Sex & Gender in Acute Care Medicine

1. Sex & Gender in Acute Care Medicine Chapter 13B: Pediatrics

2. Chapter 13B: Special Populations – Gender in Pediatrics Therese L. Canares Marleny Franco George M. Lazarus

3. Chapter Introduction • There are many physiologic differences between boys and girls during development • The following cases illustrate acute pediatric conditions in which sex affects pathophysiology, differential diagnosis, evaluation or management • These cases do not delineate all of the sex differences impacting clinical pediatrics

4. Case 1 • 11-month-old female presents with 3 days of fever to 39.1°C • Review of symptoms positive only for rhinorrhea • Heart rate: 130 bpm, resp. rate: 30, blood pressure: 100/70, O2 saturation: 99%, rectal temperature: 103.1°F • She cries but is consolable; exam otherwise unremarkable

5. Introduction • Fever without a source (FWS) is a common pediatric complaint • FWS is defined as fever not associated with signs or symptoms indicating a diagnosis • Infants with FWS are at risk for bacterial illness, including UTI, bacteremia, and meningitis • Risk factors for UTI are sex-specific

6. Prevalence and Risk Factors for UTI • The following discussion will be applicable to infants 3-24 months of age • UTI prevalence in all febrile infants with no source of fever is 5% • The prevalence in girls (6.5%) is almost twice that seen in boys (3.3%) with a relative risk of 2.27 (Baraff 2008)

7. UTI in Girls • One group of investigators found that the most sensitive predictors of UTI in girls > 24 months were: • White race • Age < 12 months • Fever > 39°C • Fever > 2 days • Absence of other source of fever • These risk factors have been validated as a screening tool (Subcommittee on UTI, 2011)

8. UTI in Girls • Behavioral factors also affect girls’ risk for UTI • A study of girls ages 5-17 identified independent risk factors for recurrent UTI, including: • Abnormal voiding frequency • Voiding postponement • Functional stool retention • Poor fluid intake

9. UTI in Boys • Age and circumcision affect boys’ risk of UTI • In children of all ages, uncircumcised, febrile males < 3 months had the highest prevalence of UTI of any group, male or female (Hansson, et al., 1999) • A meta-analysis found that the prevalence of UTI in uncircumcised vs. circumcised male infants was 20.1% vs. 2.4% (Shaikh et al., 2008)

10. UTI in Boys • Some of the anatomical differences that decrease risk of UTI in boys (and men) include: • the increased distance between the anus and the urethral meatus • the drier environment surrounding the meatus • the increased length of the urethra • the antibacterial activity of prostatic fluid

11. Reflux • Vesicoureteral Reflux (VUR) is an important risk factor for UTI, although it is not often detected until the patient’s first UTI • VUR is more prevalent in girls than boys with first UTI • This difference extends beyond infancy • Posterior Urethral Valves (PUR) are a common cause of VUR in boys and a risk factor for UTI

12. Diagnosis of UTI

13. Diagnosis of UTI • The AAP found robust evidence for obtaining sterile urine culture by catheterization or suprapubic aspiration before starting antibiotics in girls and boys with FWS • To diagnose UTI, urinalysis should demonstrate pyuria or bacteriuria • Urine culture should grow at least 50,000 singlespecies bacterial cfu/mL

14. Diagnosis of UTI Table 2. Probability of UTI in infants with FWS

15. Diagnosis of UTI • The most common pathogens causing UTI are: E. coli, Proteus, Klebsiella, Enterobacter, Pseudomonas, and Enterococcus • One study found a higher prevalence of E. Coli in girls than in boys (Edlinet al., 2013) • A number of virulence factors of E. Coli strains have been identified with differing prevalence in boys and girls

16. Management of UTI • Parenteral vs. enteral antibiotic treatment depends on clinical judgment • The AAP recommends a 7-14 day course of treatment over a single dose • Current evidence recommends a uniform approach to treatment in boys and girls

17. Complications and Post-ED Care • The rate of complication and post-ED management does not differ with the patient’ sex • Acute care clinicians should emphasize PCP follow-up for renal and bladder ultrasound following a patient’s first UTI • Renal scarring is a major cause of long-term morbidity associated with untreated first UTI

18. Conclusion • A variety of risk factors (age, fever, race, anatomy) contribute to differences in UTI prevalence by sex in infants • AAP guidelines can help the acute care physician determine which febrile infants need further diagnostic testing following acute intervention

19. Case Conclusion • The 11-month-old girl underwent urethral catheterization based on increased risk of UTI • Urinalysis revealed 0 nitrites, 2+ leukocyte esterase, 150 WBCs and 20 RBCs, few squamous cells and many bacteria • She was initially treated with cephalexin • At follow-up, her urine culture grew >50,000 cfu/mL, sensitive to cephalosporins • She had a normal bladder and renal ultrasound

