Rectal versus intravenous administration of acetaminophen; Clinical investigation of plasma level, analgesic, and antipyretic effects on 6-month to 6-year-old children in Zabol city, Iran.

OBJECTIVES: Acetaminophen is the most widely antipyretic analgesic medicine used in adults and children worldwide. Rectal acetaminophen is widely used in children who resist or cannot take oral medications. This study was designed to compare the efficacy of rectal and IV acetaminophen in children with fever and mild to moderate pain. PATIENTS AND METHODS: Total 60 children aged six months to 6 years, with fever and pain, that were treated with rectal or intravenous acetaminophen were selected and assigned in two groups. The IV group received 10mg/kg paracetamol as an IV infusion, and the rectal group received a 15mg/kg dose immediately after admission. Pain score was calculated using the FLACC method, and the axillary temperature was recorded at baseline and then 0.5, 1, 2, 4, and 6hours after drug administration. Blood samples were collected at baseline and then at 30min-intervals for the first 90minutes. RESULTS: The trend of changes in mean pain score at different time intervals was significantly different between the two groups. Body temperature decrease was more prominent in the IV group. The plasma concentration increased in both groups significantly with time. This increase was sharper in the IV group, just in the first 60minutes after drug administration. CONCLUSIONS: IV acetaminophen has more rapid onset of action, while rectal dosage form control fever and pain for longer duration. Considering its favorable effects with ease of administration and lower cost, rectal acetaminophen can be a reasonable option in selected patients with pain or fever.

Recognizing the roles of fever in host survival and in medical intervention in infectious diseases.

Fever has roles both in host defense against infectious challenges and in guidance of medical intervention. These roles remain insufficiently acknowledged and considered by both health care providers and patients and their families. This review cites reports in support of both roles and provides recommendations regarding the clinician's approach to fever, as well as points relevant for education of patients and their families.

The information seeking behaviors of caregivers in the management of childhood fever - A systematic literature review.

INTRODUCTION: Parents' and caregivers' non-evidence-based childhood fever management 'fever phobic' practices have remained relatively stable over more than 34 years despite successful educational interventions. This systematic review aimed to assess the information seeking behavior of caregivers managing fever in their children, as well as to compile the fever management practices undertaken by caregivers by investigating underlying factors influencing them. METHODS: The electronic databases Pubmed, CINAHL, Medline, and International Pharmaceutical Abstracts were searched using key terms including, fever, child, caregiver, and management. Studies were included if they were written in English, published between January 1980 and January 2021, explored generalized childhood fever management practices of caregivers, and factors which influence fever management. Data extracted included study year and design, location, dimensions of fever management explored (i.e., knowledge, beliefs, detection, and/or treatment of fever), factors influencing management, and information sources used by caregivers. RESULTS: In total, 36 studies were eligible for inclusion in the study. Twenty-nine of the studies were designed as a cross-sectional survey, six studies were interviews and the remainder were pre-post studies. The review of studies found that parents and caregivers sourced childhood fever management information most commonly from friends and family or their own personal experiences, however, participants most commonly sourced doctors/general practitioners as their first line of information when required. Over the years, trends showed that doctors as well as the internet were more frequently being used as a first line source of information by caregivers. CONCLUSIONS: Despite decades of research, education and development of evidence-based guidelines caregivers continue to exhibit 'fever phobia' when caring for febrile children. This is demonstrated by their continued use of non-evidence-based methods and increasing reliance on, and incorrect use of antipyretics, alternating antipyretics if fever is not sufficiently reduced or returns. There is an increasing need for the development of easy to access digital resources for caregiver as internet use is rising which mirrors best practice taught to professionals.

Clinical experience with bromocriptine for central hyperthermia after brain insult.

INTRODUCTION: Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. METHODS: A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. RESULTS: Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of -0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. CONCLUSION: Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events.

Antipyretic Use in Noncritically Ill Patients With Fever: A Review.

Antipyretics are one of the most frequently used agents in medicine. Numerous pharmacological agents, such as acetaminophen, non-steroidal anti-inflammatory agents (NSAIDs), salicylates, and selective cyclooxygenase 2 (COX-2) inhibitors, and nonpharmacological treatment modalities, such as tepid sponging and cooling blankets, are available for temperature reduction. There is a scarcity of definitive clinical guidelines on the choice of various agents in noncritically ill febrile patients. Our review examined the various modalities available for antipyresis and compared their safety and efficacy. The rationale for the choice of a particular pharmacological agent and route of administration were scrutinized. Our review also envisaged the perceived beneficial effects of antipyretics against the harmful side effects, including the evaluation of morbidity or mortality advantage conferred by antipyretics. The various toxicities associated with these agents were also highlighted.

Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Association between use of antipyretics and antibody titers after two doses of the BNT162b2 SARS-CoV-2 vaccine in adolescents and young adults with underlying diseases.

There are few reports on the association between antipyretic use and antibody titers in adolescents and young adults following SARS-CoV-2 vaccination. Multivariable linear regression analyses were performed to examine the association between antipyretic use and antibody titers. The use of antipyretics was not associated with antibody titers (ß coefficient [95% CI] = -0.107 [-0.438 to 0.224]).

Temperature control in sepsis.

Fever can be viewed as an adaptive response to infection. Temperature control in sepsis is aimed at preventing potential harms associated with high temperature (tachycardia, vasodilation, electrolyte and water loss) and therapeutic hypothermia may be aimed at slowing metabolic activities and protecting organs from inflammation. Although high fever (>39.5°C) control is usually performed in critically ill patients, available cohorts and randomized controlled trials do not support its use to improve sepsis prognosis. Finally, both spontaneous and therapeutic hypothermia are associated with poor outcomes in sepsis.

Current State of Knowledge on the Definition, Pathophysiology, Etiology, Outcomes, and Management of Fever in the Intensive Care Unit.

Fever-an elevated body temperature-is a prominent feature of a wide range of disease conditions and is a common finding in intensive care, affecting up to 70% of patients in the intensive care unit (ICU). The causes of fever in the ICU are multifactorial, and it can be due to a number of infective and noninfective etiologies. The production of fever represents a complex physiological, adaptive host response that is beneficial for host defense and survival but can be maladaptive and harmful if left unabated. Despite any cause, fever is associated with a wide range of cellular, local, and systemic effects, including multiorgan dysfunction, systemic inflammation, poor neurological recovery, and an increased risk of mortality. This narrative review presents the current state-of-the-art knowledge on the definition, pathophysiology, etiology, and outcomes of fever in the ICU and highlights evidence-based findings regarding the management of fever in the intensive care setting.

Acetaminophen: A Liver Killer or Thriller.

Acetaminophen, or paracetamol, ranks among the most extensively utilized analgesic and antipyretic medications globally. The administration of acetaminophen to individuals with underlying liver disease has long sparked concerns regarding the potential risk of hepatotoxicity. However, the available literature and recommendations consider it a safe option in all forms of liver diseases and is deemed safe when used at recommended doses. This article aims to offer a concise review of the pharmacokinetics, toxicity profile, and the intricate considerations surrounding the safety of acetaminophen in patients with liver disease. By delving into the liver-acetaminophen interactions, we seek to provide a nuanced perspective on the use of acetaminophen in this critical patient population.

Knowledge, attitudes, and practices toward over-the-counter antipyretics among fever patients: a cross-sectional study in the context of a policy change KAP of OTC antipyretics.

Background: On January 8, 2023, a change in the control policy for COVID-19 was implemented in China, whereby patient self-management of fever typically entails the utilization of over-the-counter fever-reducing medications. Objective: This study aimed to investigate the knowledge, attitudes, and practices (KAP) toward over-the-counter (OTC) antipyretics among fever patients. Methods: This cross-sectional study was conducted between October 2022 and February 2023 at author's hospital in Wuhan, China, among fever patients on OTC antipyretics, using a self-administered questionnaire. Results: A total of 481 valid questionnaires were collected, with the age of 36.05 ± 12.10 years, including 240 (49.90%) males, and 209 (43.45%) collected before policy change. The knowledge, attitudes, precautions for medication administration and decision-making practices scores were 6.86 ± 3.30 (possible range: 0-12), 16.67 ± 2.46 (possible range: 7-35), 29.98 ± 5.41 (possible range: 7-35) and 27.87 ± 1.28 (possible range: 8-40), respectively. The multivariable logistic regression analysis showed that knowledge (OR = 0.83, 95%CI: 0.81-0.92, p < 0.001) was independently associated with positive attitude. Knowledge (OR = 1.41, 95%CI: 1.28-1.56, p < 0.001), attitude (OR = 0.87, 95%CI: 0.79-0.95, p = 0.004), suburban (OR = 0.45, 95%CI: 0.23-0.88, p = 0.019) were independently associated with proactive precautions for medication administration practices. Knowledge (OR = 1.14, 95%CI: 1.07-1.22, p < 0.001), attitude (OR = 0.90, 95%CI: 0.82-0.98, p = 0.018), responding after policy change, 2023 (OR = 1.70, 95%CI: 1.10-2.63, p = 0.016) were independently associated with proactive decision making practices. Conclusion: Fever patients had moderate knowledge, negative attitude, proactive precautions for medication administration practices, moderate decision-making practices. After the policy change, there was a significant increase in knowledge regarding medication administration precautions and decision-making.

