Notes compiled for Pediatrics

Reproduction

(Med I, Block 4, RP) Contents

Class number Class name Type Department Instructor

RP010 Development of Genito-Urinary L AN Dr. M Torchia System RP011 Embryology of the GU system A/GLP AN Dr. M Torchia RP015 Congenital anomalies and L RP Dr. M Morris benign conditions of the Vulva and Vagina RP016 Congenital anomalies and L RP Dr. M Morris benign conditions of the Uterus and Cervix RP018 Congenital anomalies and L RP Dr. M Morris benign conditions of the ovaries and tubes RP029 Amenorrhea, Oligomenorrhea L RP Dr. M Morris and Hyperandrogenic disorders RP049 Perinatal Genetics L GN Dr. B Chodirker RP051 Neonatal Recussitation and L RP Dr. S Dakshinamurti assessment RP062 Infections in Pregnancy and the L ID/RP Dr. J Embree Neonate RP063 Perinatal Infections and HIV in L ID/RP Dr. J Embree Pregnancy

RP 010/KD 2 Dr. M.G. Torchia Department of Surgery

Lecture Notes

Summary of Developmental Facts

 kidneys are unique in their development - progression of more and more complex “kidneys” as the embryo/fetus grows and develops  urinary and genital systems come from a common source - intermediate mesoderm  parts of one renal system are incorporated by another during development while others are lost through apoptotic processes  differentiation, development and growth of many structures are dependent on the interaction between epithelial and mesenchymal cells  most sex related structures begin as indifferent in structure and under the influence of hormones and factors differentiate into appropriate male and female structures  the urinary system forms before the gonadal system

Enveloping of the yolk sac is important for the development of the bladder, GI tract etc.

“Renal Systems” Figure 13-6 Cloaca (formed from the enveloping of the yolk sac) Moore and Persaud

 Pronephros

o Epithelial cords differentiate from intermediate mesoderm (day 22) o Pronephric ducts begin to grow down toward the cloaca and has a single nephron o Pronephros in lower animals and fish - find hematopoietic cells o Pronephric cells disappear through the process of apoptosis

 Mesonephros

o Pronephric ducts stimulate mesoderm - mesonephric tubules (cranial 4-6 pairs) o Later mesonephric tubules condense from mesoderm and are composed of . vascular glomerulus within an epithelial capsule o Lumen is complete and mesonephric (wolffian) duct connects to cloaca (28 d) o Urinary function is unclear but in fish and amphibians the mesonephros is capable of producing a filtrate (no need to conserve water so no concentrating) o New evidence in humans that yolk sac hematopoietic cells are only transient while the definitive, long lived adult system hematopoietic cells are found in the aortic-gonadal-mesonephric region o Mesonephros is chickens has been shown to be necessary for limb development o Leftover mesonephric tissue can end up as lesions in the wall of cervix, prostate, renal pelvis and may be falsely interpreted as adenocarcinoma due to their tubule Development of the Genito-Urinary System RP10/KD002 like structures mimicking glands.

 Metanephros (figure 13-6)

. Mesonephric duct forms a ureteric bud (epithelial cells) that grows and branches (approximately 15 times) into surrounding intermediate mesoderm (30-34 d) . Buds become the collecting ducts . Inductive interactions between mesoderm and epithelium result in formation of the metanephros (both must be present for normal development) . Mesoderm condenses into metanephric blastoma which forms the renal tubules . Together mesoderm cells, epithelial (bud) cells and ingrowing vascular endothelial cells from the dorsal aorta (blood supply) form the nephrons . Nephrons start out as rounded group of cells to a comma shaped hollow and then into an S-shape due to growth and cell differentiation . Portion of nephrons most distal to tubule forms Bowman‟s capsule around glomerulus while proximal portion of the S shape forms proximal and distal convoluted tubule and Loop of Henle . There are about 15 generations of nephrons formed with the proximal maturing faster . While sets of nephrons are forming, kidney is enlarging, ducts enlarge and form pelvis and calyces (major and minor based on generation of tubule) to guide urine from kidney to bladder . Kidneys are lobulated in fetus but lobulations disappear soon after birth

Position of kidneys

 Move from pelvis to abdomen due to caudal growth of embryo (4th lumbar to 1st lumbar to 12th thoracic) with a rotation from ventral facing to anteromedial - brings them together with adrenals  Retroperitoneal  Vascular lobes of kidney (typically 5) are originally fed from segmental arteries off the aorta and are usually reduced to a single artery (75% of patients)

Accessory Renal Artery: end arteries

Autosamal recessive polycystic KD: rare, bilateral, 100‟s small uniform cysts; lung hypoplasia (oligohydramnios); transplant needed; many cysts in the parenchyma, few glomeruli; massive, non-functional kidneys

Multicystic Dysplastic KD: large cysts within the kidneys; 85% unilateral, the cysts slowly progress through adulthood (not as life-threatening as the previous condition)

Development of the Genito-Urinary System RP10/KD002 Horseshoe Kidney: if the budding is close together they end up in the midline in the pelvis

Duplicate Ureters

Ectopic (pelvic) Kidney: one kidney remains in the pelvis area

Urinary Bladder

 Formed during division of the cloaca by the urorectal septum (between hindgut and allantois) during week 6-7  Cloaca is divided into rectum and urogenital sinus also dividing the cloaca membrane into anal membrane and urogenital membrane  Area of fusion of urorectal sinus, lateral body folds, and cloacal membrane is the perineum  Allantois base expands to form the transitional epithelium of bladder while distal ends forms urachus (median umbilical ligament - bladder to umbilicus)  Other layers of bladder form from mesenchyme  Growing bladder incorporates mesonephric ducts and proximal ureteric buds ending up with separate openings for both in bladder (figure 13-18)  Area where mesonephric ducts enter elongates and forms urethra  Distal urethra (male only) forms from endodermal downgrowth from surface of penis

Urine

 During changeover from mesonephros to metanephros, amniotic fluid constituents change with an increase in creatinine, γ-glutamyltransferase, β-2-microglobulin (10-11 weeks)  Urine is excreted into amniotic cavity forming major portion of amniotic fluid  Renal functioning before birth to remove metabolic waste from blood not „necessary‟ due to placenta  Oligohydramnios (too little fluid) - urethral obstruction, renal agenesis - lung hypoplasia  Polyhydramnios (too much fluid) - usually due to GI obstruction/no swallowing; premature membrane rupture Genital system

Germ cells

 Form in posterior wall of yolk sac ( 24 d) and are recognizable by size and alkaline phosphatase content  Migrate through hindgut and dorsal mesentery (move by ameboid movement, tissue displacement, and cytoplasmic linkages)  Migration stops as cell reach developing gonadal ridges (5th week)  Number 1000-2000  Aberrant locations form germ cells that survive may produce teratomas Development of the Genito-Urinary System RP10/KD002

Gonads

 Form along ventromedial border of mesonephros (cranial portion of mesonephros becomes the primordia of adrenal cortex - caudal becomes genital ridges (5th wk)  Genital ridges of male/female are indifferent and only under influence of the Sry gene (Y Xsome, testes-determining factor) and mesonephros signals (which may be a switch for other genes) does differentiation occur

o Testes

. Testes develop quicker ovaries . When germ cells reach genital ridges, epithelial cells in the ridges (coelemic) move inward forming primitive sex cords - testis also attract endothelial and myoepithelial cells from mesonephros . By 6 weeks testes show cell differentiation leading to formation of tunica albuginea (connective tissue), seminiferous tubules . By 8 weeks Leydig cells within testes synthesize testosterone and androstenedione but stop this production by about week 17/18 until puberty . By 8 weeks the Sertoli cells produce Müllerian inhibiting substance causing involution of the female genital ducts

o Ovaries

. Absence of Sry and therefore, testosterone, leads to formation of ovary . Germ cells must reach genital ridge or “primitive streak ovaries” form . Interior structure is thought to be formed in a similar way to testes . From the time of entry into the genital ridge to about 120 days oogonia undergo mitosis and gradually begin to undergo first meiotic division to become oocytes (signals possibly from mesonephros) but stop development at prophase of 1st meiotic division . Over fifty years may pass until some oocytes complete meiosis resulting in increased incidence of abnormalities Sexual duct system

 At the indifferent stage mesonephric (Wolffian) duct and paramesonephric (Müllerian) ducts along mesonephric ridge  Paramesonephric ducts terminate at urogenital sinus caudally and coelomic cavity in a funnel shape cranially

o Males

. Müllerian inhibiting substance causes paramesonephric duct cells to undergo apoptosis leaving only tiny identifiable terminal portions Development of the Genito-Urinary System RP10/KD002 . Testosterone causes mesonephric ducts to differentiate into ductus deferens . Accessory sex glands form from epithelial outgrowth of ducts (seminal vesicles, prostate, bulbourethral glands) through epithelial - mesenchyme interaction and androgens

o Female

. Without testosterone the mesonephric ducts regress . Cranial paramesonephric duct become uterine tubes with open fimbriated ends . Caudal end, the paramesonephric ducts approach and fuse forming uterus . Vagina thought to form by the most caudal mesonephric ducts contributing cells and inducing other changes in surrounding tissues

Descent of Testes

 Testes are retroperitoneal  Three phases to descent o Enlargement of testes and regression of mesonephric kidneys o Regression of paramesonephric ducts - descent to inguinal ring o Testosterone + gubernaculum (mesonephric ligament) - into scrotum (7th month to birth)

External Genitalia

 Indifferent initially - derived from mesoderm tissue around cloaca forming a genital tubercle flanked by a pair of genital folds with pair of genital swelling farther lateral

o Males . Dihydrotestosterone influences elongation of genital tubercle to form penis, genital swelling to form scrotal pouches . Groove on underside of penis formed from genital folds, become a groove continuous with urogenital sinus, and closes to form penile part of urethra . Urogenital sinus closes and forms prostatic part of urethra

o Females

. Without action of dihydrotestosterone genital tubercle forms clitoris, genital folds become labia minora, genital swellings become labia majora . Urethra develops from cranial part of urogenital sinus (i.e. prostatic urethra)

