Adult outcomes of urinary, sexual functions and fertility after pediatric management of differences in sex development: Who should be followed and how?

The management of Differences of Sex Development (DSD) has evolved considerably in recent years. The questioning of systematic early childhood treatment of DSD requires a better understanding of the outcomes of such treatments and long-term studies are therefore essential to better evaluate the prognosis of DSD. Unfortunately, limitations are numerous including the limited size of the series, the absence of standardized methodology, the evaluation of managements that no longer take place today and the absence of prospective and comparative studies. Despite these difficulties, the purpose of this paper is to present the current data on the long-term follow-up of patients with DSD from the urological, sexual and fertility points of view. Even if it remains difficult at present to establish precise recommendations, we recapitulate the most important points that should drive follow-up of these patients especially the constitution of a multidisciplinary team with a holistic approach, the organization of the transition between adolescence and adulthood, a particular attention to psychological care, a careful communication with the patients and his/her family and the use of standardized data collection systems.

The importance of animal specificity in animal experimentation, part I: Anatomy in relation to pediatric urology.

Why and when is animal experimentation relevant? The answer to this question depends on the research question. In this short educational article we aim to raise awareness of the importance of formulating a very specific research question before choosing an animal species. An awareness of anatomical and physiological differences vis-a-vis similarities between species, will increase the potential for obtaining data that is relevant for translation to human conditions.

The importance of animal specificity in animal experimentation, part II: Physiological challenges and opportunities in relation to pediatric urology.

When performing animal experimentation in Pediatric Urology studies, it is important to be aware of physiological differences between species and to understand when relevant disease models are available. Diseased animal models may be more relevant in many cases, rather than performing studies in healthy and normally developed animals. For example, they may be more appropriate for the study of congenital malformations, to investigate the secondary effects of prenatal urinary obstruction, to study the effect of prenatal exposure to endogenous or exogenous factors which may lead to disease, or in testing bioengineered structures. In this short educational article, we aim to describe some disease models that have been used to simulate human pathologies and how, if properly designed, these studies can lead to important new knowledge for human translation. In addition, we also highlight the importance of formulating a research question(s) before deciding on the animal experimental model and species to choose.

COVID-19 lockdown related to decrease in premature birth rate and increase in birth weight in metropolitan France.

Introduction: The worldwide rate of preterm birth (PTB) has been increasing over the last two decades. COVID-19 lockdowns provide a unique opportunity to assess the effects of socioenvironmental and lifestyle factors on premature birth and birth weight. We explored the effects of COVID-19 lockdowns on the PTB rate and birth weight at a nationwide scale in France until one year after their occurrence. Material and Methods: This national retrospective observational study evaluated the rate of PTB and birth weight in France from January 2016 to December 2020. Data were obtained from the national Programme Médicalisé des Systèmes d'Information database. The rates of global and sub-categories of PTB were tested. The birth weight was studied before and after lockdown for all live births, for term and premature neonates, and for each category of low birth weight (LBW) by a stratified analysis. Results: Data from 2,949,372 births from January 2016 to December 2019, including 228,857 PTB, were compared to those of 699,344 births and 51,886 PTB from January to December 2020. The national rate of PTB decreased significantly from 7.7% to 7.3%, when compared with the 2016-2019 period. This decrease was persistent up to 9 months later. It was observed only for moderate PTB, whereas very PTB and extremely PTB remained stable. The national mean birth weight for full-term babies increased after the lockdown and was still observable up to 8 months later (+0.16%, p < 0.0001). The proportion of children with LBW also decreased 2 months after lockdown (-0.15%; p = 0.02). For VLBW, the difference only appeared over the 6-month post-lockdown period (-0.06%; p = 0.006). Conclusion: This nationwide study shows a significant reduction in prematurity and a significant increase in birth weight in France after the lockdown for a period of time not limited to the lockdown itself. A more in-depth study of the factors determining these variations may help to drive PTB prevention policies.

Birth Outcomes in DES Children and Grandchildren: A Multigenerational National Cohort Study on Informative Families.