Does the use of antipyretics prolong illness? A systematic review of the literature and meta-analysis on the effects of antipyretics in acute upper and lower respiratory tract infections.

OBJECTIVE: Fever contributes to the inflammatory response; in some infections, antipyretics could prolong the illness. The objective of our study was to evaluate the impact of antipyretic treatments on the evolution of acute upper and lower respiratory tract infections (RTI). METHOD: A systematic literature review of randomized controlled trials (RCTs) with meta-analysis was conducted. Our primary endpoint was the time to recovery from illness. Our prespecified secondary endpoints were quality of life, duration and number of fever episodes, repeated medical visits, and adverse events. RESULTS: Out of the 1466 references found, 25 RCTs were included. There were two studies assessing mean fever clearance time, and five studies examining the duration of symptoms associated with the illness studied. No statistically significant differences were found when pooling the results of the different studies. The assessment of adverse events showed a significant difference disadvantaging non-steroidal anti-inflammatory drugs. No meta-analysis could be performed for our other secondary endpoints. The quality of the evidence is limited by the small number of studies included for our primary endpoint and by heterogeneity between the studies. CONCLUSION: Our results suggest that the use of antipyretics does not prolong or shorten illness duration in acute upper and lower RTI. The symptomatic efficacy of antipyretics must be weighed against their adverse effects, particularly when fever is well-tolerated.

Effectiveness of Traditional Chinese Medicine on coronavirus disease 2019 in 92 patients: a retrospective study.

OBJECTIVE: To investigate the antipyretic effect of early treatment with Traditional Chinese Medicine (TCM) on coronavirus disease 2019 (COVID-19) patients. METHODS: We retrospectively analyzed 369 patients from January 26th, 2020 to April 15th, 2020, who had been diagnosed with COVID-19. Among 92 eligible cases, 45 cases were identified as treatment group Ⅰ ( 45) and 47 cases were identified as treatment group Ⅱ. Patients in the treatment group Ⅰ were treated with TCM herbal decoction within 5 d after admission. Patients in the treatment group Ⅱ were treated with TCM herbal decoction after the 6th admission day. The onset time of antipyretic effect, the antipyretic time, the time of negative oropharyngeal swab nucleic acid conversion, and the changes of cell count in blood routine test were compared. RESULTS: The treatment group I showed shorter average antipyretic duration (4 7 d; <0.05), and shorter average time for polymerase chain reaction (PCR) nucleic acid test results to turn negative (7 11 d; <0.05) than the treatment group II. For patients ( 54) with body temperature>38 ℃, patients in the treatment group I had shorter median onset time of antipyretic effect than those in the treatment group II (3 4 d; <0.05). The absolute lymphocyte (LYMPH) count and absolute eosinophil (EOS) count on the 3rd day after admission and the neutrophil/lymphocyte ratio on the 6th day after admission of patients in the treatment group I were notably different from those in the treatment group II at the same time point (0.05). Based on Spearman's rank correlation analysis, the change of body temperature on the 3rd day after admission was positively correlated with the increase of EOS count and the increase of EOS count and LYMPH counts on the 6th day after admission (0.01). CONCLUSIONS: Early TCM intervention within 5 d after hospital admission shortened the onset time of antipyretic effect and fever duration of COVID-19 patients, reduced the time required for PCR test results to turn negative. Moreover, early TCM intervention also improved the results of inflammatory markers for COVID-19 patients. LYMPH and EOS counts can be used as indicators of TCM antipyretic effect.

Heart rate and respiratory rate in predicting risk of serious bacterial infection in febrile children given antipyretics: prospective observational study.

