde, acrolein), benzene, carbon dioxide, chloroform, dichlorofluoromethane, hydrogen chloride, hydrogen cyanide, methylene chloride, nitrogen dioxide, nitrogen oxide, perchloroethylene, sulfur dioxide, toluene, trichloroethylene, and trichlorophenol.

Recent concerns regarding perfluoroalkyl substances (PFAS) and firefighter health have emerged. Though evidence is limited regarding how much of these “forever chemicals” are “safe” in the human body, there are concerns related to PFAS and human health. Through the Women Firefighters Biomonitoring Collaborative, Trowbridge and colleagues [17] measured serum concentrations of PFAS in women firefighters compared to office workers and found firefighters had higher mean concentrations of PFAS. Clarity and colleagues [18] measured serum concentrations of PFAS and found significant associations between perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS; both kinds of PFAS) and telomere length. Telomere length is associated with fertility (longer telomeres indicating fertility). When stratified by occupation, there were stronger associations among firefighters compared to office workers, meaning firefighters were more likely to have reduced telomere length indicating potential infertility. Trowbridge and colleagues [19] also examined exposure to flame retardants (a class of suspected endocrine-disrupting chemicals) and thyroid hormone dysregulation among women firefighters. They found higher levels of flame retardants among women firefighters, which was associated with decreased thyroid hormone levels. Though thyroid hormone dysregulation can lead to endocrine disruption and breast cancer risk, more research is necessary to understand the mechanisms by which exposure to flame retardants may impact firefighter health and fertility.

Davidson and colleagues [13] recently examined anti-mullerian hormone (AMH), which measures ovarian reserve and can indicate fertility. AMH indicates a woman’s ability to produce eggs that can be fertilized for pregnancy; this number peaks during childbearing years and decreases with age. AMH levels help show how many potential egg cells a woman has left and may be a useful biomarker for measuring the effects of exposures that target the ovaries. A reduction in AMH has been associated with inhaled environmental toxicants such as cigarette smoking, burning fuels indoors for cooking, and the use of pesticides. Firefighters had a 33% lower AMH value compared to non-firefighters, potentially indicating issues with fertility [13]. More research is necessary to determine the mechanisms by which firefighting could impact AMH levels and affect fertility.

In addition to fertility, women firefighters are concerned about returning to work and continuing to breastfeed their offspring. Burgess and colleagues released unpublished preliminary results from a small pilot trial examining women firefighters’ breastmilk. Preliminary recommendations suggested that women firefighters who are breastfeeding should not be exposed to “Immediately Dangerous to Life or Health” (IDLH) environments to protect exposing their offspring to toxins (Aryl Hydrocarbon Receptor, AhR) that can be found in breastmilk for up to 72 hours post-incident. However, a larger, more recent study [20] found no variation in polybrominated diphenyl ethers (PBDEs) or AhR response in breastmilk extracts of firefighters and non-firefighters. There was no significant variation after fire exposure, further confounding recommendations for breast feeding after returning to work. It is important to note that these studies only examined specific chemical exposures. Women firefighters may choose to “pump and dump” (pumping to expel breastmilk but discarding it due to potential presence of carcinogens) after returning to work if they have been exposed to live fire conditions (IDLH atmosphere or other chemicals present). More research is necessary to examine all possible chemicals present in breast milk after fire exposure.

Park and colleagues [21] examined hospital admissions for pregnancy, childbirth, and puerperium (the period approximately 6 weeks after childbirth) outcomes among women firefighters in Korea. They found, compared to the general population of women in Korea, the women firefighters’ standardized admission ratios (SARs) were higher in all admissions for puerperium outcomes; pregnancy and abortive outcomes; maternal disorders related to pregnancy; maternal hospitalization for adverse outcomes related to the fetus and amniotic cavity; labor and delivery complications; and complications related to puerperium.

Other non-chemical occupational risks also may impact reproductive health. Evanoff and Rosenstock [5] identified reproductive hazards associated with firefighting as early as 1986. Agnew and colleagues [7] also summarized potential non-chemical hazards associated with firefighter reproductive health in 1991. Collectively, they include heat, physical activity, noise, psychological stress, radiation, and biological agents. The physiologic strain of fire and rescue activities can negatively impact reproductive health [22]. Given the changes in a woman’s body as a result of pregnancy, extreme physical activity can put them at risk for injury [22]. Evidence also suggests that pregnant women’s exposure to loud noises (e.g., air horns, sirens) may lead to lower fetal weight and increased risk of fetal mortality [22,23]. In an international survey of women firefighters, Watkins and colleagues [24] found women firefighters in North America reported a higher prevalence of lower back (49%) and lower limb (51%) injuries than the other groups (United Kingdom, Ireland, Australia, and mainland Europe). North American firefighters reported more heat-related illnesses (45%) than respondents from other countries (36%). Thirty-nine percent of respondents thought their menstrual cycle and menopause affected work. It is important to note that both men and women firefighters suffer from fireground and training injuries and heat illness; however, women firefighters also must accommodate changing hormonal cycles which can impact fertility and the body’s ability to handle heat stress. More research is necessary to ensure women firefighters are protected from these dangers if/when they decide to become pregnant while in the fire service.

Women firefighters have exhibited significant concern regarding their reproductive health [25] and have identified a lack of available resources [10]. In a study of 1,821 women firefighters [10], participants reported between 22.6% and 31.7% of pregnancies ended in miscarriage. The crude overall rate of miscarriage across pregnancies while in the fire service was 27.0%, two times higher than the US national average [10]. Jahnke and colleagues also found high rates of pre-term birth, jaundice, and low birth weight among women firefighters [10]. Alarmingly, nearly a quarter of respondents (23.9%) reported their department had no policy related to pregnancy, and 20% reported their department had no policy related to maternity leave. Jung and colleagues [12] found similar results in a follow-up study; 22% of firefighters in the sample of 1,074 women firefighters had experienced a miscarriage. As women aged, this risk increased; the age-standardized prevalence of miscarriage was 2.33 times greater compared to an occupational cohort of US nurses. Volunteer firefighters had 1.42 times the risk of self-reported miscarriage compared to career firefighters. Among wildland/wildland urban interface (WUI) firefighters, volunteers had 2.53 times the risk of miscarriage compared to their career counterparts [12].

Of note, fireground exposure risks are not limited to women. Research by Olshan and colleagues [23] in a cohort of firefighters suggested that toxic exposures experienced by men firefighters may increase the likelihood of birth defects among their offspring. More recently, Petersen and colleagues [11] found that full-time firefighters had an increased risk of infertility compared to non-firefighters, and this risk appeared to be associated with the length of time in the occupation of firefighting. Engelsman and colleagues [26] examined the fertility of firefighters via survey and semen analysis. In an exploratory study, they found that, overall, firefighter semen parameters were below World Health Organization reference values designated for fertility in men. Firefighters younger than 45 had a higher incidence of abnormal semen parameters (42%) than those aged 45 years or greater (9%). Increased frequency of fire exposure was associated with a reduction in normal forms, volume, sperm concentration, and total sperm count. While this is only an exploratory study (small sample size), results suggest an association between firefighting and male-factor fertility.