OBJECTIVE: Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause permanent adverse health effects in the exposed mothers, their children (exposed in utero), and also their grandchildren through germline contribution to the zygote. This study evaluated pregnancy duration and birthweight (BW) variations in the children and grandchildren born before, during, and after maternal DES treatment in the same informative families, to rule out genetic, endocrine, and environmental factors. DESIGN AND SETTING: Nationwide retrospective observational study on 529 families of DES-treated women registered at the HHORAGES-France Association. The inclusion criteria were: (i) women with at least three pregnancies and three viable children among whom the first was not exposed in utero to DES, followed by one or more children with fetal exposure to DES, and then by one or more children born after DES treatment; (ii) women with at least one pre-DES or post-DES grandchild and one DES grandchild; (iii) confirmed data on total DES dose. Women with severe pathologies or whose illness status, habitat, lifestyle habits, profession, treatment changed between pregnancies, and all mothers who reported pregnancy-related problems, were excluded. RESULTS: In all, 74 women met all criteria. The preterm birth (PTB) rate was 2.7% in pre-DES, 14.9% in DES, and 10.8% in post-DES children (Cochran-Armitage test for trend, p = 0.0095). The mean BW was higher in DES than pre-DES full-term neonates (≥37 weeks of gestation) (p = 0.007). In grandchildren, BW was not different, whereas the PTB and low BW rates were slightly increased in children of DES women. CONCLUSIONS: These data within the same informative families show the DES impact on BW and PTB in DES and post-DES children and grandchildren. In particular, mean BW was higher in DES than pre-DES full-term neonates. This result may be in opposition to previous data from American cohorts, which reported lower BW in DES children, but is consistent with animal study. Our retrospective observational study highlights a multigenerational and likely transgenerational effect of this EDC in humans.

Endoscopic injection of bulking agents in pediatric vesicoureteral reflux: a narrative review of the literature.

In the last 20 years, endoscopic injection (EI) has affirmed as a valid alternative to open surgery for management of pediatric vesicoureteral reflux (VUR). This study aimed to investigate and discuss some debated aspects such as indications, bulking agents and comparison, techniques of injection and comparison, predictive factors of success, use in specific situations. EI is minimally invasive, well accepted by patients and families, with short learning curve and low-morbidity profile. It provides reflux resolution rates approaching those of open reimplantation, ranging from 69 to 100%. Obviously, the success rate may be influenced by several factors. Recently, it is adopted as first-line therapy also in high grade reflux or complex anatomy such as duplex, bladder diverticula, ectopic ureters. The two most used materials for injection are Deflux and Vantris. The first is absorbable, easier to inject, has lower risk of obstruction, but can lose efficacy over time. The second is non-absorbable, more difficult to inject, has higher risk of obstruction, but it is potentially more durable. The two main techniques are STING and HIT. To date, the ideal material and technique of injection has not yet clearly established, but the choice remains dependent on surgeon's preference and experience.

Changes in the clinical management of 5α-reductase type 2 and 17ß-hydroxysteroid dehydrogenase type 3 deficiencies in France.

Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17ß-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994-2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients' age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0-53.2) years for patients born before 2007 and 0.4 (0-9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

Outcome of long gap esophageal atresia at 6 years: A prospective case control cohort study.

BACKGROUND DATA: EA is the most frequent congenital esophageal malformation. Long gap EA remains a therapeutic challenge for pediatric surgeons. A case case-control prospective study from a multi-institutional national French data base was performed to assess the outcome, at age of 1 and 6 years, of long gap esophageal atresia (EA) compared with non-long gap EA/tracheo-esophageal fistula (TEF). The secondary aim was to assess whether initial treatment (delayed primary anastomosis of native esophagus vs. esophageal replacement) influenced mortality and morbidity at ages 1 and 6 years. METHODS: A multicentric population-based prospective study was performed and included all patients who underwent EA surgery in France from January 1, 2008 to December 31, 2010. A comparative study was performed with non-long gap EA/TEF patients. Morbidity at birth, 1 year, and 6 years was assessed. RESULTS: Thirty-one patients with long gap EA were compared with 62 non-long gap EA/TEF patients. At age 1 year, the long gap EA group had longer parenteral nutrition support and longer hospital stay and were significantly more likely to have complications both early post-operatively and before age 1 year compared with the non-long gap EA/TEF group. At 6 years, digestive complications were more frequent in long gap compared to non-long gap EA/TEF patients. Tracheomalacia was the only respiratory complication that differed between the groups. Spine deformation was less frequent in the long gap group. There were no differences between conservative and replacement groups at ages 1 and 6 years except feeding difficulties that were more common in the native esophagus group. CONCLUSIONS: Long gap strongly influenced digestive morbidity at age 6 years.