Clinical algorithms used in the assessment of febrile children in the Paediatric Emergency Departments are commonly based on threshold values for vital signs, which in children with fever are often outside the normal range. Our aim was to assess the diagnostic value of heart and respiratory rate for serious bacterial infection (SBI) in children after temperature lowering following administration of antipyretics. A prospective cohort of children presenting with fever between June 2014 and March 2015 at the Paediatric Emergency Department of a large teaching hospital in London, UK, was performed. Seven hundred forty children aged 1 month-16 years presenting with a fever and ≥ 1 warning signs of SBI given antipyretics were included. Tachycardia or tachypnoea were defined by different threshold values: (a) APLS threshold values, (b) age-specific and temperature-adjusted centiles charts and (c) relative difference in z-score. SBI was defined by a composite reference standard (cultures from a sterile site, microbiology and virology results, radiological abnormalities, expert panel). Persistent tachypnoea after body temperature lowering was an important predictor of SBI (OR 1.92, 95% CI 1.15, 3.30). This effect was only observed for pneumonia but not other SBIs. Threshold values for tachypnoea > 97th centile at repeat measurement achieved high specificity (0.95 (0.93, 0.96)) and positive likelihood ratios (LR + 3.25 (1.73, 6.11)) and may be useful for ruling in SBI, specifically pneumonia. Persistent tachycardia was not an independent predictor of SBI and had limited value as a diagnostic test.  Conclusion: Among children given antipyretics, tachypnoea at repeat measurement had some value in predicting SBI and was useful to rule in pneumonia. The diagnostic value of tachycardia was poor. Overreliance on heart rate as a diagnostic feature following body temperature lowering may not be justified to facilitate safe discharge. What is Known: • Abnormal vital signs at triage have limited value as a diagnostic test to identify children with SBI, and fever alters the specificity of commonly used threshold values for vital signs. • The observed temperature response after antipyretics is not a clinically useful indicator to differentiate the cause of febrile illness. What is New: • Persistent tachycardia following reduction in body temperature was not associated with an increased risk of SBI and of poor value as a diagnostic test, whilst persistent tachypnoea may indicate the presence of pneumonia.

Trends in pediatric nonprescription analgesic/antipyretic exposures during the COVID-19 pandemic.

OBJECTIVE: To examine pediatric exposure trends involving selected nonprescription analgesics/antipyretics, before and during the COVID-19 pandemic. METHODS: Using descriptive and interrupted time-series analyses, we assessed monthly United States poison center data involving pediatric (<18 years) exposures to nonprescription paracetamol (acetaminophen), ibuprofen, acetylsalicylic acid, and naproxen before (January 2015-February 2020) and during (March 2020-April 2021) the pandemic. Statins and proton pump inhibitors (prescription or nonprescription) served as controls. RESULTS: Most nonprescription analgesic/antipyretic exposures (75-90%) were single-substance; unintentional exposures typically involved children <6 years (84-92%), while intentional exposures involved females (82-85%) and adolescents, 13-17 years (91-93%). Unintentional exposures among children <6 years, declined for all four analgesics/antipyretics immediately after the World Health Organization declared COVID-19 a pandemic (March 11, 2020), but most significantly for ibuprofen (30-39%). Most intentional exposures were classified as suspected suicide. Intentional exposures were relatively low and stable among males. Intentional exposures in females declined immediately after the pandemic was announced but subsequently increased to pre-pandemic levels for acetylsalicylic acid and naproxen and above pre-pandemic levels for paracetamol and ibuprofen. For paracetamol, female intentional exposures increased from 513 average monthly cases in the pre-pandemic to 641 average monthly cases during the pandemic; and reached 888 cases by the end of the study period in April 2021. While for ibuprofen, average monthly cases rose from 194 in the pre-pandemic, to 223 during the pandemic; and reached 352 cases in April 2021. Patterns were similar among females 6-12 and 13-17 years. CONCLUSION: Nonprescription analgesic/antipyretic unintentional exposure cases declined among young children, while intentional exposure cases increased among females, 6-17 years, during the pandemic. Findings highlight the importance of safely storing medications and being alert to signs that adolescents may be in need of mental health support services; caregivers should seek medical care or call poison control centers for any suspected poisoning event.

The Three W's of Acetaminophen In Children: Who, Why, and Which Administration Mode.

Acetaminophen is one of the oldest medications commonly administered in children. Its efficacy in treating fever and pain is well accepted among clinicians. However, the available evidence supporting the use of acetaminophen's different modes of administration remains relatively scarce and poorly known. This short report summarizes the available evidence and provides a framework to guide clinicians regarding a rational use of acetaminophen in children.

Adverse drugs reactions to paracetamol and ibuprofen in children: a 5-year report from a pediatric poison control center in Italy.