Discussion

Firefighting is a known dangerous occupation; however, specific considerations must be paid to firefighter reproductive health, including potential health concerns for firefighters’ offspring. While not specific to firefighters, our literature review returned several articles with relevant exposure data. While firefighters are provided with self-contained breathing apparatus (SCBA) to combat inhaled exposures, the air available is time-limited, and evidence suggests firefighters do not always use them consistently [27]. In particular, many firefighters remove their SCBAs during the overhaul period when the air appears clear [27]. Fent and colleagues have demonstrated the presence of numerous toxicants present in the air and on firefighters’ personal protective ensembles after the fire is extinguished [28-30].

Many of the chemicals and products of combustion associated with firefighting are also associated with adverse reproductive health outcomes, which can lead to miscarriage, low birth weight, developmental disorders, or infertility [31]. In particular, exposures during the first three months have been linked to miscarriage and birth defects, while exposures during the last six months may slow fetal growth, impede brain development, or lead to premature labor [31]. Treitman and associates [32] monitored personal air sampling devices among Boston firefighters and found carbon disulfide, which has been found to lead to changes in the menstrual cycle of women and, in turn, may contribute to fertility issues [31]. Of particular concern is the finding that even small exposures, if they occur during a particularly vulnerable period of time, can trigger lasting adverse health consequences [33].

Of note, the International Agency for Research on Cancer (IARC) recently updated its classification of the occupation of firefighting as “carcinogenic to humans” (Group 1) based on “sufficient” evidence [34]. There was “sufficient” evidence in humans for mesothelioma and bladder cancer. There was “limited” evidence for colon, prostate, and testicular cancers, melanoma, and non-Hodgkin lymphoma. There was also “strong” mechanistic evidence that occupational exposure as a firefighter induces epigenetic alterations, oxidative stress, and chronic inflammation, modulates receptor-mediated effects, and is genotoxic. Prenatal exposure to environmental factors that affect the epigenome (stress, infection, toxins) can disrupt gene expression programming in the embryo/fetus, resulting in developmental deficits, including abnormal brain development that can lead to later-life behavioral disorders [35].

Though not specific to firefighters, shift work has been recognized as deleterious to health by interrupting the body’s circadian rhythms [36,37]. It has been posited that disruptions in the endogenous timing system, through its interaction with the hypothalamic-pituitary axis, can interrupt the reproductive cycle of women working shift work [38]. While results are somewhat mixed, evidence suggests a possible link between shift work and miscarriage, low birth weight, and pre-term delivery [39,40].

While exercise during pregnancy has been found to have a beneficial impact on fetal development overall [41], guidelines recommend caution for strenuous activities such as those required by firefighting and rescue activities [31,42,43] because they may result in spontaneous abortion, pre-term birth, and low birth weight [44-46]. High ambient temperatures such as those experienced by firefighters while wearing encapsulating gear inside fires can increase core temperature to extremely high levels [47]. Evidence suggests even an eighteen-minute bout of firefighting will raise core temperature 1.2°C (0.67°F) [47,48] and that, among instructors exposed to repeated firefighting tasks, core temperature rises to an average of 38.9°C (102.02°F) [48] which is the temperature identified as the threshold for posing a teratogenic effect on an embryo or fetus [42]. Finally, evidence also suggests that pregnant women’s exposure to loud noises (e.g., air horns, sirens) may lead to lower fetal weight, increased risk of fetal mortality [22,23], and increased risk of hearing impairment among their offspring [49].

Another notable concern for women firefighters is the discrimination they experience regarding pregnancy and pregnancy-related issues [50]. While organizations such as the International Association of Firefighters (IAFF), the union which represents the majority of career firefighters, encourages accommodations for all women throughout their pregnancy and after the birth of their children [51], and federal law has protected workers against pregnancy discrimination since 1978 (e.g., Pregnancy Discrimination Act of 1978) [52], it is not clear that departments follow such non-discrimination policies [53]. Research indicates that hostility and discriminatory attitudes are common for women in the workplace, particularly male-dominated professions [54].

Organizations are increasingly sensitive to the challenges women face both physically and emotionally related to pregnancy, and the impact of policy on retention. For instance, the Secretary of the United States Air Force (USAF) recently released a memorandum extending the post-pregnancy deployment deferment from six months to a year to assist new mothers in managing the work/life balance and as a means of increasing diversity in the USAF [55]. In response to the physical challenges resulting from pregnancy, the USAF extended the deferment of participation in fitness testing from six months to a year for new moms and women who have experienced a miscarriage after 20 weeks. Anecdotal evidence and fire service trade journals suggest that similar accommodations have not yet been developed by the fire service [53]. Despite recommendations from national organizations [51], it does not seem that policies are consistently implemented [53], although data on policies nationally is lacking.

This review found a large gap in the literature examining reproductive health outcomes of firefighters published between the early 1990s and the present (starting in 2018). There has been significant work examining the exposures firefighters face (both chemical and non-chemical), and there is non-firefighter data to support the adverse reproductive effects of many of the exposures common on the fireground (chemical, biological, heat, noise, radiation, extreme physical work). Subsequently, there is an absence of information for physicians and healthcare providers to fully grasp the risks women firefighters face. This lack of data specifically on reproductive health for women firefighters has also led to minimal policy recommendations (i.e., when to restrict duties during pregnancy, guidance for breastfeeding, post-partum return to work, etc.) implemented in fire departments, if any at all. Future research should examine other potential hazards of firefighting on reproductive health. Male and female-mediated factors will be essential to examine.

Strengths

Limited research has examined reproductive health among firefighters. Moreover, minimal reviews have been published since the late 1980s and early 1990s. A noted strength of this review is amalgamating the relevant literature into one place and providing a thorough review of what exists and what still needs to be examined. Though limited, the research to date presents consistent findings that there are adverse reproductive health issues associated with the occupation of firefighting. Miscarriage and pre-term birth rates were consistently found among large samples of women firefighters in the US. Research both nationally and internationally highlights concerns for women and men firefighters. More research is necessary to examine specific mechanistic pathways for adverse reproductive health outcomes as well as how this information can impact policy and procedure in the fire service.

Limitations

Though this study has several strengths, the authors also acknowledge limitations. Though researchers used only one database for this literature review, the use of PubMed, which comprises more than 35 million citations for biomedical literature from MEDLINE, life science journals, and online books, provides a comprehensive picture of the available literature. There are also limitations when drawing conclusions from the examination of chemical exposure. The complexity of chemicals associated with firefighting may make it difficult to examine all pregnancy outcomes and chemical relationships properly. For example, while Jung and colleagues [20] recently found no difference in chemicals present in the breastmilk of women firefighters compared to women in the general population, only PBDEs and AhR response were examined. Future research must examine a wider range of chemicals to which firefighters are exposed to determine if they are present in breastmilk after fire exposure. Very little literature exists examining reproductive outcomes of firefighter among men. This is an area for future exploration.

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DOI: 10.31038/AWHC.2023612

Abstract

Focusing on the need to develop rapid ways to understand and solve social problems, the study reported here had 61 respondents each evaluate a set of 24 vignettes systematically created to represent different aspects of the problem. The topic was the expected impact of a park to be built in northern Israel, in Haifa, a simulated problem typical of local social issues world-wide. The objective was to demonstrate the ability of the emerging science of Mind Genomics to evaluate different aspects of a local issue, with rapid, affordable experiments. The study, done within the period of a few hours from start to finish, including data analysis, revealed two mind-sets of respondents, one group focusing on issues of environmental impact, the other focusing on the benefits to people. The process shows how to probe deeply into the minds of people, even when the people cannot easily express their concerns.