Long-Term Functional Outcomes of an Anorectal Malformation French National Cohort.

OBJECTIVES: The present study aimed to assess long-term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France. METHODS: Retrospective cross-sectional study of patients ages 6-30 years that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups. RESULTS: Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR] = 1.84 [1.31-2.57], P < 0.001), or soiling (OR = 1.72 [1.31-2.25], P < 0.001), which was also associated with the inability to discriminate between stool and gas (OR = 2.45 [1.28-4.67], P = 0.007) and the presence of constipation (OR = 2.97 [1.74-5.08], P < 0.001). Risk factors for constipation were sacral abnormalities [OR = 2.26 [1.23-4.25], P = 0.01) and surgical procedures without an abdominal approach (OR = 2.98 [1.29-6.87], P = 0.01). Only the holding of voluntary bowel movements and soiling rates improved with age. CONCLUSION: This cross-sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long-term follow-up of all patients to help them with supportive care.

How the First Year of COVID-19 Affected Elective Pediatric Urology Patients: A Longitudinal Study Based on Waiting Lists and Surveys From 10 European Centers.

Introduction: COVID-19 impacted healthcare systems worldwide, and elective surgical activity was brought to a minimum. Although children were not primarily affected by the disease, pediatric urology was halted by clinical closedown and staff allocation. We aimed to document how these prioritizations affected waiting lists, and to investigate how European centers dealt with the challenge of these logistical and financial prioritizations. Materials and Methods: This was a 1-year prospective study, starting March 2020. Participants were surveyed at 3-month intervals about waiting lists for several common procedures as well as OR capacity and funding. Further, centers retrospectively reported on surgical and outpatient activity rates during 2019-2021. Waiting list tendencies were evaluated in relation to study baseline. Results: A marked decrease in surgical and outpatient activity was seen in the spring of 2020. Some included pediatric urology centers were able to increase their budget (15%) and staff working hours (20%) during part of the study period. Still, at the end of the study, the centers had increased the total number of patients on waiting lists with 11%, whereas the average days on waiting lists had accumulated with 73%, yielding a total of 6,102 accumulated waiting days in the study population. Centers with decreased resources had markedly negative effects on waiting lists. Conclusions: Correlations between COVID-19 derived burdening of healthcare systems and the availability of pediatric urology greatly depends on the prioritizations made at individual centers. Ongoing monitoring of these correlations is warranted to safely avoid unnecessary negative impact on the pediatric population.

Genetics: The diagnostic frontier in pediatric urology.

In the course of human history few scientific breakthroughs can rival the importance of the discovery of DNA. Our ever increasing ability to unravel the secrets contained in this molecule allow new insight in to the etiology and eventual treatment of human conditions ranging from congenital structural disorders to cancer. It is the focus of this article to touch upon sequencing technologies and their potential to provide information that can revolutionize healthcare.

Prenatal Exposure to Diethylstilbestrol and Multigenerational Psychiatric Disorders: An Informative Family.

BACKGROUND: Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders. CASE PRESENTATION: We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; n = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities. CONCLUSIONS: To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.

Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health.

Previous studies have demonstrated that endocrine disruptors (EDs) can promote the transgenerational inheritance of disease susceptibility. Among the many existing EDs, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) affects reproductive health, including in humans, following direct occupational exposure or environmental disasters, for instance the Agent Orange sprayed during the Vietnam War. Conversely, few studies have focused on TCDD multigenerational and transgenerational effects on human reproductive health, despite the high amount of evidence in animal models of such effects on male and female reproductive health that mimic human reproductive system disorders. Importantly, these studies show that paternal ancestral TCDD exposure substantially contributes to pregnancy outcome and fetal health, although pregnancy outcome is considered tightly related to the woman's health. In this work, we conducted a systematic review of the literature and a knowledge synthesis in order (i) to describe the findings obtained in rodent models concerning TCDD transgenerational effects on reproductive health and (ii) to discuss the epigenetic molecular alterations that might be involved in this process. As ancestral toxicant exposure cannot be changed in humans, identifying the crucial reproductive functions that are negatively affected by such exposure may help clinicians to preserve male and female fertility and to avoid adverse pregnancy outcomes.

Endocrine-Disrupting Chemicals and Disorders of Penile Development in Humans.

This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health.

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

BACKGROUND: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease. CASE PRESENTATION: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery. CONCLUSIONS: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.

Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo-obstruction syndrome.

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.