Causes of Intersex: Development of the Genito-Urinary System RP10/KD002 o Ovotestes: rare; have both testicular and ovarian tissue o Congenital adrenal hyperplasia: XX; pseudo-hermaphrodites; enzymatic error  adrenal gland cannot produce cortisol  thereofore pumps out more and more androgrens  masculization due to more male phenotypic structures o Androgen insensitivity syndrome: XY; testosterone receptor error; again it‟s a pseudo- hermaphrodite; there is a fight between the male and female phenotype

Reproduction 010 and 011 Study Guide

Reproduction 010 L Development of the Genito-urinary System 2

Learning Objectives 1. Describe the role of the intermediate mesoderm in the development of the urinary system. 2. Discuss the development of the three sets of human excretory organs, with special emphasis on the permanent kidneys. 3. Describe congenital abnormalities relating to positional changes of the kidneys during development of the renal vessels. 4. Explain the formation of the urogenital sinus, urinary bladder and urethra. 5. Briefly discuss the following: duplication of the upper urinary tract, renal ectopia, horseshoe kidney, congenital polycystic disease of the kidney, urachal malformations and exstrophy of the bladder. Learning Outcomes for Reproduction The student will be able to provide counseling and care for a patient with congenital anomalies of the reproductive tract, including counseling on future fertility and sexual function.

Reproduction 011 LP Embryology of the Genito-urinary System

Learning Objectives 1. Understand how the three sets of excretory organs develop and change. 2. Describe the process of nephrogenesis (development of nephrons). 3. Describe the partitioning of the cloaca and the derivatives formed from the urogenital sinus. 4. Describe the development of the gonads and genital ducts. 5. Describe the formation of external genitalia. 6. Relate the effects on the uro-genital system to normal and deficient excretion of testes-determining factor, mullerian inhibiting substance, and testosterone. 7. Understand the basic principles involved in the histogenesis of the adrenal glands. 8. Describe the pathogenesis of urogenital defects including renal agenesis, ectopic kidney, horseshoe kidney, exstrophy of the bladder, intersexuality, cryptorchidism, and inguinal hernia.

Text: Hacker and Moore Chapter 3 pages 20-28.

Key Study Points

A sound understanding of the normal anatomy and development of the genito-urinary tract is an important cornerstone for understanding clinical problems in caring for those with congenital abnormalities or disease processes in the genito-urinary tract.

The urogenital system develops from the:  Intermediate mesoderm  Mesothelium lining the abdominal cavity  Endoderm of the urogenital sinus.

The urinary system begins to develop about 3 weeks before the genital system is evident. Three successive kidney systems develop:  The pronephri which are vestigial and nonfunctional  The mesonephroi whihc serves as temporary excretory organs.  The metanephros which become the permanent kidneys.

The metanephri or permanent kidneys develop from 2 sources:  The metanephric diverticulum or ureteric bud which gives rise to the ureter, renal plevis, calices and collecting tubules.  The metanephric mass of intermediate mesoderm which gives rise to the nephrons.  The kidneys develop in the pelvis but migrate up during normal development.  Abnormalities in development of the metanephros and paramesonephric ducts can accompany each other for example in patients with a left hemi-uterus and an absent right kidney.

For reproduction the embryology can be divided into: 1. Development of the external genitalia 2. Development of the internal genitalia 3. Development of the ovaries and testes.

The reason for this division is simple.  Each of these has a separate origin; clinically this means that abnormalities in the different areas are usually not related. For example abnormalities in development of the uterus are not usually accompanied by abnormalities of the external genitalia or abnormalities of ovarian development.  The appearance of the external genitalia is heavily influenced as well by hormonal stimulation in utero, an abnormality of the external genitalia may actually be endocrine in origin (for example testicular feminization or congenital adrenal hyperplasia) and not be related to any abnormality in the embryologic development.

 Embryos are unisex on visual inspection until ~ 7 weeks gestation.  Female genitalia are readily distinguishable by 12 weeks and visible on ultrasound (as absence of a phallus at 18-20 weeks)  The urogenital sinus development results in a i. Small vaginal contribution (likely the lower third but controversial) ii. Hymen iii. Skene’s glands iv. Bartholin’s glands v. Prostate, prostatic utricle, Cowper’s gland in male  The medial urogenital fold results in development of clitoris, prepuce of the clitoris and the labia minora (penis in male)  The lateral genital folds result in development of the labial majora (Scrotum in male).

See next page for image of the adult vulva and try and compare the structures.

Think about what an abnormality of central fusion of the urogenital folds would look like. We see this in patients who are born with bladder exstrophy, an example of failure of midline fusion. They will have a normal vagina past the lower third, a normal cervix and normal uterus.

Internal Genital Development

 The upper vagina, cervix, uterus and fallopian tubes are formed from the paramesonephric (Mullerian) ducts.  The male homologous structure is the hydatid testis.  Paramesonephric development will occur at the expense of mesonephric development in the absence of the Y chromosome. o With a Y chromosome present mullerian inhibiting substance is produced and the mesonephric duct develops instead.

 Female sexual development does not depend on the presence of ovaries or hormones, in contrast to the male who needs the testosterone production to develop normally.  Most anomalies of the uterus and vagina result from abnormal fusion of the paramesonephric ducts.

 Early embryologic development of the genital tract and vaginal plate. o PD= paramesonephric duct o MD= mesonephric duct o US= urogenital sinus o MT=mullerian tubercle o UVP=utero-vaginal primordium o VP= vaginal plate. Ovaries:  At 4 weeks post-conception thickening of coelomic (peritoneal) epithelium on the ventro-medial surface of the genital ridge occurs.  A bulging genital ridge is subsequently produced by rapid proliferation of the coelomic epithelium an area that is medial but parallel to the mesonephros.  After 5 weeks projections from the germinal epithelium extend into the mesenchyme to form primary sex cords.  Definite ovarian characteristics do not appear until 10-12 weeks.  At 3 weeks large primordial germ cells appear intermixed with other cells in the endoderm of the yolk sac wall of the primitive hindgut.  These germ cell precursors migrate along the hindgut dorsal mesentery and are all contained in the mesenchyme of the undifferentiated urogenital ridge by 8 weeks.  The oogonia are incorporated into the cortical sex cords of the genital ridge.  The first histologic evidence of follicles is seen at ~ 20 weeks with germ cells surrounded by flattened cells derived from the cortical sex cords/. These cells are recognizable as granulosa cells of coelomic epithelial origin and theca cells of mesenchymal origin.

Their origin is separate from the paramesonephros and urogenital sinus, abnormalities in the ovaries will be independent of these systems.

Clinical cases:

1. A 19-year-old female presents with primary amenorrhea. She has a mosaic XO/XX chromosome pattern. Serum estrogen levels are low and breast development is absent. (Turner’s syndrome) Would you expect her internal genitalia to be normal?

2. A 16-year-old female presents to the clinic with primary amenorrhea. She has normal female external genitalia but a small blind vagina. She does not have any axillary or pubic hair. Her chromosome pattern is XY. What has happened here?

3. A 20-year-old woman comes to see you about her future fertility. She was born with bladder extrophy and has had multiple surgeries with construction of a continent bladder stoma. She is sexually active without difficulty and is on an oral contraceptive for family planning.

Answers on next page. Answers: 1. Her internal genitalia would be normal but would be small as her ovaries may not have been able to make sufficient estrogen to complete growth of the uterus that occurs after onset of puberty. 2. This is a case of complete androgen insensitivity. The testes would be normal and healthy and able to produce mullerian inhibiting substance but the tissues in this disorder do not respond to testosterone. The male appearance of external genitalia is dependant on testosterone action. 3. Bladder extropy is a severe developmental abnormality of the urogenital sinus. AS the internal genitalia develop from para mesonephric ducts they should not be affected. Her fertility would be normal except for the possibility that some of her surgical procedures may have interfered with tubal patency. She also probably wants to know the risk of her infant being affected by the same disorder. Learning Objectives:

• Vulva 1. Describe the congenital abnormalities of the vulva Reproduction 015 and outline the clinical importance of the differential diagnosis. 2. List 6 common structural and benign conditions of the vulva. Congenital Anomalies and Benign 3. Describe 2 types of vulvar trauma. Conditions of the Vulva and Vagina 4. Describe 6 common benign epithelial conditions of the vulva.

Congenital abnormalities of the vulva Congenital abnormalities of the vulva

• Very important to deal with at birth as gender • Congenital adrenal assignment can be difficult. hyperplasia in a – Sensitivity and avoidance of hasty decisions female fetus. important. • Most important to • Careful physical examination, pelvic recognize clinically in the newborn period as ultrasonography, hormonal studies, buccal can be life smear, karyotyping and consultation threatening. necessary.

Benign Conditions of the Vulva: Non- Congenital abnormalities of the vulva infectious • Female pseudohermaphroditism – Virulized female. • Labial agglutination – Caused by masculinization in utero. • Thin atrophic labia minora • Male pseudo hermaphroditism adhere if irritated or traumatized. – Inadequately virulized male. • Treatment with topical – For example in androgen insensitivity. estrogens. • True hermaphroditism • Good local care to prevent – Very rare, needs both ovarian and testicular material. recurrences.

1 Benign Conditions of the Vulva: Non- Benign Conditions of the Vulva: Non- infectious infectious • Fox-Fordyce Disease • Epidermal inclusion cysts and sebaceous cysts. – Pruritic raised yellowish retention cysts – Located below the epidermis • Often inflamed – Mobile, nontender, spherical and slow growing. • Can occur in axilla, mons, or labia – Excision if symptomatic. • Keratin plugged apocrine glands. • Treatment difficult.