Introduction – A World of Issues and Prospective Answers

We live in a world rife with issues, with problems whose solutions may in their wake create other problems, or perhaps simply exacerbate these other problems. How does one approach this issue, where the solution to problems creates other problems? History seems to be the story of this problem-solution balancing acts. Philosophers such as the German romantic, Hegel, recognized this delicate balance as an ongoing pattern which characterizes history [1]. Hegel put the issue elegantly as ‘thesis, antithesis, combining to yield synthesis’, a process and balancing act which lies at the essence of world progress.

This paper reports efforts to adapt an emerging discipline, Mind Genomics, to the study of policy, using a combination of experimental psychology, statistical design of ideas, and consumer research methods, respectively. The paper is crafted as a demonstration of what could be accomplished by using the Mind Genomics approach, coupled with artificial intelligence, to investigate different aspects of a problem, structure a way to understand these aspects, and assess the response of people to various solutions. The paper also demonstrates a practical way to approach issues of public policy, in a way which is inexpensive, fast, and most of all powerful because of the ability to iterate to answers, rather than spending great time learning, hypothesizing, and then confirming or falsifying one’s conjectures.

The unpleasant reality confronting the world and its inhabitants, not to mention engineers of policy, is that for most problems there is probably no perfect solution. The language of everyday recognizes the reality that solutions come with their own problems. Truisms such as ‘there’s no free lunch’, or ‘the piper must be paid’ are tribute to this reality. And, of course, even when the objective is noble, such as helping others to escape poverty, there is always the issue of negative consequences, expected or unexpected. One need only recognize that in the history of society’s efforts to advance materially come at the price of damage to the environment [2]. There are the big picture issues, such as the deforestation of the amazon rainforest, a possibly dubious necessity there are to be farms to grow food for people to eat [3].

The issue addressed here is how to ‘surface’ the issues involved when there is a conflict between the noble effort to improve the lot of people and the effect that this effort has or could have on the local environment. Can we develop an approach to answer this everyday problem, not so much to paint a ‘grand picture’ but instead actively address a local, small, seemingly irrelevant issue? Instead of spending efforts ‘tilting at windmills’ with long, philosophically driven, coffee-powered discussions of grand issues, can we create a system which can address a real problem, small in comparison, local in nature, but equally fractious and important to those involved. In other words, do something when something should be done.

The One-at-a-Time Effort and Its Evolution to the Systematic Studies Using Mixtures

Today’s researchers are taught the ‘scientific method’, reinforced again and again that the ideal way to ‘understand’ the nature of something, some phenomenon consists of isolating that ‘something’, and studying the isolated something, to understand it deeply. Where possible, it Is important to reduce ‘noise’ around the phenomenon, whether that noise reduction be accomplished by removing all sources of variation, so that the phenomenon can be explored and its different facets revealed, or by averaging out the noise. When the phenomenon in question is one driven by behavior, the idea is to isolate the person, one way to reduce noise, and make many measurements of th same phenomena, the phenomenon being affected by different types of factors. The former strategy reduces the noise, the latter averages out the noise.

The reality of behavior is that cancelling the noise by isolating the person in an experiment may be attractive, but it is not the best way to understand how people react to the real world around them, and how people make decisions. The reality is that decision-making must work in a world of complexity, in a world presenting different choices. To understand how people make decisions, especially those involving ‘soft’ facts, such as policy issues demands that the researcher consider the many types of information presented, their interactions which inevitably mess up the isolation, and the possibility that there is no single ‘best answer’ or certainly no single ‘right answer, rather there are many ‘best answers,’ many ‘right answers.

Statisticians have long recognized that it is vital to study mixtures in many areas, those studies of mixtures teaching a great deal about the nature of the components that the mixture comprises. In the world of statistics, this topic is known as ‘experimental design’ [4]. The ingoing assumption of experimental design is that to understand the variables it is important to understand how these variables behave when they are combined, forced to interact, and then yield a result. Statisticians also realize that if one variable is studied in ‘splendid isolation’ the knowledge thus obtained will not be valid because the variable occurs in conjunction with many other variables. What nature presents to the researcher is the outcome of the interactions, the competition and cooperation of these variables as “drivers” of that which is measured.

Applying the Studies of Systematically Created Mixtures to Options in Public Policy

This paper focuses on the study of mixtures of ideas to understand responses to public policy, and to a simple situation, the creation of a child’s park outside a major city (Haifa, in Israel). The actual experiment is real, but the situation, creation of the park, is chosen simply as a topic which is meaningful to people. The paper will show the way one can incorporate thinking about mixtures of policy ideas to optimize public policy and understand the nature of variations in response to a policy idea.

The approach used here, Mind Genomics, is as an emerging branch of experimental psychology, with the focus on how people make decisions when they are faced with alternatives. Mind Genomics is empirical, not positing theory about why people make decisions, but rather focusing on how to measure the thinking of people who are instructed to make these decisions. Rather than positing that people behave in a certain way to optimize some criteria, Mind Genomics looks at a topic issue, constructs an experiment to observe decision behavior regarding topics involving this issue, and emerges with empirical results to understand the topic. The goal of Mind Genomics is thus to restructure the issue in a way amenable to a certain type of test, do the testing, come up with the results, and finally use the research to reveal how people make decisions at the specific, granular level of the situation, viz., where the activity of decision making really takes place [5,6].

Mind Genomics studies follow a simple protocol based upon the belief that the study is designed to identify areas of interest, rather than to affirm or to falsify a hypothesis, viz. to explore the unknown territory. Mind Genomics is inductive, empirical, building from the ground up, seeking patterns. Rather than following ‘calls from the literature to fill gaps in our knowledge, to fill holes in the literature as the activity is often described, Mind Genomics attempts to describe the interaction of variables in a system as drivers of a phenomenon of human experience. The discipline is experimental design. There are no intervening variables nor hypothetical constructs. There are only emergent patterns, patterns to be described and perhaps understood in a deep fashion. There may be an underlying pattern which lends itself to theory, but that theory is of secondary importance in Mind Genomics. Of primary interest is the enticing repetition of in nature, patterns which make sense, patterns which reaffirm a regularity in the universe.

Following the foregoing viewpoint, that the focus be on regularity which informs and teachers, not on slavishly affirming or falsifying a hypothesis, we now move to a demonstration of the approach. To make the study interesting, beyond just the facts, we can add a level of excitement by framing Mind Genomics as a process which demonstrates an ‘industrial-scale production of knowledge. As part of the project reported here, we also focus on the exceptional speedy creation of knowledge, and what that means for the project of science.

Mind Genomics for Industrial-Scale Production of Knowledge Regarding How People Think

We now proceed by running an experiment using Mind Genomics to set up the study, and then doing the study with 50 respondents. The Mind Genomics process follows a templated format, designed to simplify the process of thinking about the topic, generating questions, and generating answers. These different aspects will be explained as the paper proceeds.

