Fetal Development and Embryology

Fetal Development

• The table of contents includes fetal development, pregnancy and menstruation, pathologies of pregnancy, female pathology, male pathology, and pharmacology.
• The outline includes fetal embryology, germ layers, teratogens, pharyngeal apparatus, sexual differentiation, disorders of genital embryology, chromosomal disorders, sexual development disorders, male anatomy, and female anatomy.

Early Development

• Fertilization occurs in the ampulla of the oviduct.
• A morula forms 4 days post-fertilization.
• The blastocyst implants on day 6 in either an ectopic pregnancy or becomes the placenta previa.
• The trophoblast penetrates the endometrium and divides to form syncytiotrophoblast and cytotrophoblast.
• The bilaminar embryonic disc consists of the epiblast (amniotic sac) and hypoblast (yolk sac).
• During gastrulation, the epiblast forms the primitive streak, which then differentiates into the ectoderm, endoderm, and mesoderm.
• The notochord becomes the nucleus pulposus, and the neural plate develops into the brain and spinal cord.
• Teratogen exposure between weeks 3 and 8 can lead to embryonic malformations.
• Major organ development starts during the embryonic period.
• The neural tube closes, the heart beats, and limb formation begins around week 4.
• Fetal movement occurs in week 8.
• The sex of the fetus becomes recognizable around week 10.

Germ Layers

• The ectoderm forms the epidermis, adenohypophysis, hair, nails, and salivary glands.
• The neuroectoderm develops into the CNS and brain.
• Neural crest cells, derived from the ectoderm, give rise to neurons of the PNS, leptomeninges, bones and connective tissue of the skull, endocardial cushions, melanocytes, chromaffin cells of the adrenal medulla, and enterochromaffin cells.
• The mesoderm forms the notochord (nucleus pulposus), vertebrae, ribs, skeletal muscles, kidneys, gonads, cardiovascular system, microglia, hematopoietic stem cells, and limbs.
• The endoderm forms the Eustachian tube, thymus, parathyroid gland, tonsils, pharynx, GI tract, respiratory tract, and urinary bladder (except the trigone).

Teratogenic Medications

• ACE inhibitors can cause fetal kidney damage and oligohydramnios.
• Anti-epileptics/Folate antagonists can cause neural tube defects.
• Fluoroquinolones can cause cartilage damage.
• Tetracycline can discolor teeth and decrease bone growth.
• Chloramphenicol can cause Gray baby syndrome.
• NSAIDs can cause premature closure of the ductus arteriosus.
• Methimazole can cause aplasia cutis.
• Lithium can cause Ebstein anomaly.
• Thalidomide can cause limb defects.
• Tretinoin/Vitamin A toxicity increases the risk of spontaneous abortion.

Recreational Drugs

• Alcohol use during pregnancy can result in fetal alcohol syndrome, characterized by intellectual disability, a thin upper lip, a flat philtrum, and down-slanting palpebral fissures.
• Cocaine can lead to placental abruption due to widespread vasoconstriction.
• Cigarettes cause widespread vasoconstriction, and CO can cause hypoxia for the fetus.
• Opioids can cause neonatal abstinence syndrome, with features including uncoordinated suckling responses, high-pitched crying, and sneezing; managed with methadone, morphine, or buprenorphine.

Pharyngeal Apparatus

• Pharyngeal clefts are derived from the ectoderm. -The first cleft develops into the external auditory meatus. -The second cleft normally obliterates, but persistence results in a branchial cleft sinus.
• Pharyngeal pouches are derived from the endoderm. -The first pouch forms the middle ear cells, mastoid air cells, and Eustachian tube. -The second pouch forms the epithelium of palatine tonsils. -The third pouch develops into inferior parathyroid glands (dorsal wing) and the thymus (ventral wing). -The fourth pouch forms the superior parathyroid (dorsal wing) and parafollicular cells of the thyroid (ventral wing).
• Pharyngeal arches are derived from mesoderm and neural crest cells. -The first arch develops into the mandibular/maxillary process, muscles of mastication, and the anterior two-thirds of the tongue, innervated by CN V₃. -The second arch develops into the stapedius/stylohyoid process, facial muscles, and stapes, and lesser horn of hyoid bone, innervated by CN VII. -The third arch develops into the stylopharyngeus muscle and greater horn of the hyoid bone, innervated by CN IX. -The fourth arch develops into the pharyngeal constrictors and is innervated by the superior laryngeal nerve. -The sixth arch develops into the larynx muscles (except cricothyroid) and is innervated by the recurrent laryngeal nerve. -Disorders include Pierre Robin Sequence and Treacher Collins Syndrome.
• Aortic arches: -The first aortic arch becomes the maxillary artery. -The second aortic arch becomes the stapedius artery. -The third aortic arch becomes the common carotid and internal carotid arteries. -The fourth aortic arch becomes the aortic arch and right subclavian artery. -The sixth aortic arch becomes the ductus arteriosus (DA) and pulmonary arteries.