Benign Conditions of the Vulva: Non- Clinical Case infectious • Vulvar varicosities • 7 year old female with • More common multiparous women. a 1 year history of • Urethral caruncle painless swelling on – Small fleshy outgrowths of the urethral mucosa. vulva, previous history • In children results from prolapse of mucos. of straddle injury to • In postmenopausal women occurs when the area. hypoestrogenic vaginal mucosa contracts away from urethral mucosa. • Diagnosis? • Inclusion cyst.

Benign Conditions of the Vulva: Non- Benign Conditions of the Vulva: Non- infectious infectious • Vulvar vestibulitis • 4 year old with history – Inflammation of one or more of the minor of urinary frequency vestibular glands. and dysuria, MSU – Severe introital dyspareunia showing no growth – 1-4mm erythematous dots that are very tender • Diagnosis? when touched with a Q-tip. • Urethral prolapse – Difficult to treat, some response to corticosteroids.

2 Benign growths of the vulva Benign growths of the vulva

• Lentigo and nevi can be found on the vulva and may • Hidradenoma need to be biopsied to exclude the possibility of – Apocrine gland tumor melanoma. • Neurofibroma • Fibromas – Associated with Von Recklinghausen’s disease • Form in deeper connective tissue of the vulva and may become • Angiomata large requiring excision. – Small cherry angioma can appear during life, larger • Lipomas congenital angiomas require more complex investigation • are slow growing tumors composed of adipose tissue and may and possibly surgery. require excision.

Vulvar trauma Epithelial Conditions of the Vulva

• Straddle injuries • Squamous cell hyperplasia • Female genital mutilation. • Lichen sclerosis • Obstetric injuries • Lichen planus • Common skin conditions appearing on the vulva • Eczema • Psoriasis • Pemphigus

Atrophic and hypertrophic vulvar dystrophies Management

• Biopsy • Biopsy • Biopsy • Cannot visually rule out a premalignant or malignant lesion in an adult! • Topical corticosteroids mainstay of therapy.

3 Vulvar Symptoms Contact Dermatitis

• Erythema and burning, exam can also reveal edema • Lichen sclerosus and excoriations in severe cases. • Thin atrophic epithelium on biopsy • Treatment; • Symptoms controlled by application – Biopsy of any thickened or white areas. of steroid cream to affected area – Removal of the irritant – Topical mild or moderately strong corticosteroids – Antihistamines and bland emollients.

Learning Objectives: Congenital abnormalities of the Vagina

1. Describe 2 congenital abnormalities of the vagina • Canalization abnormalities and outline their clinical significance. – Imperforate hymen 2. Describe 5 structural and benign conditions of the – Transverse vaginal septum vagina. – Upper genital tract normal 3. Describe 2 causes for vaginal trauma and outline • Mullerian associated anomalies the treatment. – Longitudinal vaginal septum 4. Describe one functional disorder of the vagina. – Vaginal agenesis or atresia. – Often associated with uterine and cervical anomalies.

Embryonic Remnants Structural and Benign Conditions

• Gartner Duct cysts • Urethral diverticula – Thick walled soft cysts resulting from mesonephric • Inclusion cysts remnants(vas deferens , seminal vesicle in the male) – Can vary in size from 1-5 cm. • Bartholin duct cyst – Usually found on the anterior and lateral walls • Loss of pelvic supports: high in the vagina or laterally lower in the vagina. • Cystocoele – Excision if symptomatic • Rectocoele • Enterocoele.

4 Bartholin duct cyst Vaginal Trauma

• Commonest cause sexual assault • 1-year-old female brought to emergency department after a 2 day history of vaginal bleeding.

Dermtologic conditions Vaginismus

• Condyloma accuminata • Painful involuntary contraction of the vaginal • Herpes simplex virus introital and levator ani muscles. • Lichen planus – Can preclude or prevent vaginal penetration during coitus, pelvic examination or tampon use. – Sexual dysfunction clinic after ruling out pathology that is treatable.

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Objectives

1. Describe the common congenital anomalies of the uterus and cervix, and outline their clinical Reproduction 016 importance. 2. Discuss the symptoms, differential diagnosis, investigation and management of uterine Congenital Anomalies and Benign leiomyomas and endometrial polyps. Conditions of the Uterus and Cervix

Objectives Congenital Anomalies of the Uterine Corpus and Cervix 3. Describe 2 common benign neoplastic lesions of the cervix. • Remember: absence of a Y chromosome leads to regression of the mesonephric system and development of the paramesonephric system. a. Define Nabothian cyst • The most common anomalies result from either b. Endo and ectocervical polyps – incomplete fusion of the paramesonephric ducts, 4. Define endometrial hyperplasia and outline its risk – incomplete fusion of the ducts factors. – formation failures. 5. Outline a treatment plan for a patient with endometrial • Uterus didelphys is the most extreme failure of fusion. hyperplasia. • Cervical anomalies most commonly associated with fusion defects in the uterus. 6. Describe functional conditions of the uterine corpus and • Normal karyotype but need to rule out associated renal anomalies. cervix.

Variations in uterine and cervical Clinical Significance development • Defects associated with obstruction can cause dyspareunia, hematocolpos or hematometra, as well as infertility. • Defects associated with abnormalities in the size and shape of the uterine cavity can cause preterm labor and increased need for C/S due to malpresentation.

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Structural and Benign Neoplastic Conditions Uterine Leiomyomas

• Uterine Leiomyomas • Uterine Leiomyomas (fibroids) – Benign tumors derived from smooth muscle cells of the – Rare before menarche, can regress in menopause. myometrium. – May enlarge dramatically in pregnancy. – At least 45% of women will have them by the fifth decade – Calcification may occur of life. – Degeneration may be a source of pain. – Most are asymptomatic – Location crucial in understanding symptoms. – Can cause: – Malignant leiomyosarcomas rare. • excessive uterine bleeding, • pelvic pressure and pain, • infertility.

Uterine Leiomyomas Uterine Leiomyomas

• Symptoms • Submucosal – Majority are asymptomatic – Mass effect can cause pelvic pressure, congestion • Subserosal and bloating, as well as constipation and urinary frequency from pressure on the bladder. – Urinary retention a rare complication. • Intramural – Menorrhagia a major risk with intramural and submucosal fibroids.

Uterine Leiomyomas Differential Diagnosis

• Case History • The differential diagnosis must include other pelvic A 45-year-old woman presented with menorrhagia masses and other causes of menorrhagia. resulting in chronic anemia. (Hgb 79). Pelvic – Most common differential is an ovarian neoplasm examination showed a slightly bulky anteverted – tubo-ovarian inflammatory mass uterus with normal adnexa. – Pelvic kidney She failed to respond to hormonal suppression – Diverticular or inflammatory bowel mass therapy. Pelvic ultrasound showed a 2 cm. fibroid – Cancer of the colon. intramurally in the cornual area of the uterus. – Pregnancy – Adenomyosis

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Treatment Patient Choices

• Medical Management • Based on – Hormonal – Informed consent • Progestin-only therapy • Combination hormonal contraceptive methods – Desire for future fertility • GnRH agonists – Willingness to undergo a surgical procedure • Surgical Management – Willingness to undergo medical therapy and any • Myomectomy potential side effects. • Hysterectomy • Embolization of uterine arteries • Ablation of submucosal fibroids via hysteroscopy.

Hysteroscopy Fibroids via the Hysteroscope

• Dextrose 5% and saline in water • Office or OR • Diagnostic or therapeutic

Endometrial Polyps Diagnosis and treatment

• Endometrial polyps form from the • Diagnosis can be made on endometrium to create abnormal protrusions – Ultrasonography of friable tissue into the endometrial cavity. – Hysteroscopy • Can cause unpredictable bleeding and • Treatment menorrhagia. – Endocervical and endometrial polyps that • Source of post-menopausal bleeding. protrude from the endocervix can often be • Benign. removed in the office. – Remainder require D&C or operative hysteroscopy.

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Hysteroscopic Image Benign Conditions of the Cervix

• Endo and ecto-cervical polyps • Hysteroscopic image – Commonest benign growth of the cervix. of an endometrial – Cause post-coital or coital bleeding or menorrhagia polyp – Local proliferation of cells – Narrow based polyps can be removed by twisting them off • This would be at the base in the office. accessible to excision – Broader base polyps require removal with cautery in an using electrocautery operative setting. at the time of – All specimens must be sent for pathology, as early hysteroscopy. adenocarcinomas may present this way.

Epithelial conditions of the uterine Nabothian Cysts corpus and cervix • Endometrial Hyperplasia • Very common – Seen at times of unopposed estrogen stimulation • Result from the process of • PCOS squamous metaplasia • Obesity • Layer of superficial • Estrogen therapy squamous cells cover over • Use of tamoxifen. an invagination of columnar cells under the • Diagnosis by endometrial biopsy cervix. – Suspect in intermenstrual bleeding, • May cause dyspareunia. Dysfunctional uterine bleeding and menorrhagia.

Treatment Asherman’s syndrome

• Iatrogenic • Simple hyperplasia (no atypia) • – Medroxyprogesterone acetate 5-10mg orally for 10 days each Loss of a large component of the functional month endometrial lining. • Repeat endometrial biopsy to confirm successful treatment • Case History • Treat the underlying cause – A 22-year-old woman underwent a D&C in the postpartum • Complex hyperplasia period for retained products of conception, and – Needs formal evaluation of endometrium with fractional D&C subsequently developed prolonged amenorrhea. – Treat with daily progesterone therapy for 3 months. • • Complex hyperplasia with atypia Commonest cause D&C in high risk setting. – Hysterectomy or careful follow-up after 3 months of • Endometrial ablation a deliberate intent to cause this progesterone. to ameliorate menorrhagia.

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Functional Conditions of the uterine corpus and cervix • Cervical stenosis – Usually as a result of trauma • Endocervical curettage, dilation or conization – or hypoestrogenism • Cervical incompetence – Cervix is unable to maintain pressure under the increasing demands of a pregnant uterus. – Can be intrinsic – Can be due to cervical surgery.