Step 1: Name the Study

Mind Genomics begins by creating a new project, giving the project a name, and agreeing not to record personal information about the respondent. If personal information is desired, then the respondent can be asked permission, and the respondent must provide that information. Figure 1 shows an example of this page.

Figure 1: Example of the front page

Step 2: Create Four Targeted Questions about the Topic

The questions require information-rich answers in the form of phrases, not just yes/no. is at this point in the process that the researcher feels stymied, simply because all too often education does not often teach a person how to think in an investigative way. Sadly, thinking ends up being displaced by memorization. To help the thinking along, Mind Genomics has made a provision (Idea Coach), in which the researcher can type the background of the study, and in return the underlying AI will generate up to 30 questions. Idea Coach can be resubmitted, until the researcher has selected the requisite four questions.

The paragraph below shows the description of the problem submitted to Idea Coach. Figure 2 (left panel) shows the request for four questions to be used for the Mind Genomics study. Figure 2 (right panel) shows the last part of the paragraph embedded in the Idea Coach screen, Outside Haifa, Israel a group of Arab and Israeli partners want to create a children’s park, including places where the children of different groups can play together. The plans include changing some of the existing land, which was held ‘wild and undeveloped’ for tourists, taking that land and changing its topography, building it up. The beneficiaries will be the people, but there are concerns that the local natural environment will be permanently changed, and not for the better.

Figure 2: The request for the four questions (left panel) and part of the background paragraph typed into Idea Coach (right panel).

Idea Coach turns with a set of 25-30 questions for the specific paragraph entered into the Idea Coach ‘box.’ Figure 3 shows the first eight of 25-30 questions returned by Idea Coach when the same paragraph was used. Idea Coach returns with different, albeit overlapping sets of questions for each iteration of the same description. Table 1 shows the set of 29 questions returned by Mind Genomics in the actual run of the study.

Figure 3: Idea Coach returns with sets of 25-30 questions for a specific background paragraph

From the set of 29 questions shown in Table 1, or from a new set, or from one’s own thinking, select four questions. The questions need not be from the set presented, but can be edited versions of the questions, or even new questions constructed by the researcher after reading the different question emerging from the AI of Idea Coach. It is at this point that the value of artificial intelligence begins to show itself. One need not know anything. Idea Coach can either be used directly to select questions, or to augment existing questions, or even better, to stimulate thinking. The four questions selected for further evaluation by Mind Genomics were:

How will the park be maintained?

What are the expected environmental impacts made by the park?

What are the expected economic impacts made by the park?

What are the expected social impacts made by the park?

Table 1: The 29 questions about the topic returned by Idea Coach

Step 3: For Each Question Selected, Create Four Answers, Expressed as Simple Declarative Statements

Once again Idea Coach can be used to select the questions, or to jump-start creative thinking (Figure 4) Table 2 presents four questions and up to 15 answers, exactly in the way AI-based Idea Coach returned the list. Table 2 shows the answers as they emerged from the Idea Coach.

Figure 4: Screen shots showing the four questions, Question 1 of 4, and two sets of answers from Idea Coach for Question 1 of 4.

Table 2: The answers to each question, exactly in the language returned by Idea Coach

Step 4: Create a Self-profiling Classification Questionnaire

The self-profiling questionnaire will be to capture ‘who’ the respondent IS, and how the respondent FEELS about certain issues. Table 3 shows the distribution of responses, from Total Panel, as well as from two emergent mind-sets.

Table 3: Self profiling questionnaire and number of respondents in each group

Step 5: Lay Out the Combinations of Elements (So-called Vignettes)

Mind Genomics works by presenting respondents with combinations of elements, specified by the underlying plan called the experimental design. The design used by Mind Genomics for this specific set of four questions and four elements (answers) for each question is known as a permuted design [7]. Each respondent evaluates exactly 24 vignettes, with each vignette comprising either two, three, or four elements, with at most one element from a question, but often no elements from a question. The permuted design presents each of the 16 elements five times in 24 vignettes. Furthermore, each question contributes one element or answer to 20 of the 24 vignettes and contributes no answer to four of the 24 vignettes. Each respondent evaluates a totally unique set of 24 vignettes, with each of the 16 elements statistically independent of every other vignette. The happy consequence is that the researcher can estimate an equation either for a specified group of respondent or even for each respondent separately. The latter ability to estimate the individual-level respondent will allow the researcher to divide the respondents by the pattern of their responses, more correctly by the pattern of the coefficients for an equation relating the presence/absence of the elements to the ratings. That regression strategy is explained below.

Step 6: Create the Orientation and Rating Scale

Create a short paragraph introducing the topic and a scale of five questions from which the ‘respondent’ must choose the ‘appropriate answer’ for each of 24 vignettes. Table 4 shows the introduction (also presented above) and the rating scale.

Table 4: The orientation for the respondent

Step 7: Run the Experiment with Respondents Who Represent the Target Audience

For this study the respondents belong to a multi-million-person database run by Luc.id Inc., located in Louisiana, USA. The respondents used by Luc.id, Inc. came from other panels. Luc.id is the panel aggregator. The Mind Genomics program (www.BimiLeap.com) features a link which makes it easy to create specific requirements for the respondent panel and recruit those respondents. The entire process, from launch to the completion of the field work requires approximately 1-2 hours, with the individual ‘interaction with each respondent lasting about 3-4 minutes.

Step 8: Create the Database in a Format that Will Be Ready for Downstream Statistical Analysis

The data for each respondent comprises 24 rows, one row for each vignette. The information contained in each row groups of columns. The first group of columns in the database comprises information about the respondent from the self-profiling classification. The second group of columns comprises information about the composition of the vignette (16 additional columns, ‘1’ coding element present in vignette, ‘0’ coding element absent from the vignette). The third group of columns comprises information about the response to the vignette (the order of the vignette for the respondent from 01 to 24, the rating assigned by the respondent, and the response time for the vignette, defined as the number of hundredths of seconds between the appearance of the vignette and the assigned rating.)

Update the database by creating new variables, R1, R2, R3, R4, and R5, respectively. These new variables, R1-R5, are binary transformations of the ratings. The rationale for the transformed variables comes from the experience of author HRM, with users of the Mind Genomics results. Most users want to make decisions using the data. To do so, the user must ‘understand’ the meaning of the results. An average score on a scale does not help the user. The user is far more likely to understand the average when the average is couched in the language of ‘yes/no.’ Thus, it has become common practice to convert the ratings to a binary scale. For these data, each of the five rating points has been made into its own binary scale, generating five new binary transformation scales, R1 – R5. For example, when the respondent assigned a rating of ‘5’ to the vignette, variable R5 becomes ‘100’, whereas variables R1-R4 each become ‘0’. For purposes of subsequent statistical analysis, a vanishingly small random number (<10^-4) is added to the newly created binary transformed scale. In this fashion the data are prepared for subsequent statistical analysis with the out of that statistical analysis immediately understandable to the user of the data.