20. Gaps in Knowledge /Research Questions • Areas of potential research include: • Continued surveillance of how sex affects antimicrobial resistance patterns • The potential relationship, if any, between sex and multidrug resistant bacteria • Developing point of care blood and urine tests to identify bacterial infection, while forgoing invasive procedures such as urinary tract catheterization

21. Case 2 • A 2-week-old full-term boy presents with 3 days of worsening emesis, decreased feeding, and 1 day of increased sleeping • ROS notable for decreased urine output and failure to regain birth weight • HR 175 bpm, respiratory rate 40, blood pressure 60/30, O2 saturation 96% on R.A., rectal temperature 98.5°F

22. Case 2 • On exam, patient appears listless • Anterior fontanelle is sunken, mucosa are dry • Skin is ashen, extremities cool with 4-second capillary refill • Exam otherwise unremarkable • Shock not reversed despite 60 mg/kg 0.9% normal saline, prostaglandins, and dopamine infusion

23. Introduction • It is imperative that clinicians recognize the signs and symptoms of shock in a neonate: • Tachycardia • Mild tachypnea • Slight delayed capillary refill • Orthostatic changes • Mild irritability • Congenital Adrenal Hyperplasia (CAH) is one of many causes of neonatal shock

24. Pathophysiology of CAH • CAH is caused by enzymatic deficiencies of the adrenal cortisol biosynthesis pathway • Autosomal recessive inheritance • Occurs in 1 in 15,000 live births • In developed nations, prevalence of CAH is the same in both sexes

25. Cortisol Biosynthesis Pathway

26. Pathophysiology of CAH • 21-hydroxylase deficiency (21OHD) accounts for 95% of cases of CAH in children (Speiser et al. 2010) • Varying levels of deficiency in mineralocorticoids (aldosterone) and glucocorticoids (cortisol) and excess androgens • Cortisol deficiency leads to stimulation of adrenocorticotropic hormone (ACTH) and results in adrenal hyperplasia

27. Clinical Manifestations • The clinical manifestations of CAH result from: • Adrenal insufficiency • Accumulated precursors proximal to the enzymatic block • Androgen excess • CAH can be divided into classic and non-classic forms based on symptoms and enzyme activity

28. Clinical Manifestations • Classic CAH can be divided into salt-wasting (SW) and non-salt-wasting (NSW) types • SW-CAH comprises 75% of classic CAH cases and is characterized by complete absence of 21OH • Resultant lack of aldosterone leads to renal sodium loss, hypovolemia, and hyperkalemia

29. Clinical Manifestations • Patients usually present in the 2nd week of life with nonspecific symptoms such as poor feeding, emesis, and irritability • Symptoms may progress to adrenal crisis and potentially fatal hypovolemic shock • Girls was SW-CAH may be diagnosed earlier due to ambiguous genitalia

30. Clinical Manifestations • Phenotypes range from clitoral hypertrophy and partial labioscrotal fusion to completely phenotypically male genitalia • An apparently male neonate with no palpable testes warrants careful scrutiny • Ambiguous genitalia should prompt urgent genetic and gonadal sex determination

31. Clinical Manifestations • Boys with SW-CAH may have more subtle effects, such as mild phallic enlargement or hyperpigmentation • These subtle changes can lead to delayed diagnosis until the infant presents in shock

32. Clinical Manifestations • In patients with NSW-CAH, 1-2% of enzyme activity remains, resulting in: • Mild virilization • Sparing of aldosterone • No salt wasting • Girls may have ambiguous genitalia, however diagnosis is often delayed until puberty • Boys may present with precocious puberty

33. Clinical Manifestations • In non-classic CAH, remaining 21OH activity is 20-50% • Most patients are asymptomatic or exhibit mild symptoms such as precocious pubarcheor signs of androgen excess in female adolescence • The following discussion focuses on classic CAH

34. Diagnosis • Although CAH screening is included in newborn screening in all 50 states, results may not be available for 3-4 weeks • Diagnosis of CAH in the ED is based on clinical suspicion, physical exam, and laboratory abnormalities • The most urgent blood tests to obtain are serum electrolytes and blood glucose

35. Diagnosis • 1stclue to underlying CAH in a boy with normal appearing genitalia is often the combination of hyperkalemia and hyponatremia • Expected elevation in serum potassium may be obscured by ongoing GI losses caused by acute salt wasting crisis • Blood glucose levels may be low due to decreased oral intake and decreased cortisol, or may be normal