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Objectives

1. Outline the congenital abnormalities of the ovaries Reproduction 018 and tubes. 2. Describe the common functional and benign tumors of the ovary. 3. Discuss the clinical management of these tumors. Congenital Anomalies and Benign 4. Describe 3 benign conditions of the fallopian tubes Conditions of the Ovaries and Tubes and their management.

Congenital Anomalies of the Ovaries Benign Conditions of the Ovaries

• Rare! • Functional – Congenital duplication or absence of one ovary can occur and is not – Follicular cysts associated with paramesonephric abnormalities. – Lutein cysts • Genetic chromosomal disorders such as Turner’s (XO) are – Polycystic sclerotic ovaries associated with abnormal gonadal development. – (small, early loss of function) • Inflammatory • Y chromosome predominant in situations like Kleinfelter’s – Salpingo-oophoritis (XXY) – Pyogenic oophoritis • XY gonadal genesis or testicular feminization – Granulomatous oophoritis – Presence of the Y chromosome necessitates removal after puberty • Metaplastic because of risk of germ cell tumors. – Endometriomas

Neoplastic Tumors of the Ovaries The Ovary

• Premenarchal years • Amazing ability to develop a wide variety of tumors, – 10% are malignant. the majority of which are benign. – 90% benign. • Need to be able to recognize when a malignancy is more likely to exist. • Reproductive or menstrual years • During childbearing years 70% of ovarian masses are – 15% are malignant functional • Menopausal years – Remainder are neoplastic or metaplastic (endometriomas) – 50% are malignant.

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Functional Cysts Functional Cysts- continued

• Dozens of follicles form each cycle. • Hemorrhagic cysts • If one persists and is larger than 3 cm it is defined as • Hemorrhage occurs into the cysts as a result of invasion of ovarian vessels into the functional cysts a functional cysts. • More likely to be symptomatic • If it is a persistent follicle it is classified as a follicular • Theca-lutein cysts cysts and may produce estrogen. – Associated with high levels of HCG – Lined by granulosa cells – Also can be associated with ovarian hyperstimulation • If it is a persistent corpus luteum, it is defined as a (inducing ovulation in IVF) lutein cyst and may produce progesterone, delaying • Luteomas of pregnancy onset of menses. • Polycystic ovarian syndrome

Symptoms Torsion of Ovarian Cyst

• Often asymptomatic • Can reach sizes up to 15 cm. • Lutein cysts more likely to delay menses than follicular cysts • Hemorrhagic cysts more likely to be symptomatic with severe pain • Torsion – surgical emergency • Rupture – May be a surgical emergency.

Diagnosis Management

• Pelvic examination – In the non-obese patient palpable after reaching a • Reproductive age patient presenting with < 6 cm cyst size of 5-6 cm. ok to wait and reexamine after next menses. (pelvic exam or U/S) – Cysts are mobile unilateral and not associated • If > 6 cm, or feels solid or fixed ultrasound imaging is with ascites. (Except PCOS which will be bilateral) appropriate. • Pelvic ultrasound very useful in trying to • If lesion is painful, multilocular or partially solid (on differentiate between functional and US) surgical exploration is indicated. neoplastic cysts, but not infallible. • Laparoscopy/laparotomy • Spontaneous regression will occur in up to 70% of adnexal cysts.

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Benign Neoplastic Ovarian Tumors Epithelial Ovarian Neoplasm

• Ovarian Neoplasms • Derived from the mesothelium lining the peritoneal – Divided into cavity • Epithelial – ovarian surface • Maintain their ability for example to develop the • Stromal different types of histologic tissue seen in the • Germ cell mullerian tract. – • Benign cystic teratoma ( dermoid) is the most Serous – Mucinous common, from the germ cell group. – Endometrioid – Brenner - bladder mucosa

Epithelial Ovarian Tumors Sex-cord stromal tumors

• Serous tumors • Granulosa-theca cell tumors – 70% will be benign – Feminizing tumors due to their ability to produce estrogen – 5-10% borderline malignant potential • Precocious puberty in the child – 20-25% are malignant. • Menorrhagia and endometrial hyperplasia in the adult • Mucinous tumors can attain a massive size – Sertoli-Leydig cell tumors – 85% are benign • Less common but can cause virulizing symptoms – Rarely complicated by pseudomyxoma peritoneii • All have low malignant potential • Brenner tumors • Fibromas • Smooth solid tumor made of interlacing bundles of fibrocytes – Cells resemble transitional cells of the bladder • Benign but can be associated with ascites – Rare, benign • Meigs syndrome: trans thoracic flow thru lymphatics of the fluid can cause ascites and hydrothorax.

Germ cell tumors Diagnosis

• Make up ~ 60% of ovarian neoplasms in • Again most asymptomatic unless torsion or children. rupture occur. • Benign cystic teratoma the most common. • Bimanual examination in the non-obese patient. (aka dermoid cyst) • Pelvic ultrasonography, particularly transvginal in • 10-15% bilateral obese patient • Ectodermal tissue • Tumor markers – Sweat and sebaceous glands, hair follicles, teeth • CA 125 – tumour marker for ovarian cancer but not sense or – Some mesodermal and rarely endodermal elements spec enough for screening; useful for following malignancy • All tissue benign in nature. • Hormone markers • Laparoscopy – if unsure by US

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Management Benign Ovarian Cyst Operative View

• Solid tumours generally treated with unilateral • A 15-year-old female salpingo-oophorectomy presented with abdominal • Ovarian cystectomy in younger women a possibility if pain and a larges simple it is unilocular. cyst on ultrasound. The • Ovarian fibromas an exception, although solid can be treated mass did not have a solid with cystectomy. component. • Dermoids can also be treated with cystectomy. • Operative laparoscopy • Ascitic fluid needs to be sent for cytology performed for ovarian • TAH –BSO for the older woman may be appropriate. cystectomy, lower picture • Total hysterectomy and bilateral salpingo-oopherectomy is the post-op view! • Due to large risk of malignancy

Benign Conditions of the Fallopian Tube Management

• Pyosalpinx is aggressively treated with IV • Most lesions inflammatory in nature antibiotics as for salpingitis – Hydrosalpinx – tube distended with fluid – Pyosalpinx – tube distended with pus • Surgical excision may be required. • Tubes have less tendency towards neoplastic • Instant infertility and early menopause transformation  Rare • Hydrosalpinx may be managed conservatively • Neoplasms that do occur if it is asymptomatic – Epithelial adenomas – Salpingectomy if symptomatic. (it doesn’t serve – Polyps any function anyway) – Myomas • Benign growths may be excised via – Inclusion cysts laparoscopy. – Angiomas.

Objectives

1. Outline the congenital abnormalities of the ovaries and tubes. 2. Describe the common functional and benign tumors of the ovary. 3. Discuss the clinical management of these tumors. 4. Describe 3 benign conditions of the fallopian tubes and their management.

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Objectives

• Define primary amenorrhea and state when a RP029 patient should be investigated for it. • Classify primary amenorrhea disorders based on presence or absence of secondary sexual characteristics and presence of mullerian Amenorrhea, Oligomenorrhea and anomalies. Hyperandrogenic Disorders

Definition of Primary Amenorrhea Rule # 1 1. No period by age 14 in the absence of growth or • Rule out pregnancy first development of secondary sexual characteristics. – This is never a wrong answer! 2. No period by age 16 regardless of the presence of normal growth and development with the appearance of secondary sexual characteristics.

Diagnostic Strategy Using the Compartment 1 disorders Compartment System • Compartment 1 • Disorders of the outflow tract or uterus • Disorders of the outflow tract or uterine target organ. – Obstructive Mullerian tract anomalies • Compartment 2 – Agenesis of the Mullerian tract (MRK) • Disorders of the ovary – Hypoplastic Mullerian anomalies • Compartment 3 – Imperforate Hymen • Disorders of the anterior pituitary – Complete androgen insensitivity (XY) • Compartment 4 – Rare forms of CAH (XY) • Disorders of the central nervous system.

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Compartment 2 Disorders Compartment 3 Disorders

• Disorders of the ovary • Disorders of the anterior pituitary – Gonadal agenesis or dysgenesis – Pituitary tumor • XO, XXX, Mosaic • Producing excess PRL, TSH, – Growth hormone (can initially present with high PRL and amenorrhea).

Compartment 4 Disorders Puberty Milestones Review

• Disorders of the central nervous system – Hypogonadotropic hypogonadism • Kallmann’s syndrome-accompanying anosmia. • Stress related amenorrhea – Exercise – Chronic illness • Anorexia nervosa • Hypothyroidism • Craniopharyngioma can present as primary amenorrhea, hypogonadotropic hypogonadism and delayed puberty warrant an MRI to rule out

Puberty Milestones Review Puberty Milestones Review

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Puberty Milestones Review Puberty Milestones Review

Presence of Secondary Sexual Characteristics Absence of Secondary Sexual Characteristics

• Puberty has been initiated normally • Puberty has not been initiated normally • Look for : – Look for: – Mullerian tract anomalies • Hypothalamic causes • • Obstructive Pituitary causes • • Hypoplastic Ovarian agenesis or dysgenesis. • Agenesis – Complete androgen insensitivity – Rare forms of CAH

Objectives Definition of Secondary Amenorrhea

• Define secondary amenorrhea. 1. In a woman who has been menstruating, the • Discuss the differential diagnosis for secondary absence of periods for a length of time equivalent amenorrhea associated with hypoestrogenism. to a total of at least three of the previous cycle • Discuss the etiology, diagnosis and treatment of intervals or 6 months of amenorrhea. amenorrhea associated with hyperprolactinemia. • Define mild hypothalamic dysfunction causing amenorrhea and outline its treatment.