Step 9: Relate the Presence/Absence of the 16 Elements to the Transformed Dependent Variable

OLS (ordinary least-squares) regression, also known as ‘curve fitting,’ is a standard analytic technique in statistics. OLS regression attempts to determine the contribution of each of the 16 elements to the transformed binary rating. For the analyses run in this study, we will use a variation of OLS regression which forces the equation through the origin, rather than estimating an additive constant. The traditional analysis for Mind Genomics studies has been to fit an equation of the form below to the data, with the additive constant, k0, showing the estimated value of the transformed variable in the absence of any elements. The additive constant, k0, has been treated as the baseline value, the value of the dependent transformed variable in the absence of elements. All vignettes comprise 2-4 elements, according to the underlying design, so that the additive constant is statistically correct, but may not necessarily add much information, since the focus is on the contribution of the elements themselves, not on the baseline value.

Transformed Variable with additive constant (e.g., R5)=k₀ + k₁(A1) + k₂(A2) … k₁₆(D4)

Transformed Variable without additive constant (e.g., R5)=k₁(A1) + k₂A2) … k₁₆(D4)

To assess the impact of using an equation without the additive constant (called ‘forcing the equation through the origin’) we created nine dependent variables, as shown in Figure 5. The first five dependent variables were R5 – R1 The second set of four dependent variables were binary sums of the binary variables, to denote responses of ‘people better off’ (P+) ‘environment improved (E+), ‘people not better off’ (P-), and ‘environment damaged’ (E-). Figure 5 shows that the values of the coefficients (k₁-k₁₆) may differ, but in all cases the coefficients are virtually parallel, albeit with different values. This demonstration gives us the confidence to work with the equations lacking an additive constant.

Figure 5: Scatterplot of coefficients for Total Panel for nine binary dependent variables, for equations with vs without an additive constant.

Step 10: Analyze the Results from the Total Panel

In a sense the major effort of the Mind Genomics exercise is to discover how the different elements drive the response. For our study we focus on six different responses, expressed by the dependent variables. These are positive and negative responses to the elements in terms of people and environment, respectively, as well as the rating of ‘don’t know’. Tables 5 and 6 show all coefficients of +11 or higher. These are elements which would be ‘statistically significant’ for equations without an additive constant, the T statistic being 2 or higher. Table 5 also shows all coefficients of 20 or higher in shaded cells to highlight the fact that they are to be considered ‘very strong performers.’

Table 5: Coefficients for selected equations relating the presence/absence of elements to key dependent variables. Strong performing elements are shown in shaded cells. Elements with coefficients 10 and lower are not shown.

Table 6: Coefficients for the 16 elements, estimated for the two mind-sets on five dependent variables

Table 5 shows only one element which performs well for the total panel, D1, The park is expected to increase physical activity and promote healthy living. This element performs well on both driving personal well-being (P+) and driving good for the environment (E+).

Two elements are seen to be both positive for the environment (E+) as well as negative for the environment (E-).

A2             The park will be maintained by a team of park rangers.

A4             The park will be maintained by donations.

In contrast, no element is seen to be negative for the people (P-), perhaps because the concept was developed for people, with the environmental impact as an afterthought.

During the setup of the study, and quite inadvertently, the topic of ‘tourism’ was included twice, one as a general statement, the other time as a specific statement. The coefficients for these elements differed. The coefficient for element B3 ‘The park is expected to increase tourism’ emerged as positive for the people (coefficient +12 for dependent variable P+) but negative for the environment (coefficient + 13 for dependent variable E-). In contrast, when the text was changed in element C2 ‘The park is expected to increase tourism in the area’ the pattern of coefficients changes. C2 now generated a coefficient of +11 for dependent variable P+E+, and coefficients +19 for dependent variable P+ and +17 for dependent E+, respectively. This finding suggests that in the mind of the respondent it is not only the action but also an enhanced explanation of the action which ends up driving the response.

Step 11: Uncovering Mind-sets, viz. Respondents Who Think Similarly about the Granular Topic of this Park

The world of consumer research has long recognized that people are different from each other, but for many years the researchers relied on differences in the way people described themselves. A hallmark of Mind Genomics is the effort uncover mind-sets, different ways of thinking about the same granular level topic. By mind-set we refer to data-based patterns which seem to ‘tell a coherent’ story (interpretability), and which seem to require only a few of these patterns (parsimony).

The mind-sets are uncovered by creating individual-level models of the type shown in Table 5, but with each respondent generating a complete model comprising 16 coefficients. The dependent is R5 (good for the people; good for the environment). The coefficients can be positive, zero or negative, depending upon the data set. The OLS regression modeling creates one equation for each of the 61 respondents, able to do so because the underlying permuted experimental design creates a valid design for each respondent. The data for each respondent can be analyzed, person-by-person, to estimate the values of each of the 16 coefficients.

The only steps left are to divide the 61 respondents for this study into two (or possibly more) groups, based upon an objective viz., non-judgment-based metric. The metric is (1-Pearson R), computed on the 16 pairs of corresponding coefficients for two respondents. The analysis returns with the measure (1-R), where R is the Pearson coefficient computed for the 16 pairs of coefficients. R measures degree of relation. When the variables are parallel to each other, they are almost indistinguishable. They probably measure the same thing, and the value (1-R) is 0 because R=1. In contrast, when the variables are opposite, then they are probably measuring different things, and the value (1-R) is 2 because R=-1.

An underlying clustering program assigns the 61 respondents first to two different groups, and then to three different groups, based upon the pattern of their distances from each other. The clustering program [8] uses objective criteria. It is the job of the researcher to interpret these mind-sets which emerge. Table 6 shows the coefficients for two mind-sets, M1 and M2. There clusters emerging appeared to be clear, obviating the need for a third cluster. Mind-Set 1 (M1) appears to respond more strongly to environmental issues and implications. Mind-Set 2 (M2) appears to respondent more strongly to the welfare of the people who will use the park.

Step 12: Scenario Analysis to Uncover Pairwise Interactions among Elements

An ongoing issue in the study of communications and decision making is to understand how ideas or messages interact with each other [9]. The importance of interactions is well known in the world of physical design when an actual object is created. When the interactions ‘work’ there is a positive response to the combination. When the interaction does not ‘work’, there is a sense of something wrong with the combination, and the designer or fabricator tries another combination. When the topic turns to language, the issue of interactions becomes less clear.

The Mind Genomics process enables the discovery of how one element affects another element. We illustrate the study of the interactions with our data on the park. The process will work when the researcher uses the permuted design. We illustrate the approach using the interactions of the four elements from Question A (how the park is cared for), with each of the remaining 12 elements, four each from Questions B, C, and D, respectively.

1. Create a new variable. We call this variable ‘ByA.’ For each vignette tested, this new variable takes on one of five values, depending upon the which of element The variable takes on one of five values, 0-4, depending upon the which of the four elements from Question A appears in the vignette, or when Question A does not contribute to the vignette.
2. Separate the data into five strata, depending upon the value of ByA.
3. For each stratum, create an equation expressed as: R5=k₅(B1) + k₆(B2) .. k_{16 (}D4).
4. Put the do this analysis for any defined group. For our study we compare the results across the two emergent mind-sets, Mind-Set 1 who were defined as ‘environment’ oriented, and Mind-Set 2 who were defined as People Oriented.
5. Table 7 shows the parameters of the equations. Table 7 shows five columns of coefficients, one column for each element contributed (or not contributed) by Question. Table 8 divides into two parts, the top for Mind-Set 1 (Environment focused) and the bottom for Mind-Set 2 (People focused).
6. Scenario analysis is simple a method to look at interactions, generating a great deal of data. It is important to arrange the output in a way which generates relevant insights. The header rows in Table 7 show the relevant comparisons in shade.

