Meta-Research: A Poor Research Landscape Hinders the Progression of Knowledge and Treatment of Reproductive Diseases

Reproductive diseases have gone under the radar for many years, resulting in insufficient diagnostics and treatments. Infertility rates are rising, preeclampsia claims over 70 000 maternal and 500 000 neonatal lives globally per year, and endometriosis affects 10% of all reproductive-aged women but is often undiagnosed for many years. Changes in policy have been enacted to mitigate the gender inequality in research investigators and subjects of medical research. However, the disparities in reproductive research advancement still exist. Here, we analyzed the reproductive science research landscape in attempt to quantify the gravity of the current situation. We find that non-reproductive organs are annually researched 5-20 times more than reproductive organs leading to an exponentially increasing relative knowledge gap in reproductive sciences. Additionally, reproductive organs (breast and prostate) are mainly researched when there is a disease-focus, leading to a lack of basic understanding of the reproductive organs. This gap in knowledge affects reproductive syndromes, as well as other bodily systems and research areas, such as cancer biology and regenerative medicine. Action must be taken by current researchers, funding organizations, and educators to combat this longstanding disregard of reproductive science.


INTRODUCTION 41
Biological reproduction is essential to the continuation of a species. Despite the 42 continued growth of the global human population, infertility rates are rising. More critically, 43 adverse pregnancies that include preterm delivery, low birthweight, hypertensive and 44 gestationally diabetic impact the acute and chronic health of the population. In fact, 20% of all 45 pregnancies require medical intervention and in lower resource settings, pregnancy and delivery 46 complications account for over 90% of all maternal and neonatal deaths (WHO, 2019). In 1992, 47 the Institute of Medicine (United States (US)) Committee on Research Capabilities of Academic 48 Departments of Obstetrics and Gynecology published and outlined areas needing improvement, 49 such as low birthweight infants, infertility, and pregnancy-induced hypertension (Townsend, 50 1992). Two decades later, and despite the essential nature and impact of the reproductive system, 51 these issues are still major challenges in reproductive health. 52 Infertility is a global health problem that affects approximately 8-12% of all couples 53 (Inhorn & Patrizio, 2015). The rates of infertility have increased since 1990 and continues to rise 54 in prevalence worldwide (Mascarenhas et al., 2012;Sun H et al., 2019). Beyond emotional 55 complications of infertility, there are real physiological consequences for many people. 56 Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder 57 affecting females of reproductive age, with a prevalence of approximately 8% in the US 58 (Bednarska & Siejka, 2017;Trivax & Azziz, 2007). The various hormonal disturbances in PCOS 59 predispose these individuals to multiple comorbidities, such as cardiovascular disease (CVD), 60 diabetes, and metabolic syndrome. The metabolic disorder has been well-established, with 61 evidence of insulin resistance and hyperinsulinemia in 60-80% of all PCOS patients (Lazaridou 62 et al., 2017). Research in PCOS has focused on managing symptoms, rather than uncovering the 63 underlying pathogenesis to discover more clear diagnostics and targeted treatments. 64 Endometriosis is a disease characterized by the growth of endometrial cells-the lining of the 65 uterus-outside the uterine cavity that affects an estimated 10% of all reproductive-aged women 66 (Chapron et al., 2019;Kiesel & Sourouni, 2019). Endometrial cell growth outside the uterine 67 cavity may result in severe pelvic pain, possible infertility, and intense dysmenorrhea-painful 68 menstruation (Mehedintu et al., 2014). However, cases of endometriosis may present 69 asymptomatically, which contributes to the difficulty in diagnosis and may result in individuals 70 being undiagnosed for 8-12 years ( The research landscape may change over time, and recent increased efforts to remove 118 gender bias in research may improve reproductive research output. We reassessed the 119 publications on the 12 organs as a function of time from the years 1915-2020 (Figure 1.a). 120 Publication rates of all organs are relatively low with a minimal rate of increase until the 1940s. 121 Following the 1940s, the non-reproductive organs display a near-uniform rise in publications 122 until the early 1970s where the publication rates begin to diverge and increase rapidly. 123 Throughout this rise in organ-focused research, the reproductive organs do not follow the same 124 pattern. The majority of reproductive organs examined maintain a very low publication rate 125 Beginning in the 1970s, a war on cancer was initiated by the National Institutes of Health 134 (NIH) and both breast and prostate are organs associated with sex-specific cancers. We 135 research-enriched organs of brain, heart, and liver are 10 times less. While suggestive that many 153 reproductive organs achieve a good balance of basic versus applied research, the paucity of 154 research is highly problematic to the field. 155 156