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Rule # 1 Diagnostic Strategy Using the Compartment System • Rule out pregnancy first • Compartment 1 • Disorders of the outflow tract or uterine target organ. – This is never a wrong answer! • Compartment 2 • Disorders of the ovary • Compartment 3 • Disorders of the anterior pituitary • Compartment 4 • Disorders of the central nervous system.

Compartment 1 disorders Compartment 2 Disorders

• Disorders of the outflow tract or uterine target • Disorders of the ovary organ. – Premature ovarian failure – Asherman’s syndrome • Autoimmune • Chromosomal mosaicism • Partial CAH (adrenal as well)

Compartment 3 Disorders Compartment 4 Disorders

• Disorders of the anterior pituitary • Disorders of the central nervous system – Pituitary tumors – Hypogonadotropic hypogonadism • PRL, TSH • Stress related amenorrhea – Sheehan’s syndrome – Exercise – Chronic illness • Anorexia nervosa • Hypothyroidism

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Secondary amenorrhea associated with hypoestrogenism. Amenorrhea associated with hyperprolactinemia. • Hypothalamic-pituitary dysfunction • Treatment objectives – Includes patients with severe weight loss or excessive – Elimination of lactation exercise, anorexia nervosa, severe systemic diseases, • Medical with bromocriptine (dopamine agonist) pituitary or CNS lesions and pituitary failure. • Surgical for visual field defects or failure to improve on medical • Premature ovarian failure therapy. – Ovarian failure before the age of 40. – Establishment of normal estrogen secretion • Hyperprolactinemia – Induction of ovulation when fertility is desired. – If not explained by drug use or hypothyroidism, a CT or – Treatment of tumors as indicated. MRI of the sella turcica should be performed. • Mass effects of prolactinomas • Craniopharyngiomas.

Mild hypothalamic dysfunction Case History

• Patients with adequate estrogen levels but who are • A 16-year-old female comes to your clinic with a diagnosis of anovulatory may have a mild form of hypothalamic primary amenorrhea. anovulation. • She has had breast development at age 12 – Nutrition/exercise mismatch • TSH and Prolactin are normal. – Psychological stress • She has been on an oral contraceptive ( for contraception) – Recent use of DepoProvera with no withdrawal bleed. – Recent pregnancy or lactation. – When pregnancy not desried, observation and periodic withdrawal bleeds with progesterone appropriate.

Case History Case History

• A 25-year-old female presents with secondary amenorrhea. • A 23-year-old competitive track and field athlete presents BMI is 22. with a 6 month history of amenorrhea. • Her TSH and Prolactin are normal. • Her TSH and prolactin are normal • She has a withdrawal bleed on progesterone. • She fails to bleed after a Progesterone challenge. • After being placed on an OCP she does have regular withdrawal bleeds. • FSH is low.

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Case History Case History

• An 18-year-old female presents with • A 17-year-old female presents with secondary oligomenorrhea. She has a BMI of 29. TSH is amenorrhea. Her TSH and prolactin are elevated and her prolactin is mildly elevated. normal. She fails to have a withdrawal bleed She has a withdrawal bleed after on progesterone, but does bleed after one progesterone. cycle on an OCP (combined).Her FSH is high.

Objectives Ovarian ultrasound

• Outline the medical treatment for a patent with a diagnosis of polycystic ovarian syndrome.

Treatment Aims Hyperandrogenism

• Correct the hyperandrogenisim and its effects • Hirsuitism and acne • Correct the anovulation and its adverse effects – Combination oral contraceptive therapy or Depo-Provera – Protect the endometrium from hyperplasia • Need mechanical methods to remove pre-existing hair. • Diane 35 containing cyproterone acetate is best available product – Restore fertility when desired. for treatment of androgen symptoms. • Identify and treat insulin resistance. hyperlipidemias – Spironolactone (aldosterone antagonist) also indicated for and hypertension when present. treatment of hirsuitism when ovarian suppression therapy fails. – Weight loss

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Differential Diagnosis for hyperandrogenic Treatment disorders • Congenital adrenal hyperplasia • Insulin resistance • Cushing’s syndrome – Weight loss • Adrenal neoplasms – Oral hypoglycemics • Racial differences in expression of androgenic effects in the skin can lead to difficulties in diagnosis (excess • Hyperlipidemias hair with normal androgens, minimal hirsuitism in the face of elevated androgens) – Weight loss – Medical therapy.

7 RP049 - Perinatal Genetics

Perinatal Genetics: Learning Objectives Metabolic / Genetic Disorders After this lecture the student should be able to in Pregnancy  Describe the effects of genetic/ metabolic diseases in the mother on the mother or pregnancy and provide examples  Describe the effects of genetic/ metabolic diseases in the mother on the fetus and provide examples Bernie Chodirker  Describe the effects of genetic/metabolic diseases in the fetus on the mother and provide an example

Definitions: Mother = Mother and pregnancy and delivery Fetus = Fetus, placenta and baby Effects of Metabolic / Genetic Disorders in Pregnancy

 Four Main categories Effects of disease in the mother on the mother/pregnancy 1 Effects of disease in the mother on the fetus 2 Effects of disease in the fetus on the mother/pregnancy 3 Effects of disease in the fetus on the fetus

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Genetic Disorders Affecting Fertility

 GALACTOSEMIA -females with classical galactosemia develop  Turner Syndrome hypergonadotrophic hypogonadism Pregnancy possible if mosaic or with assisted reproduction  fertility is rare 2 patients died of aortic dissection in third trimester  CYSTIC FIBROSIS- CBAVD in males  CONG. ADRENAL HYPERPLASIA  HOMOCYSTINURIA-? S.A. Myotonic Dystrophy Myotonic Dystrophy CTG repeats

24/69 none adult 5/845/75 13/300 juvenile

congenital 13/1125/160 13/205 16/200

14/2100 13/730

Myotonic Dystrophy  Mother on Mother  Prolonged labor due to maternal weakness  post-partum hemorrhage, pre-term labor  respiratory distress with small amounts of resp depressants  Mother on Fetus  Old theory was maternal non-genetic factor  fetus on mother 1  hydramnious (10% of idiopathic hydramnious)  fetus on fetus  Congenital myotonic Dystophy

Genetic Disorder in Mother Genetic Disorder in Mother Affecting Mother Affecting Mother  Neurofibromatosis NF1 (Dugoff 1996)  Marfan Syndrome (Rossiter 1995) 105 women 247 pregnancies 21 women, 45 pregnancies 182 livebirths, 44 SA’s, 21 TA’s, 2 ectopic aortic root < 40, tolerate pregnancy well 7 C-section due to NF (eg. Pelvic 2 aortic dissections neurofibroma no increase in pregnancy complications eg. Preeclampsia 60% new neurofibromas, 52% enlargement of neurofibromas Genetic Disorder in Mother Affecting Mother Genetic Disorder in Mother Affecting Mother

 Ehlers Danlos Syndrome IV-  Ehlers Danlos Syndrome IV- Vascular type Vascular type  Pepin (NEJM, 2000) Thin, 83 pregnancies translucent,fragile,premature aged skin 12 deaths minimal joint hypermobility 5 uterine rupture during labor Spontaneous rupture of arteries 2 of blood vessel rupture at delivery and internal organs 5 of blood vessel rupture within 2 weeks  colon, uterus after delivery average life span 40 Autosomal Dominant unknown if CS would help

Genetic Disorder in Mother Affecting Mother More Genetic disorder in mother affecting mother  Skeletal dysplasia (Allanson, 1986) 46 women (26 Achondroplasia) 89 pregnancies (70 to term)  CF: 1/2 have serious /progress lung decompensation 9 women had resp distress in last 2/12  Asthma - 43% no change, 43% worse, 14% better 63/70 deliveries were C-Section  Multiple Sclerosis- relapse rate similar to non-pregnant epidural successful in 23  Epilepsy Suggest if 1 seizure/month prior, most worse baseline pulmonary function if 0 seizure/ 9 months prior, 25% worse careful with general anesthetic small trachea, spine instability, lower body mass,

Genetic Disease in Mother affecting Mother Metabolic Disease in Mother affecting Mother

 Metabolic decompensation after delivery  Metabolic disease causing further organ damage Urea Cycle Disorders during pregnancy (OTC Deficiency) Glycogen storage disease I (renal) CPS deficiency Cystinosis (renal) Glycogen Storage Disease III (cardiomyopathy) Maternal Maple Syrup Urine Disease Poryphyria ( 50% had attacks during pregnancy, 1 Maternal Homocystinuria maternal death) High risk for postpartum thromboembolism Maternal Disease Affecting Fetus

PKU phenylalanine ------x------>Tryosine Autosomal recessive 2  1/ 12,000 Caucasian births carrier frequency 1/50 Disease can range from Classic to mild hyperphenylalanemia

Maternal Disease Affecting Fetus Maternal PKU

 MATERNAL PKU  Developmental Follow-up  routine NB screening began in 1960’s, early rx women are now fertile, Waisbren et al (2000) –FU in 149 offspring  ~2800 fertile women with normal IQ in U.S. (~300 in Canada) by 1990. Good control= mean score 99  Rouse et al (2000) 413 offspring to 354 women with PKU 47% without control by 20 weeks IQ<2SD 31 CHD, Overall 30% of children have social /behavioral problems 17 microcephaly with MR, Treatment at any stage may be helpful no control before 4-8 weeks. Need for metabolic control prior to pregnancy

Nutritional Rickets Maternal PKU  Vitamin D Deficiency  Do we know all the moms with PKU? Hanley et al (1999) retrospective survey, of 414 women with maternal PKU, Inadequate vitamin D in diet (milk, liver, fish) 17 diagnosed for 1st time in pregnancy, including 6 only after birth of the affected offspring  Recommendations Inadequate exposure to Diet life long ; consider PKU embryopathy in children sunlight for dermal vitamin with microcephaly, MR, CHD if firstborn, other D synthesis affected, mom with MR “Consider Prenatal screening for any woman born before 66” Congenital Rickets