Table 7: Summary worksheet for Scenario analysis. The defining stratum is Question A

Table 8: Presents the two set of response times, the top for Mind-Set 1 (environment oriented), the bottom for Mind-Set 2 (people oriented).

Mind-Set 1 (Environment oriented) – compare column A=0 (no element about maintenance) to column A=2 (The park will be maintained by a team of park rangers). We would expect that adding ‘team of park rangers’ to the vignette would ‘synergize’ with the other elements, increasing their magnitude. The coefficients are sorted by their magnitude when in the presence of A2 (team of park rangers). The synergistic effect is dramatic, as shown by the highest scoring element. This element is B4, ‘The park is expected to provide habitat for wildlife and help improve local biodiversity’. In the absence of any element from maintenance, B4 is still a strong performer, with a coefficient of +18. When, however, the ‘team of park rangers’, is added to the vignette, the coefficient for B4 virtually doubles, from 18 to 34. Unfortunately, however, for Mind-Set 1 focusing on the environment, synergisms are not common. This relatively rarity of synergisms suggests the possibility that the ‘way of thinking’ of Mind-Set 1 may be ‘particularistic’, looking at one item at a time, the key item.

Mind-Set 2 (People oriented) – compare column A=0 (no element about maintenance) to column A=1 (The park will be maintained by a combination of volunteers, city, state, federal, private, and public funding). There are four synergisms, all from Question D, about what the park will provide to people. Mind-Set 2 may be ‘integrative’, looking at combinations of items, rather than focusing on the one aspect, viz., the environment.

Step 13: Scenario Analysis Applied to Response Time

The Mind Genomics program, www.BimiLeap.com, measures the times between the appearance of a vignette of the respondent’s computer screen and the assignment of the response. For two centuries, researchers have used the response time as a measure of internal psychological processes that may or may not be readily explained [10]. The assumption made by researchers is that the response time elapsing between the stimulus appearance and the response is an indicator of underlying psychological processes. For the most part, the response times are either to posit the existence of some underlying psychological process, or to show differences in the speed of response due to external factors imposed on the respondent.

The pattern of responses times for the two mind-sets suggests different priorities in what engages attention.

When we look at Mind-Set 1, focus on the environment, and pay attention to the potentially synergistic effects with element A2 (The park will be maintained by a team of park rangers) we find a lot more engagement (viz., longer response times) emerging with elements dealing with the general public good.

The park is expected to provide habitat for wildlife and help to improve local biodiversity.

The park is expected to increase tourism in the area.

The park is expected to increase tourism.

When we look at Mind-Set 2, focus on people, and pay attention to the potentially synergistic effects with element A1 (The park will be maintained by a combination of volunteers, city, state, federal, private, and public funding). we find more engagement (viz., longer response times) emerging with elements dealing with the public good.

The park is expected to provide a space for relaxation and contemplation.

The park is expected to provide habitat for wildlife and help to improve local biodiversity.

The park is expected to increase foot traffic in the area.

Discussion and Conclusions

The use of research to deal with issues of public policy is well accepted. What is not so well accepted is the ability to use so-called ‘high powered’ research methods for local problems. Typically, when local issues arise there might be a referendum called, with people answering a few questions on an easily tabulated questionnaire or showing up for a town-hall type meeting where the topic is discussed, and a vote taken. These methods are the working of local democracy and occupy a hallowed place in the machinery of local government.

The advent of DIY (do it yourself) research has made it attractive to use stronger methods to understand people. For example the small problem of public opinion about the effects of the park has been elevated from an opportunity to measure responses to a momentary issue to a deeper way to understand the way people think. The scale of the problem is important. The world abounds in small-scale problems, important to some, but most important ‘real’. Rather than simply creating an artificial test situation to explore how we make decisions, or perhaps waiting for very rare major events to occur, the researcher can now apply powerful tools to everyday issues to extract information about the mind of the average citizen for real-world but minor issues.

A popular method for approaching problems is called scenario analysis [11]. It is from the conventional scenario analysis that the name was adopted for Mind Genomics. The notion is to lay out the combinations of different factors, not necessarily in the fashion of experimental design, but still lay out reasonably complete, and alternative combinations. An analysis of these scenarios gives a sense of what alternatives are optimal in a world where one can choose different paths. The standard methods have been used in areas such as hospital design [12], the environment [13], and as a method for risk analysis [14].

Armed with these new tools such as Mind Genomics, and applying these tools to many types of problems, and in many countries, one can only speculate on the further evolution of our knowledge of the ‘mind of society.’ It may well turn out that topics which produce a great deal of ‘heat’ through argumentation from different viewpoints may end up producing knowledge of different ‘minds’, and the opportunity to find middle-positions through the research, positions allowing for constructive solutions.

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DOI: 10.31038/AWHC.2023611

Abstract

Introduction: The symptom complex caused by vulvovaginal atrophy negatively impacts postmenopausal women’s quality of life. Several studies have already conferred a solid base to the rationale for vulvovaginal restructuring and control of atrophy-related symptoms thanks to a few sessions of PN-HPT^® injected in the vulvar skin dermis and mucosal lamina propria in combination with hyaluronic acid.

Methods: A real-world cohort of 60 ambulatory women spontaneously seeking help to alleviate their menopausal vulvovaginal atrophy symptoms. Treatment: a five-session cycle of vulvar injections with a Class-III CE-mark medical device (NewGyn^®, Mastelli, Sanremo, Italy)—PN-HPT^® (10 mg per mL), HA (10 mg per mL), mannitol (220 micromoles per mL). Assessments: vaginal dryness, irritation, dyspareunia, itching, tenderness and tingling, blood losses, urgency, dysuria, recurrent urinary infections; scoring with 10-cm visual analogue scales (VAS, 0=no symptom, 10=unbearable symptom).

Results: The typical VVA symptoms that were more severe at baseline improved markedly over the 90-day follow-up period: –63.5% for vaginal dryness, –57.7% for irritation, –59.4% for dyspareunia,–68.8% for itching, and –70.0% for tenderness/tingling. The occasional mild local pain and irritation at the injection site, expected and known in the previous PN-HPT^® literature, were of no clinical significance and rapidly transitory.

Conclusions: Once again, the outcomes of this real-world cohort study suggest that the PN-HPT^® bio-restructuring properties in connective tissues and the documented synergy between PN-HPT^® and hyaluronic acid translate into a fine control of vulvovaginal atrophy symptoms.

Keywords

Hyaluronic acid, PN-HPT^®, Polynucleotides Highly Purified Technology, Vulvovaginal atrophy, Vulvar skin quality

Introduction

Embryologically, the female genital and lower urinary tract share a common origin, with the trigone, vulvar vestibule, upper vagina, and urethra and bladder deriving from the primitive urogenital sinus tissue rich in estrogen receptors [1]. Unfortunately, only a little circulating oestradiol survives in the postmenopausal woman—less than 30 pg/mL indirectly originating from adrenal androgens after conversion via estrone in adipose tissue [2,3].