Comparison of Publication Rates of Diseases by Prevalence 157
As the majority of research grants are awarded though publicly (tax) funded agencies, an 158 assumption is that disease prevalence and impact (quality of life and mortality) might drive 159 research rates. Acute rates of disease are estimated from the yearly new case diagnoses. Research (CIHR) and NIH funding databases were used. The keywords brain, heart, liver, breast, 183 prostate, placenta, and testes were entered into each database and funding data from the years 184 2013-2018 were extracted. Table II (CIHR) and Table III ( CIHR and NIH using pathology keywords as used for publication analyses (Figure 3 and 4)

Overview of Research Landscape 218
Reproductive organ research is substantially less published than other organs. Our 219 hypothesis was that hindrance in research progression specific to female reproductive organs is 220 due to sex bias. Gender inequality and bias has been an issue since the onset of the fields of 221     Basic science research refers to the exploration of gaps in knowledge, whereas applied 256 research refers to findings that can be translated to create a practical diagnostic or treatment. A 257 lack of basic reproductive science research was cited in the 1992 book "Strengthening Research 258 in Academic OB/GYN Departments" (Townsend, 1992). Our analysis indicates that basic 259 research is a focus for reproductive organs with a strong bias away from applied. Therefore, the 260 likely critical problem to the reproductive field is the overall low level of published research 261 relative to other organs (brain, heart and liver). The low body of knowledge represented by the 262 publication record creates a gap in knowledge that hinders and slows discovery of effective 263 diagnostic and treatment options for pathologies such as preeclampsia, PCOS, and 264 endometriosis. A caveat to our approach is that inconsistencies in data reporting challenge the 265 separation of basic and applied research by keywords alone. However, the discrepancies between 266 these different organs are immense and unlikely to be a result of missing search terms. 267 In a competitive funding system, publications are correlated to successful grants and 268 dollar values awarded. Across research areas we found that the mean grant dollar amounts per 269 project are similar. However, reproductive organ focused grants were awarded 2-10-fold fewer 270 projects per year -in-line with observed publication rates (Table 1) Menstruation is one function that has faced stigmatization that persists today (Litman, 2018;289 Pickering, 2019), with women often feeling too embarrassed to talk about this natural process or 290 even complete an essential task, such as purchasing menstrual products at a local store. Political 291 power highly affects reproductive health care and rights over other biological processes. Within 292 many countries, there are ongoing political and legal battles that directly affect access to safe 293 reproductive health care, including contraception, safe abortion, and gender identity rights (Pugh,  The time to act is now as waiting longer will not improve the situation. 363

METHODS 365
Publication Rates 366 Published research manuscripts were searched in NCBI's PubMed database 367 (https://pubmed.ncbi.nlm.nih.gov/) as of January 2021, therefore, the entire year of 2020 was 368 accounted for. Keywords for each search pertained to a specific organ or disease and were 369 limited to the title/abstract of the manuscripts. The organs used for these analyses were brain, 370 heart, brain liver, lung, kidney, breast, prostate, ovary, uterus, penis, and placenta. The organ 371 publication timelines were restricted to the years 1915-2020 and the annual article count was 372 extracted. The organ publication timeline was reconducted with the addition of the search 373 parameter "NOT cancer". The acute and chronic diseases used for this analysis were breast 374 cancer, ovarian cancer, prostate cancer, preeclampsia, PCOS, autism, tuberculosis, Crohn's 375 disease, and lupus. The keywords for these diseases were: "preeclampsia", "polycystic, ovary 376 OR ovarian, AND syndrome", "autism", "tuberculosis", "crohn OR crohn's, AND disease", and 377 "lupus". The number of cancer diagnoses were retrieved from the National Cancer Institute 378 (https://pubmed.ncbi.nlm.nih.gov/) as of January 2021. Two searches were completed for each 387 organ. The first search was the organ in the title/abstract. The second search was the same organ 388 in the title/abstract with the added search parameters "NOT disease, NOT disorder, NOT 389 condition, NOT cancer". The second search retrieved articles that were considered as basic 390 research for this analysis. The second search article count was then subtracted from the first 391 search article count to represent the articles deemed as applied research for this analysis. 392

Funding Rates 394
Grant funding data was obtained from the Canadian Institutes of Health Research funding 395 database (https://webapps.cihr-irsc.gc.ca/funding/Search?p_language=E&p_version=CIHR) and 396 the National Institute of Health's funding reporter database tool (https://reporter.nih.gov). 397 Keywords used for these searches were brain, heart, liver, breast, prostate, placenta, and testes. 398 The years were restricted to 2013-2018. The total number of projects pertaining to each search 399 during this time period was extracted, as well as the total amount of funding for those projects 400 that was then averaged. 401

DATA AVAILABILITY 407
Data underlying this article was extracted from publicly accessible databases. Code used to 408 generate analyses will be made available after reasonable request to the corresponding author.