Innes et al 2002, 4 Aboriginal Manitoba babies with Congenital Rickets 3 whose mothers had evidence of Vitamin D deficiency, did not consume milk, little prenatal care, no vitamins,

Mirror syndrome Fetal conditions with Mirror syndrome

 Also called “pseudotoxemia”, “triple edema  Placental Chorioangioma syndrome”, “maternal hydrops”, Ballantyne  Viral infections syndrome”.  Alpha-thalassemia  Fluid retention in women with hydropic fetus  Sacrococcygeal teratoma complications include pulmonary edema  Trisomy 13 may also get pre-eclampsia  Rh erythroblastosis  Outcome poor for mother and baby without prompt delivery or treatment of hydrops  Ebstein Anomaly  Cardiac arrhythmia

Complete Mole  Diploid karyotype Histologically, the 85% 46,XX 15% 46,XY hydatidiform mole has 80-100% paternal only large diandric diploidy avascular villi and areas  Diploid complete moles occasionally go to of trophoblastic choriocarcinoma proliferation. 15% local invasion, 4% distant can also present with hyperemesis, pre-eclampsia,heavy vag bleed, RDS, hypertyhroidism due to trophoblastic hyperplasia and high HCG Well recognized pregnancy complications Metabolic Fetal Disease Affecting Mother

Hyperemesis Gravidarum : very common  LCHAD (long chain-3-hydroxylacyl-CoA dehydrogenase), Pre-eclampsia : common (5%)  MCAD (medium chain-acyl-CoA dehydrogenase), HELLP CPT-1 (Carnitine Palmitoyltransferase 1) def. & (Hemolysis, Elevated Liver enzymes, Low ?others are part of a new class of metabolic disorders Platelets) syndrome uncommon (1/200) called fatty acid oxidation defects (FAOD) AFLP (Acute Fatty Liver of Preg)  FAOD are only recently characterized; in childhood jaundice, encephalopathy, (1/10000) present as Reye-like syndrome, ALTE, cardiomyopathy etc

Plasma Free Fatty Acids Long Chain Signs and Symptoms of Fatty Acids Cytoplasm Fatty Acid Oxidation Defects Outer Mt. Memb CPT1 lethargy seizures Inner Mt. Memb hepatomegaly cardiomyopathy CPT2 myopathy sudden death Reye-like episodes coma Mitochondrial Fatty Acyl-CoA Matrix failure to thrive hypoketotic hypoglycemia MCAD LCAD Acetyl-CoA LCHAD

Fetal disease affecting mother

 There are now well- documented studies showing association of LCHAD with preeclampsia, HELLP and esp. AFLP and HELLP  Ibdah et al. A fetal fatty acid oxidation disorder as a cause of liver disease in pregnant women. NEJM. 1999;340:1723-31. Liver Steatosis Cardiomyopathy in FAOD in FAOD 24 children with Fetal disease affecting mother hypoketotic hypoglycemia and fatty liver  ? Mechanism In presence of Glu474Gln mutation, metabolites 8 homozygotes 11 compound 5 with produced by fetus or placenta accumulate in the for heterozygotes for cardiomyopathy/neuropathy mother and are highly toxic to liver. glu474gln LCHAD glu474gln LCHAD no glu474gln mutations Metabolites overwhelm the mitochondrial oxidation machinery of the heterozygous mother who is already 7 had AFLP 8 had AFLP 0 had AFLP under stress from the increased demand for fatty acid oxidation in later stages of pregnancy.. and/or HELLP and/or HELLP and/or HELLP

Fetal disease affecting mother Signs and Symptoms of Fatty Acid Oxidation Defects  Pre-eclampsia and HELLP also associated with lethargy seizures MCAD deficiency hepatomegaly cardiomyopathy myopathy sudden death  hyperemesis gravidarum HELLP and AFLP also Reye-like episodes coma associated with hepatic CPT-1 deficiency failure to thrive hypoketotic hypoglycemia

hyperemesis gravidarum Pre-eclampsia HELLP syndrome acute fatty liver of pregnancy

Recommendations Conclusions

 Strauss et al b Seminars in Perinatology (1999):  Some of the disorders mentioned may be modified  Maternal AFLP / recurrent HELLP prenatally or postnatally by diet e.g.PKU, screen for common LCHAD mutation in parents  Pregnancies can cause significant complications from investigate baby for FAOD- glucose, urinary organic Genetics disorders for mother or baby acids, acylcarnitine profile, carnitine, palmitate oxidation & DNA testing  Pregnancy or birth of an affected child may often be  Yield will be lower for isolated HELLP the “presenting symptom” of an inborn error of metabolism in the family Learning Objectives

After this lecture the student should be able to  Describe the effects of genetic/ metabolic diseases in the mother on the mother or pregnancy and provide examples  Describe the effects of genetic/ metabolic diseases in the mother on the fetus and provide examples  Describe the effects of genetic/metabolic diseases in the fetus on the mother and provide an example 7/22/2009

Objectives

At the end of this lecture, you will be responsible to Newborn Assessment know the following: and Resuscitation • Immediate assessment of the newborn • Apgar score: its elements and implications • Major complications of term delivery • Physiology of perinatal depression and of basic resuscitative measures Med II RP051 • Common causes of failed resuscitation Shyamala Dakshinamurti • Principles of gestational age assessment Section of Neonatology • Major complications of prematurity

• 5 million neonatal deaths per year worldwide • Birth asphyxia accounts for 19% of neonatal deaths and is a major source of perinatal mortality You Are Called to Attend a Delivery…

• 10% of newborns require some respiratory assistance at birth • 1% of newborns require extensive resuscitation at birth • 30,000 deliveries a year in Manitoba • This means 300 newborn resuscitations per year • You will be doing some of these!

Newborn Assessment Newborn Assessment

• You are called to attend this delivery • Immediate questions: • Is the baby breathing? • Maternal history: 26 yr G1 P0, medically healthy, swabs • What is the baby’s heart rate? and serologies normal, in spontaneous labour at term (39 • What is the baby’s colour? wks GA) • Why are you asking these questions? • Intrapartum fetal tracing has shown deep variable decelerations, but these have resolved with changes in Basic Physiology of Neonatal Transition: maternal position • Oxygenation switches from placental to pulmonary • Respiratory drive needs to be stimulated • Mild shoulder dystocia, otherwise delivery uneventful • High vagal tone controlling heart rate • Baby is born flat, blue, not breathing • Hypoxia is a vagal stimulant • Now what? • Almost all cardiorespiratory depression is therefore respiratory in origin. Almost.

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Respiratory Adaptation Circulatory Adaptation

• During fetal life, high pulmonary vascular resistance means blood from the right ventricle • Alveolar fluid is absorbed by the lung (active Na+ ion transport at bypasses the lung birth, stimulated by O2) circulation • Lung inflation initially requires very negative intrathoracic pressure • Blood enters aorta via to recruit alveolar expansion the ductus arteriosus • Stimuli for respiratory effort include rising PO2 at birth and hormonal changes associated with birth, including decreased prostaglandin production • After birth, lungs are oxygenated with first breaths • A supraphysiologic PCO2 also stimulates peripheral chemoreceptors; and pulmonary vascular resistance falls a PCO2 below the apneic threshhold abolishes breathing activity • Ductus closes; Blood enters the lungs via pulmonary • Physical stimuli stimulate breathing by increasing arousal artery, and is oxygenated

insult insult continues… Primary and Secondary Apnea

Primary Apnea regular • ‘stunned infant’ respiratory gasping • Transient apnea; can be associated with drop in HR effort respiration • Spontaneous recovery possible with appropriate stimulation

Secondary Apnea HR falls; HR falls; • ‘down for the count’ Sat may fall Sat falls; • Protracted apnea, associated with bradycardia and BP falls desaturation • Spontaneous recovery not possible; will need resuscitation BP stable

At first glance, these look the same!

Physiology of Resuscitation Causes of Neonatal Cardiorespiratory Compromise • Primary apnea lasts 1 to 2 min, followed by gasping of progressively increasing vigour • • Secondary (terminal) apnea can persist for over 10 Respiratory minutes prior to cardiac arrest • Apnea increases vagal tone and causes bradycardia • Hypoxemia itself inhibits respiratory effort • Respiratory acidosis can be a direct cause of hemodynamic compromise • In severe asphyxia, PaCO2 rises by 10 mmHg/min; pH can drop from 7.30 to 6.80 in 5 min • Cardiac • PaO2 drops as low as 30 mmHg within 5 min of severe asphyxia, with lactic acidosis and onset of hypotension • Blood loss (placenta; cord accident) • Cerebral blood flow decreases with hypoxia • Arrhythmia • Reperfusion injury and oxygen radicals cause much of the • Anemia (high output failure) eg. Rh incompatibility CNS damage in perinatal hypoxia/resuscitation • Septic shock

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Decision Tree Facilitating Neonatal Adaptation Dry Clear airway • Place baby in a warm location • Dry the baby off – and remove the wet linens! observe Breathing? Good respir effort Heart rate? HR > 100 • Clear the airway of mucus and fluid; position for observe Colour pink? open airway (sniffing position) No respir effort or • Stimulate respiration by gentle rubbing of skin Baby to mom; Poor respir effort on back You can go • Watch for onset of respiratory efforts get a coffee

• You have 30 seconds for this stage PPV

Causes of Perinatal Respiratory Distress While you’re thinking: Decision Tree Can’t breathe: dry, clear airway • Mechanical airway obstruction (meconium, blood, mucus) • Parenchymal lung disease (retained alveolar fluid, pneumonia, Poor respir effort etc) • Prematurity and hyaline membrane disease PPV x 30 sec • Space-occupying lesion in pleural space (air, liquid, …gut) Good respir effort observe Breathing? Pinking up Won’t breathe: Heart rate? HR > 100 • Intrauterine asphyxia Poor respir effort Stop PPV and observe • CNS depressants (narcotics, barbiturates, alcohol, HR > 100 anaesthetics, magnesium) • Trauma (cerebral edema, hemorrhage) Keep doing PPV • Neurologic disorders; congenital anomalies

What does APGAR stand for? What is the Apgar at 1 min?