The atrophic vulvovaginal symptoms and signs, experienced by middle-aged women and often extended to the bladder and urethral areas, do not subside without treatment. The resulting severe burden on the woman’s quality of life is a troubling perspective, both socially and individually, since Western women can reasonably expect to live almost 40% of their existence in the menopausal condition [4].

The labia, clitoris, vestibule, introitus, and vagina, but also the urethra and bladder, change in up to 50% of menopausal women. The collective label of Genitourinary Syndrome of Menopause (GSM) summarises the related symptom cohort of genital dryness with burning and irritation, lack of lubrication leading to discomfort or frank dyspareunia during sexual activity, and dysuria, urgency, and recurrent urinary tract infections [1,4].

Symptomatic vulvovaginal atrophy (VVA) dominates the GSM picture. Several surveys have documented the impact of VVA on postmenopausal women’s life. Recent examples are the “Real Women’s Views of Treatment Options for Menopausal Vaginal Changes” (REVIVE) in 3,046 US women or the multinational “Vaginal Health: Insights, Views & Attitudes” (VIVA) online survey in 3,520 women [5,6]. In the VIVA survey, 80% of women reported a negative effect on their lives, including severe interference with sexual intimacy for almost all of them, but also “feeling less sexual” and attractive (68%) and, often and dramatically for self-confidence, “feeling old” (26%) [6].

The label PN-HPT^® indicates a mixture of highly purified DNA polynucleotides extracted from male salmon trout gonads; advanced purification and high‐temperature sterilisation procedures ensure the high PN-HPT^® safety [7-9]. Intradermal vulvar injections of PN-HPT^® in combination with hyaluronic acid, a technically simple and safe procedure, already showed to improve VVA symptoms with a visually evident restructuring of local connective tissues and improvement of genital atrophy and related symptoms [10,11]. A recent study focused on the disrupted sexual life and couple relationship of menopausal women showed great benefits, assessed with the internationally validated “Personal Assessment of Intimacy in Relationships” (PAIR) scale, from a five-session course of technically simple PN-HPT^®/HA vulvar injections every fifteen days [11].

This cohort study followed and complemented the previous investigation in a similar cohort of menopausal women centred on the sexual problems of menopause and the benefits of PN-HPT^® and HA protected with mannitol [11]. This new study aimed to complement the previous information with more data about PN-HPT^®/HA/mannitol vulvar rejuvenation and benefits for VVA symptoms.

Methods

Study Design

A prospective real-world cohort of 60 ambulatory menopausal women with prominent VVA symptoms spontaneously looking to alleviate postmenopausal vaginal dryness and other disturbing atrophy symptoms like thinning or loss of rugae, mucosal pallor, petechiae, and tenderness of the vaginal introitus. The adopted experimental design qualifies the study as observational. Preserving the real-world nature of the investigation required adopting only a few exclusion criteria—genitourinary infections, pelvic organ prolapse surpassing the hymenal ring, vulvar dermatitis or dystrophy causing vulvodynia or chronic vulvar pain, viral infections, and high risk for human Papillomavirus infections, positive Papanicolau test, hormone replacement therapy and all local treatment aimed at the control of vulvovaginal symptoms.

The office-based study respected the Helsinki Declaration and Good Clinical Practice principles. All study materials, which included informed consent forms, study protocol, and case report forms, were preliminarily peer-reviewed for ethical problems.

Vulvar Injection Technique

After full disclosure and written acceptance, by signing an informed consent form, of the foreseeable benefits and risks of vulvar PN-HPT^®/HA injections, all enrolled women underwent a five-session cycle of PN-HPT^®/HA injections in the skin dermis and mucosal lamina propria of the vulva. Content of the Class-III CE-mark medical device chosen for the study (NewGyn^®, Mastelli, Sanremo, Italy)—PN-HPT^® (10 mg per mL), HA (molecular weight, 1000-1500 kDa; 10 mg per mL), and mannitol as an inhibitor of enzymatic and oxidative HA degradation (220 micromoles per mL). Formulation: isotonic viscoelastic gel in 2-mL prefilled single-use sterile apyrogenic syringes with 30G/13 mm needles.

As in the previous study that focused on VVA disruption of personal sexual gratification and couple relationships [11], linear retrograde injections were the usual technique in the labia majora area, while micro-wheals were the preferred technique in the labia minora area and around the vaginal meatus and peri-clitoral areas (0.1 mL per wheal with wheals distanced 0.5-1 cm). Needle inclination during intradermal injections: 30-45 degrees.

The usual procedure involved no more than two injections below the posterior labial commissure overlying the perineal body and one or two injections at the anterior labial commissure below the mons pubis. The usual technique calls for injecting the residual syringe content in several small hives on the labia minora at the side of the vestibule and towards the prepuce. Other injection techniques (fan-like pattern, reticular pattern, mixed) were occasionally helpful in individual cases.

The preliminary preparation involved local disinfection and, if needed, a galenic (e.g., 30% lidocaine gel) or proprietary anaesthetic cream applied at the smallest dose sufficient to numb the target vulvar area 30 minutes before the injection. All sessions ended with a prolonged massage of the treated areas to help the local gel diffusion, the suggestion of self-administering further PN-HPT^® topically as either vaginal pessaries or vaginal cream at home, and the recommendation of avoiding intercourse and other activities involving rubbing or pressure on treated areas for some days.

Clinical Assessments, Timing, and Parameters

Assessment of demographics and vulvovaginal symptoms — vaginal dryness, irritation, dyspareunia, itching, tenderness/tingling, blood losses, vaginal discharge, urgency, dysuria, recurrent urinary infections; scoring with 10-cm visual analogue scales (VAS, 0=no symptom, 10=unbearable symptom) — was planned at baseline (T0) and after 21, 35, 50, 70 and 90 days (T21, T35, T50, T70 and T90, respectively).

The investigator carefully questioned for side effects and complications at all study visits.

Statistics

The sample size was estimated with the G*Power statistical program version 3.14 based on the worst-case hypothesis, two effect sizes, and the assumption of a 90% power of avoiding false-negative type II errors (ß=0.10) [12]. The sample size was estimated considering a fictional cumulative VAS symptom score and conservatively assuming a conservative 60% estimated improvement at the end of the PN-HPT^®/protected HA treatment course. Under these assumptions, the statistical power to detect a significant (two-tailed) divergence in clinical evolution (curves of symptom VAS scores) in 60 postmenopausal women would have been greater than 0.85.

Descriptive data were tabulated as means ± standard errors of the mean (SEM). The statistical analysis was based on the general linear model for repeated measures (Kruskal-Wallis test for independent samples or non-parametric one-way ANOVA on ranks) to assess how PN-HPT^®/HA treatment influenced the symptom curves. After detecting a significant divergence from the null-hypothesis lack of treatment effect, pairwise post-hoc Šidák multiple comparisons identified the exact time points of divergence during the follow-up period. All statistical tests were two-tailed 5% significance level [13].

Results

The mean age of the 60 cohort women was 57.6 ± 5.13 years old (median 58.5 years old; range 48-68), with a standard body framework for middle-aged women (weight 64.5 ± 6.60 kg; median 64.0, range 49-78). A natural, usual-age menopause (45 to 53 years old) occurred in 50 women and late natural menopause in five women 55 to 56 years old, while five women underwent surgical menopause because of total hysterectomy in the previous five years. All women of the prospective cohort completed the study; compliance to injections, verified at all visits, was always excellent, and all women completed the planned study sessions.