36. Diagnosis • Ideally, prior to administering hydrocortisone, blood should be drawn for: • Cortisol • 17-hydroxyprogesterone (17OHP) • Dehydroepiandrosterone(DHEA) • Androstenedione • Testosterone • However, treatment should not be delayed in a critically ill infant

37. Management • Infants in hypovolemic shock require aggressive IV fluid resuscitation • A time-sensitive algorithm for pediatric shock includes 60 mL/kg normal saline bolus in the first 15 min, followed by catecholamines, if there is no response • In neonates of both sexes, hydrocortisone should also be administered as there is a high risk of adrenal insufficiency

38. Management • Maintenance fluids should include 5% dextrose at 1.5 to 2 times maintenance rates for adrenal crisis • Hydrocortisone should be administered as 50-100 mg/m2 IV bolus (typically 25 mg for a neonate), followed by 50-100 mg/m2per day divided every 6 hours • 10% calcium gluconate should be administered in the setting of hyperkalemia-induced arrhythmia

39. Post-ED Care • Once diagnosis is made, a conference with parents, endocrinologist, urologist (and patient, if old enough to participate) may include the following topics: • Growth and hormone replacement • Gender assignment • Sexual orientation • Feminizing surgery • Fertility

40. Post-ED Care • Both girls and boys with CAH display rapid growth during the neonatal period due to androgen excess • Boys may have brisk increase in height with precocious puberty • They may also have early fusion of physes leading to short stature as adults

41. Post-ED Care • Gender assignment in the 46XX child with highly virilized genitalia requires sensitivity and the expertise of a multidisciplinary team • Psychosocial support is essential for children with CAH • Consultation with a mental health specialist may be helpful for patients with CAH

42. Post-ED Care • Females with virilized genitalia may opt for feminizing surgery • Current literature suggests that the effects of feminizing surgery on sexual function are not satisfactory • Clitoral sensitivity after clitoroplasty has been shown to be impaired and is associated with anorgasmia • Vaginal reconstruction carries the risk of stricture, dyspareunia, stenosis, and other complications

43. Post-ED Care • Subfertility is common in patients with CAH • In females, subfertility depends on severity of virilization • In males, subfertility is related to aberrant adrenal tissue that can cause testicular adrenal rest tumors and abnormal sperm quality • Early pediatric endocrinology and urology consultation is key in patients with CAH

44. Case Conclusion • The boy received IV hydrocortisone, which immediately improved his vitals and perfusion • His response strongly suggested that he was in adrenal crisis, likely secondary to CAH • Pediatric endocrinology, urology, and the PICU were notified and the patient was admitted for ongoing management of adrenal crisis and workup of CAH

45. Gaps in Knowledge • Few prospective long-term studies on the psychological/functional effects of early feminizing surgery compared to post-pubertal surgery • More neuro-anatomic studies are needed to clarify the effects of in utero androgen exposure on brain development • More effective feminizing surgery techniques that yield more satisfactory results for sexual function will improve quality of life for female patients with CAH

46. Case 3 • A 14-year-old female presents with 2 days of severe right lower quadrant abdominal pain • ROS positive for 2 episodes of non-bilious, non-bloody emesis • Heart rate 110 bpm, respiratory rate 20 breaths per minute, O2 saturation 99%, oral temperature 98.0°F • On exam, her abdomen is soft with moderate RLQ tenderness, involuntary guarding without rebound tenderness

47. Introduction • The differential diagnosis of lower abdominal pain in adolescents is broad and varies depending on the sex of the patient • In girls, lower abdominal pain can be gynecologic, including pelvic inflammatory disease, ovarian pathology, and ectopic pregnancy • In boys, testicular torsion is a surgical emergency often with nonspecific symptoms

48. Introduction • Significant components of the adolescent history that clinician must obtain include: • Date of most recent menses in girls • Sexual history • High-risk behaviors • Clinicians should consider local consent laws and confidentiality issues • Workup should always include a pregnancy test in all menstruating females

49. Appendicitis • While appendicitis is more common in boys (and men), there is no difference in clinical presentation in boys and girls • Symptoms and diagnostic findings may include peri-umbilical pain that migrates to the RLQ, anorexia, nausea, vomiting, leukocytosis with left shift, and fever • Median age in children is 10-11 years

50. Appendicitis • Efforts to reduce radiation exposure have led to use of ultrasound (US) as the preferred first line imaging in children and young women • US followed by CT or MRI as needed has shown increased cost effectiveness and high accuracy compared to CT alone in both sexes • US has been shown to be more successful for diagnosis of appendicitis in children than adults and in boys compared to girls