Trick question: it’s not an acronym! • Infant is 60 seconds old… take a second to reassess: It’s named after Dr Virginia Apgar (1953) 1 • Palpating the base of the umbilical cord, you feel a heart rate of about 8 beats in 6 seconds, ie. 80 Heart Respir beats/min rate rate Colour Reflex Tone 0 • No spontaneous respir effort; you are still bagging at 2 > 100 Regular Pink Grimace, Good about 60 breaths/min Sneeze flexor 0 • or Cough tone Colour is pale, with acrocyanosis Apgar < 100 Irregular Acro- Twitch Some 0 • No response when nasopharynx is suctioned 1 score is or cyanosis tone measured 0 • Extremities are limp and flaccid, no spontaneous Gasping only at 1 min movements seen 0 None Apnea Cyanosis None Flaccid and 5 min or In sum, the 1 minute Apgar is only 1. How bad is this? Pallor

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Back to the Decision Tree… Implications of Low Apgar Scores Poor respir effort • At 1 minute, 6% of babies have Apgar score of 0-2; 24% score 3-7; 70% score 8-10 PPV x 1 min so far • This 1 minute Apgar does not correlate with a bad longterm outcome observe Breathing? while ventilating Heart rate? HR > 100 • 5 min Apgar < 4 is associated with major neurological sequelae (cerebral palsy, usually spastic diplegia) HR < 60 Continue PPV • Combination of pH < 7.0 and Apgar < 4 at 5 min has Observe for specificity and positive predictive value of ~100% (but Cardiac compressions onset of Keep doing PPV respir effort poor sensitivity, ~60%) for neurologic abnormality … another 30 seconds • pH < 7.0 and Apgar < 4 is also associated with 8-fold increased risk of neonatal death then consider drugs (epinephrine)

NRP and Drugs NRP and Drugs

Other NRP drugs: • Volume • Recall: about 10% of regular term deliveries require – Crystalloid (NS or Ringer’s lactate) usually sufficient to some intervention; about 1% of regular term deliveries restore intravascular volume in shock require resuscitation – In case of blood loss (eg. Placental abruption), emergency • Of those infants resuscitated, only about 1% require blood transfusion more than PPV +/- CPR; you don’t open the drug box • Sodium Bicarbonate very often – Almost useless – Can be used to correct a severe metabolic acidosis; but this • Epinephrine is the most commonly needed is almost always a result of poor perfusion – far better to fix resuscitation drug in NRP; it can be given iv, or via the perfusion problem endotracheal tube – Route is iv only (need an umbilical central line) • Narcan Which route will you use if you need it in this case? – To reverse effects of recent maternal narcotic therapy, if you know for a fact that there was no chronic maternal drug use

Most Common Morbidities at Term Causes of Rescuscitation Failure

• Sepsis • Inadequate thermoregulation • Commonly Group B Streptococcus • Lack of radiant heat source • Can also be enteric Gram Negative bacilli • Failure to dry infant and remove wet linen • Presents as pneumonia or septic shock; but can also be • Can stymie all further resus efforts quite subtle in onset • Poor respiratory support • Perinatal asphyxia • Take care to position head to open airway • Prolonged labour, cord compression, nuchal cord • Appropriate pressure, appropriate speed !! Ensure (usually problems reversible with good resus) chest inflates with each bagged breath • Placental abruption, placenta previa, vasa previa (can • Is tubing hooked up to an oxygen source? cause significant blood loss) • Good PPV means you rarely need to intubate • Placental insufficiency (acute on chronic)

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What is the Apgar at 5 min? A Successful Resuscitation…

nd It’s now time for your 2 Apgar assessment: But don’t forget the 2 • With your assiduous efforts at PPV, infant now has a after-care: heart rate of 12 beats in 6 seconds’ count, ie. Monitoring for late 120/min complications of 1 • Making occasional gasping respiratory effort perinatal depression 1 • Centrally has started to pink up, although extremities (includes failure of are still blue circulatory transition) 2 • Sneezes with suctioning, grimaces • iv, O2, monitor 1 • Extremities have some tone, but limbs are in an • to mother when extended position you are satisfied The 5 minute Apgar is up to 7. Good resuscitation! all is well

Prematurity: A Special Scenario Hyaline Membrane Disease

• Premature infants are considered viable after 23 weeks gestation, or > 500g – 23-24 weeks is a grey zone (mortality > 90%) – At 23 weeks, lungs are still in a canalicular phase of development (few alveoli, big A/a gradient) – At 25 weeks, mortality 40-50% – By 27 weeks, lungs are alveolarizing, and mortality is down to <20% • Primary complication of preterm birth is respiratory distress due to surfactant deficiency and hyaline membrane disease • The greatest advance in neonatal care in the last 50 years is artificial surfactant

Surfactant - Physiology

surfactant • Surfactant is a product of alveolar type II cells; artificial surfactant may be synthetic or derived from animal lung extracts • Decreases alveolar opening pressure, ie. the pressure at Hyaline Membrane Disease Post Surfactant which the lung parenchyma begins to fill beyond dead High surface tension Decrease in surface tension space volume Collapsed alveoli Inflation of alveoli Hypoventilation, V/Q mismatch Relaxation of pulmonary vessels • Achieved by lowering the surface tension at the gas Hypoxia liquid interface in the small airways and alveoli Pulmonary vascular constriction • Surfactant also stabilizes the lung on deflation, Good gas exchange maintaining functional residual capacity by preventing Respiratory failure complete collapse of previously inflated alveoli Metabolic acidosis Circulatory failure

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How Preterm is Preterm? Major Factors Determining Outcome

• The major determinate of overall perinatal mortality and Gestational age morbidity is prematurity assessment • In developed countries, preventing prematurity would • Based on physical markedly improve infant mortality figures features and on • In developing countries, sepsis is still king (and is the major neurological devt hazard for term infants in North America) • Skin thickness, skin • The main determinate of quality of life is longterm creases, devt of cartilage, breast buds, neurological function genital devt • Perinatal asphyxia, intraventricular hemorrhage, cerebral • Muscle tone (flexor vs palsy and learning disability are all increased with preterm extensor), joint laxity birth and low birth weight

Determining Neurodevelopmental Outcome: Intraventricular Hemorrhage Summary

• Incidence - ~ 20% of infants <1500g • Principles of cardiorespiratory resuscitation in • Pathogenesis the depressed infant: • Temperature regulation – Highly vascular germinal matrix with tenuous capillary • Resolve respiratory problems first integrity, poor cerebral autoregulation • Hemodynamic instability and bradycardia often (but not always) secondary to respiratory issues – Fluctuating cerebral blood flow IVH (especially in infants with • Apgar scores and their implications severe RDS) Periventricular venous congestion • Common causes of failed resuscitation Ischemia • Resuscitating the premature infant

Hemorrhagic infarct • Determinates of term and preterm outcome

Cerebral palsy, neurologic deficit

6 RP062 - Infections in pregnancy and the neonate 7/22/2009

Goal Objectives

Describe the factors that To introduce the concept of specifically affect infections during the special nature of pregnancy and the neonatal period List the most important congenital infections in pregnancy and perinatal infections List the consequences of congenital and perinatal infections Lecture Describe what determines the consequences of congenital and + perinatal infections Tutorial Outline how to diagnose congenital and perinatal infections

Definitions Congenital infections

Perinatal Infections: Occur during  Syphilis gestation, labour and delivery, or  HSV during the first month of life  Hepatitis B Congenital Infections: Occur during  HIV gestation  Varicella Vertical Infections: Occur secondary to  CMV infection of sperm or egg  Human parvovirus B19 Early Onset Neonatal Infections: Occur  Toxoplasmosis before 7 days of age  Malaria Late Onset Neonatal Infections: Occur  TB from 7 days to 3 months of age

Infections transmitted during Labour/Delivery Neonatal Sepsis

 HSV    Hepatitis B Group B hemolytic Streptococcus  E. coli  HIV   HPV Listeria monocytogenes  Enterovirus    Varicella Group A hemolytic Streptococcus   CMV Citrobacter, Enterobacter, Klebsiella, Pseudomonas  Gonococcus/Meningococcus  Staph aureus  Chlamydia  Coagulase negative Staphylococcus  Ureaplasma/Mycoplasma  Candida  GBS/E.coli/Listeria  Tuberculosis  Staph aureus/GAS/Gram negatives  Candida

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Points about Infections during Pregnancy and Possible Consequences of Congenital during the Neonatal period Infections

  transplant antigens expressed on cell  Nothing surfaces of the fetal/placental unit  Fetal Death   maternal immune responses  Fetal malformations  selective transfer of immune co-factors  Chromosomal alterations  infant immune system develops over  Progenitor Cell Death time  Scar Formation » 2 months  2 years of age  Ongoing Infection  IgG but not IgM or IgA transplant  Growth disturbances across placenta  Microcephaly  Placenta (& membranes) act as a  Cranial Calcification barrier to infection  Organ system disease  Neonate is a sterile field for microbial  Maternal death colonization

Possible Consequences of Congenital Possible Consequences of Congenital Infections Infections

Intracranial calcifications Chorioretinitis due to and hydrocephalus due to toxoplasmosis congenital CMV

Possible Consequences of Congenital Possible Consequences of Congenital Infections Infections

Hutchison’s Teeth due to Snuffles congenital syphilis

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What determines the Consequences Diagnosis

 Timing of the maternal infection during  Maternal symptoms gestation  Maternal history of exposure  Timing of the transmission to the fetus  Isolation of the pathogen from the  Maternal general health status mother, placenta and/or infant  Drugs and other treatment given  Documentation of maternal immune  Virulence of the infecting organism response (IgM or  IgG)  General health status of the infant  Infant signs and symptoms  LUCK!!!!  Infant antibody response - IgM, IgA or sustained IgG

Neonatal Sepsis Neonatal Sepsis

 Early: congenital or during labour  Broad Differential Diagnosis  Late: Congenital, labour and » Primary respiratory disease delivery, postnatal  Signs: often non-specific » Congenital cardiovascular » respiratory distress disease » fever » Inborn errors of » circulatory collapse metabolism » seizures » Neurovascular accidents » rash » Sepsis » localizing ms signs

Management

 High index of suspicion  Presume sepsis until proven otherwise  Obtain appropriate cultures THEN start antibiotics +/- antivirals  Choice of antibiotics based on clinical situation  Further therapy based on  results of cultures  identity of the pathogen  antimicrobial sensitivities  clinical condition  response to therapy

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University of Manitoba Faculty of Medicine Med 2 / Blk 4 / RP063 2008

RP63 TUTORIAL - Perinatal Infections & HIV in Pregnancy

Objectives: 1. Describe the factors that specifically affect infections during pregnancy and in the neonatal period. 2. List the most important congenital and perinatal infections. 3. List the consequences of congenital and perinatal infections. 4. Describe what determines the consequences of congenital and perinatal infections. 5. Outline the clinical & laboratory diagnosis of congenital and perinatal infections. 6. Discuss the prevention and medical management principles for congenital and perinatal infections.