Figure 1 illustrates the evolution of VAS scores at different assessment times between baseline (T0) and T90 for the more typical and troubling VVA symptoms that presented most severely at baseline—vaginal dryness, irritation, dyspareunia, itching, and tenderness/tingling. At the first short-term follow-up visit after the first intradermal injection (T21), the mean vaginal dryness, dyspareunia, and itching VAS scores had already decreased significantly by 24.0%, 24.7%, and 30.5%, respectively, vs the T0 baseline session. All VVA symptom scores but vaginal dryness and irritation were highly significant at the third treatment session (T50). Secondary VVA symptoms (vaginal discharge, dysuria, frequency, urge incontinence, recurrent urinary tract infections); yet, all women informally reported improvement of those secondary symptoms.

Figure 1: Evolution of mean VVA symptom scores for vaginal dryness, irritation, dyspareunia, itching, tenderness/tingling over the 90-day follow-up period.
* p <0.05 vs baseline; ** p <0.01 vs baseline

Table 1 analytically shows the per cent changes for all VVA symptoms over the study period. When questioned, the cohort women almost unanimously reported pain during intercourse as the most fastidious VVA symptom; only a few women reported itching as the most troubling. When considering the delicate area treated by injection, however minimally invasive, the women’s final judgements about general satisfaction and overall comfort and tolerability were satisfactory: 8.3 ± 8.0 and 6.9 ± 7.0, respectively.

Table 1: Per cent improvements of mean scores for the most representative VVA symptoms between the baseline assessment and treatment session (T0) and the last follow-up session (T90).

* p <0.05 vs baseline, ** p <0.01 vs baseline

Figure 2 shows one example of what to expect as aesthetic outcomes on labial atrophy after the five-session PN-HPT^®/HA/mannitol treatment cycle.

Figure 2: Labial aesthetic improvement at the final assessment session (T90, right photograph) compared to baseline (T0, left photograph).

The investigator and treated women consistently deemed the procedure easy with no unexpected technical difficulty, trouble or discomfort. The occasional, mild side effects at the injection site — local pain, oedema, ecchymosis, and erythema — were expected, of no clinical significance, and resolved rapidly. No other complication of the bio-revitalisation protocol occurred during the 90-day study period. Informally questioned over the study period, all women reported at least a good level of satisfaction with the vulvovaginal aesthetic outcomes.

Discussion

After Japan, Italy is the world’s most rapidly ageing country. An Italian epidemiological study of hospital outpatient services revealed an overall VVA prevalence in postmenopausal women of 79-81%, surging from 65% to 85% after, respectively, one and five years after menopause [1,14]. Regarding the phenotypic expressions of postmenopausal vulvar involution — depletion of labia majora adiposity, blundering of interlabial sulci, loss of pigmentation and hair, reduced density of sweat and sebaceous production, preputial retraction with clitoral exposure and chronic irritation, and overall dysfunction of the vaginal ecosystem — the symptoms are a burden on the woman’s self-confidence and self-image. Microscopically, the fragmentation and fusion of elastin fibres, collagen hyalinisation, and extracellular matrix depletion depict the VVA picture [1,14].

The hydrophilic PN-HPT^® polymers reorganise in tissues into a three-dimensional gel that binds water with a moisturising and volume-increasing effect.^7-9 Over the longer term, PN-HPT^® facilitate the production of new collagen fibres—the rationale for exploring the PN-HPT^®/HA option to antagonise the postmenopausal vulvar involution [7-9].

The PN-HPT^® passive action develops by replenishing the fibroblast pool of nitrogen bases, nucleosides, and nucleotide precursors and supporting the dermal fibroblast viability.⁷ PN-HPT^® are more potent on collagen production than hyaluronic acid (Figure 3); however, the two principles synergise in co-formulation [7].

Figure 3: Assessment with transmitted and polarised light and Sirius Red staining for collagen (upper and lower microphotographs, respectively): in the PN-HPT® group, the repair is almost complete with well-organised mature collagen fibres and uniform extracellular matrix (ECM) deposition. Wound healing is incomplete in the hyaluronic acid group, with only sparse collagen fibres and ECM deposition. In contrast, the torpid wound still shows no new collagen fibres and ECM in the control group. Magnification= 4X [7].

Even if rejuvenation was only limited to the vulva, a simple and safe procedure, most cohort women experienced at least some appreciable restructuring of genital connectives and alleviation of atrophy, confirmed by the rapid relief from postmenopausal VVA symptoms afforded by the HPT^®/HA/mannitol device. The first weeks of the follow-up period — until T35 and the two first intradermal injections — saw much of the overall improvement. Statistical significance vs baseline severity was attained between twenty-one and thirty-five days after the baseline session, with T35 scores falling between −40.7% for vaginal drying and −50% for tenderness/tingling compared with score improvements between −57.1% for dyspareunia and −66.7% for itching and tenderness/tingling at T90. These outcomes confirm those already perceived in the first exploratory study on VVA symptoms and a more recent study focused on sexual gratification [10,11]: a much shorter treatment course than that tested in those studies can already lead to excellent VVA symptom outcomes. Confirming the favourable impact on the often markedly disrupted sexual life, a derived study involving a subgroup of 47 women belonging to this study cohort demonstrated a significant improvement in personal sexual gratification and couple relationship with an internationally validated specific assessment instrument, the “Personal Assessment of Intimacy in Relationships” (PAIR) scale [11].

A series of maintenance treatment sessions should follow the suggested treatment course to preserve the VVA symptom and sexual gratification benefits-for instance, one maintenance session every two months or the whole three-session cycle twice yearly, according to how the clinical and morphological pictures might evolve over the following months.

The overall study cohort was not homogeneous regarding the menopause age (cohort range, 45 to 56 years old), meaning that the outcomes may have a universal value for all menopausal women. The lack of a control group is a bias; however, the bias impact may not be so severe because the study outcomes are pretty like those of the first exploratory study in menopausal VVA women treated with vulvar PN-HPT^® injections [10].

The leading study bias is resorting to impromptu non-validated VAS scoring to assess atrophy-related symptoms. Still, the highly favourable outcomes, uniformly consistent for all investigated symptoms, might lessen the bias severity. Unfortunately, no Italian-language validated translation is available for validated English-language tools like the Vulvovaginal Symptoms Questionnaire (VSQ), the Vulvovaginal Atrophy Questionnaire (VVAQ), and similar questionnaires [15-17]. The single-arm design with a lack of controls, even only a no-treatment control group, and the lack of independent evaluators are other limitations of the study.

As a final summary, the study further supports the previously explored HPT^®/HA/mannitol efficacy in restoring vulvar skin quality [18]. This is most likely the biological event underlying the VVA symptom improvement, including the disrupted female sexual life that is by now solidly established [10,11]. However, establishing the comparative effectiveness of HPT^®/HA/mannitol and other anti-VVA options must wait for future, well-designed studies.

Acknowledgements

Mastelli S.r.l., Sanremo, Italy, is the patent holder of the PN-HPT^® technology and the gel formulations of PN-HPT^® injectable polynucleotides used in the study. The authors acknowledge the contribution of Mastelli S.r.l. for supporting the publication costs.

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