BACKGROUND: This study aimed to analyze all the patients who contacted the hospital's pediatric poison control center (PPCC) for exposure to ibuprofen and acetaminophen, in order to assess the incidence of any adverse reactions. METHODS: We retrospectively reported the clinical data of children who accessed the PPCC of the Bambino Gesù Children's Hospital, IRCCS, Rome, from January 1, 2018 to September 30, 2022 due to wrong, accidental or intentional intake of inappropriate doses of acetaminophen and/or ibuprofen. In addition, we compared patients according to the intake of one of the two drugs and reported the trimestral distribution of cases during the study period. RESULTS: A total of 351 patients accessed the PPCC during the study period. The median age was 3.0 years. Most patients were females (57.8%). The most common reason for inappropriate oral intake of paracetamol or ibuprofen was a wrong use or an accidental intake (78.6%), with a fifth of patients taking the drug with suicidal intent (21.1%). According to the PPCC evaluation, most patients were not intoxicated (70.4%). Hospitalization was required for 30.5% of patients. Adverse reactions were reported in 10.5% of cases, with a similar incidence in patients who took paracetamol or ibuprofen. Nausea and vomiting were the most commonly reported adverse reactions. A higher frequency of moderate intoxication was found in patients who took paracetamol compared to ibuprofen (p = 0.001). The likelihood of intoxication was also higher in the paracetamol cohort. A spike of cases was registered at the end of 2021. CONCLUSIONS: We analyze exposures to the two most commonly used pediatric molecules, paracetamol and ibuprofen, to assess the frequency of adverse reactions. We demonstrated that these relatively "safe" drugs may be associated with intoxications and adverse reactions when inappropriately administered.

Resolution of Fever in the Pediatric Emergency Department and Bacteremia.

To determine whether a lack of response to antipyretics was associated with bacteremia, we performed a cross-sectional study involving children with an initial temperature ≥38°C presenting to a pediatric emergency department (ED) from 2012 to 2020 who received an antipyretic and had a blood culture obtained. We assessed the association of resolution of fever at specific time points after antipyretic administration with bacteremia adjusting for age, complex chronic condition, blood culture source, type of antipyretic, and height of temperature. Among 6319 febrile children, 242 (3.8%) had bacteremia. The adjusted odds ratio of bacteremia was 1.6 (95% confidence interval: 1.2-2.2) among children who remained febrile at 180 minutes and 1.7 (1.2-2.4) among children who remained febrile at 240 minutes. Among febrile children presenting to a tertiary care ED for whom a blood culture was obtained, the response to an antipyretic varies based on the presence or absence of bacteremia.

Maternal fever during pregnancy and male offspring reproductive health: A longitudinal cohort study in young Danish males.

BACKGROUND: Maternal fever during pregnancy has been associated with an increased risk of genital malformations, but the implication for long-term reproductive health in the offspring is unknown. OBJECTIVES: To investigate associations between timing, duration, and temperature of fetal exposure to maternal fever and sons' semen quality, testicular volume, and levels of reproductive hormones in early adulthood. Further, to examine whether concurrent use of antipyretics and/or antibiotics modified the effect. MATERIALS AND METHODS: We used the Fetal Programming of Semen Quality cohort consisting of men born to women enrolled in the Danish National Birth Cohort. Self-reported information on maternal fever was collected twice during pregnancy (median 16 and 31 pregnancy weeks) and categorized as any fever during pregnancy, fever during early pregnancy (weeks 1-15), and fever exclusively during late pregnancy (weeks 16-42). Semen quality and concentrations of reproductive hormones were measured at a clinical examination at the age of 18.9 years. We used negative binomial regression to examine the associations, adjusting for maternal age at birth, maternal smoking, family occupational status, and precision variables related to semen quality and hormonal levels, for example, abstinence time. RESULTS: 986 men were included in the study, of which 23% had mothers reporting at least one episode of fever. We found no strong indications of associations between maternal fever during pregnancy and male reproductive health in young men. Concurrent use of antipyretics and antibiotics did not modify the association. DISCUSSION: Strengths include the large sample size, prospectively collected data, and the adjustment for maternal factors during pregnancy and important precision variables. A limitation is the crude self-reported information on maternal fever. CONCLUSION: We found no evidence to support that timing, duration, or temperature of maternal fever during pregnancy has a long-term impact on semen characteristics, testicular volume, or level of reproductive hormones in male offspring.