CASE #1 Baby Boy A. This infant was born at 34 weeks gestation to a 25-year-old gravida 1 para 0 mother. Prenatal course was uneventful until spontaneous rupture of membranes followed 12 hours later by the onset of labor. Labor lasted 16 hours. The delivery was difficult and forceps were necessary. The baby was small, weighing 1900 grams. APGAR scores were 5 at one minute and 9 at five minutes. The baby was well until 6 hours of age when he was found to be pale and mottled with grunting respirations of 70/minute. The chest X-ray showed a bilateral reticular infiltrate which had a ground-glass appearance. A CBC was drawn and the results were as follows: Hemoglobin=124 g/L; Platelet count=18x10e9/L; WBC=3.2x10e9/L with the differential showing 37% mature and 21% young PMNs.

Comments re case: Normal APGARs of 8 and 8, Hg should be at least 130 in neonates, WBC in first month of life should be around 20-30.

QUESTIONS: 1. What could be the non-infectious and infectious causes for this child’s illness? Non-infectious: muconium aspiration hyaline membrane disease congenital heart defects

infectious: pneumonia, pneumonitis, sepsis (early onset up to seven days, vs late onset 7 days – 3 months) - E.coli - GBS - Lysteria - Herpes viruses (HSV, Varicella- especially when lesions present a few days before and after delivery in which case mom is viremic during delivery)

2. What risk factors could have predisposed this infant to an infection? - prematurity - prolonged rupture of membranes (anything more than 18 hrs is risk for sepsis) - instrumentation

3. When would this infant have probably acquired such an infection? - exposure during labor and delivery

4. What could have been done to prevent illness due to an infection in this infant? - Intrapartum Abx for mom if GBS status unknown or positive, o GBS bacteuria, previous GBS illness in previous baby, GBS swab positive - If mom has intrapartum fever - prolonged rupture of membranes

5. Comment on the results of the CBC in terms of the newborn premature infant’s ability to cope with an infection. - HgB is low, platelets low (usually same as adults), WBC is very low, significant left shift (consistent with sepsis and overwhelming sepsis)

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University of Manitoba Faculty of Medicine Med 2 / Blk 4 / RP063 2008

TX with ampicillin, gentamycin, acyclovir

CASE #2 Baby Boy E. This infant was delivered ½ hour after this 19-year-old unmarried mother was admitted to hospital in labor. Gestational age was unknown and the mother had no prenatal care. The mother would give no information about herself and wanted to sign herself out of the hospital after delivery of her infant. However, the anesthetist had noted needle marks on her arms when he had started her IV during delivery. The infant weighed 1900 grams but appears term. APGARs were 9 at one minute and 9 at five minutes. The head circumference is less than the 5th percentile for a term infant. The infant is described by the nurses as jittery and difficult to handle.

QUESTIONS: 1. What congenital or perinatal infections, if any, could this infant have? - small for gestational age/IUGR type picture - HIV, syphilis, CMV, toxoplasmosis, HBV, HCV, EBV, parvovirus (tends to cause hydrops rather than small baby) 2. What are the risk factors which predispose this infant to a congenital infection? - poor pre-natal care - high-risk maternal behavior (presumed IV drug use, maybe many sex partners) - IUGR

3. What other non-infectious problems could this infant have? - withdrawl - any other regular baby things – hypoglycemia, hypocalcemia, IUGR stress

4. What other physical findings should one look for to determine if this infant had a congenital infection? - vital signs - constellation of symptoms of specific infections - Head neck: microcephaly, cataracts (rubella), deafness, Calcifications of brain seen on CT in CMV, toxoplasmosis, - SMK: X-ray of long bones for periostitis in syph

5. How could one determine whether this infant had one or more congenital infections? - toxicology screen - HIV testing - mom’s serum Ab and baby and do baby HIV PCR at 2 weeks age o HIV positive mom will hve antibody positive baby - Hepatitis B – get mom’s status quickly, if positive give baby Anti-HBV Ig and vaccine, if unknown give vaccine and test baby for Anti-HBV Ab and wait for those results to decide if Ig should be given - Blood culture, urine culture, LP for standard pathogens - LP – Syph, CMV, - Urine for CMV culture within first 21 days of life - pathology should look at placenta (infection specific changes)

CASE #3 Baby Boy F. This infant was born at term to a 23-year-old married gravida 1 para 0 mother. The antenatal course was uneventful. The infant was born via an uncomplicated vaginal delivery after a 16-hour labor. Membranes ruptured at delivery. The infant weighed 3600 grams and the APGAR scores were 10 at both one and five minutes. The post-delivery course was uneventful until the infant was 10 days of age when his parents brought him to the Emergency Department. He had been well until that day when he became “fussy” and didn’t feed well. His mother thought he was warm and took his temperature which was 39.5C. On the way to the hospital, he seemed to become pale and mottled. His mother noted that

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University of Manitoba Faculty of Medicine Med 2 / Blk 4 / RP063 2008 he seemed to be arching his back and not responding to her. She thought he might be having a seizure.

QUESTIONS: 1. What infectious agents acquired perinatally or postnatally could be causing this child’s illness? - late onset sepsis - GBS, E.coli, lysteria - HSV (still within timeframe for disseminated infection) - enterovirus (GI infections, hand,foot,mouth disease can cause fatal infection in newborns while generally self-limitting in adulthood)

2. Discuss why infants have “late-onset” perinatal bacterial infections? - exposed later or with less virulent pathogens

3. What are the risk factors that would predispose this infant to an infection? - no risk factors

CASE #4 Mother C. A G1P0 25-year-old married woman seeks prenatal care at 9 weeks gestation. She is well and has no abnormalities on physical examination. As part of the initial screening investigations, she is found to be HIV seropositive. Her CD4 count is 400 and her HIV viral load is 55,000 RNA copies per ml. She states that she has only had one sexual lifetime partner. Her husband is tested and found to be HIV positive. He denies any risk factors but admits to have had several one night stands while in university before he was married. The woman elects to continue her pregnancy.

QUESTIONS:

1. What other infectious or non-infectious conditions, if any, could this woman have? - STI’s come in packs, test for all of them o syphilis, HPV, GC, Chlamydia, trichomonas, HepB, HepC

2. What are the potential ways that HIV could be transmitted from the mother to her infant? - transplacental (very small percent), during vaginal delivery, breastmilk

3. What interventions could be used to reduce the risk that the infant will acquire HIV from this mother? - Antiretrovirals – start at end of first trimester, triple combo (efaverin is not safe in pregnancy, the rest are) - C/S if viral load doesn’t come down below 1,000 - intrapartum IV AZT 2mg/Kg bolus and 1mg/kg/hr after that - baby gets AZT for a few weeks postpartum - Baby viral PCR at 2 weeks, and repeat times 2, do antibody screen at 1 year to confirm - No breast feeding

CASE #5 Baby Boy H. This 3-month-old infant is admitted to Children’s Hospital with pneumonia which, on X-ray has a bilateral interstitial pattern. On physical examination he is distressed and mildly cyanotic with a respiratory rate of 70 per minute. His weight, height and head circumference are all below the 5th percentile for his age. The liver edge is palpable 5 cm below the right costal margin and the spleen is palpable 2 cm below the left costal margin. He has several palpable lymph nodes 1-2 cm in diameter bilaterally in the axillar, inguinal and cervical regions.

QUESTIONS: 1. What congenital or perinatal infection, if any, could this boy have?

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University of Manitoba Faculty of Medicine Med 2 / Blk 4 / RP063 2008

- HIV + pneumocystis pneumonia until proven otherwise - Chlamydia - Community acquired pneumonia - RSV - big liver, spleen and lymphnodes : EBV, CMV, Toxoplasmosis, leukemia, - SCID would present at this age but they don’t have lymph nodes

2. How could HIV infection be diagnosed in this circumstance? - viral PCR (because he’d still have mom’s Ab) - CD4 count and CD8 counts will come back more quickly (less than 500 is the child equivalent to the adult less than 200)

3. If this infant were found to be infected with HIV, what other clinical illnesses might this child develop in the future? - any opportunistic infection (toxoplasmosis, CMV) - community acquired infections - DO ALL IMMUNIZATIONS except BCG or oral polio

4. Generally, how would you treat this boy if he were found to be HIV infected? - infants are treated at time of diagnosis because there are a subset of kids that will deteriorate very quickly in first year of life - kids diagnosed later in life are followed for CD4 and viral loads every three months o different cell count numbers

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