Sexual Differentiation

• Male development starts with testes derived from primordial germ cells at the gonadal ridge. -The SRY gene triggers the process of Testis Determining Factor (TDF) production. -Sertoli cells produce Anti-Müllerian Factor (AMH). -Leydig cells produce testosterone.
• Mesonephric ducts develop into the seminal vesicle, epididymis, ejaculatory duct, and vas deferens.
• External genitalia develop under the influence of DHT, converted from testosterone by 5⍺ reductase.
• Female development starts with the ovary derived from primordial germ cells at the gonadal ridge. -Granulosa cells produce estrogen. -Theca cells produce androgens.
• In the absence of the SRY gene, paramesonephric ducts persist and develop into the oviduct, uterus, and upper vagina.
• Estrogen is responsible for external genitalia development.
• Homologous structures: -The genital tubercle becomes the glans penis (male) or glans clitoris (female). -The urogenital sinus becomes the prostate gland (male) or Bartholin’s gland (female). -The urogenital folds become the ventral shaft of the penis (male) or labia minora (female). -The labioscrotal swelling becomes the scrotum (male) or labia majora (female).

Disorders of Genital Embryology

• Male disorders: -Epispadias: Faulty positioning of the genital tubercle results in the urethra opening dorsally, often associated with bladder exstrophy and urinary incontinence. -Hypospadias: Failure of the urogenital folds results in the urethra opening ventrally, often associated with inguinal hernias and cryptorchidism. -Cryptorchidism: Testes fail to descend.
• Female disorders: -Müllerian Agenesis: Failure of the Müllerian duct to develop, presenting with primary amenorrhea, normal development of breasts, external genitalia and body hair, absent uterus/upper-vagina/oviduct, and functional ovaries. -Bicornuate Uterus: Incomplete paramesonephric duct fusion. -Septate Uterus: Incomplete resorption of the septum. -DES exposure: Vaginal adenocarcinoma, T-shaped uterus, abnormal fimbriae.

Chromosomal Disorders

• Klinefelter Syndrome (47XXY): -Caused by meiotic nondisjunction error or advanced paternal age. -Testicular dysgenesis leads to seminiferous tubule fibrosis, causing decreased Sertoli cells and decreased inhibin and increased FSH. -Leydig cell dysfunction results in decreased testosterone, increased LH, and Leydig cell hyperplasia. -Presentation includes infertility (azoospermia), gynecomastia, increased height (SHOX), and testicular atrophy. -Labs show hypergonadotropic hypogonadism: increased LH, FSH, estradiol, and decreased testosterone. -Can have seminiferous tubule fibrosis and Leydig cell hyperplasia. Associated with increased risk of testicular and breast cancer, as well as mitral valve prolapse.
• Turner Syndrome (45XO): -Caused by errors in paternal meiotic nondisjunction or mitotic nondisjunction of embryonic cells (mosaicism). -Presentation includes primary amenorrhea, short stature (SHOX), webbed neck, and shield chest. -Labs show increased FSH and LH, and decreased estradiol. -Associations: cardiac issues such as bicuspid aortic valve and coarctation of the aorta and lymphatic obstruction like cystic hygroma and renal such as horseshoe kidney. -Pregnancy is possible with IVF and hormone supplementation.
• Double Y Syndrome (47XYY): Tall stature, potential motor or language delay, and no fertility issues.

Sexual Development Disorders Part 1

• 5⍺ Reductase Deficiency: -Leads to decreased conversion of testosterone to DHT, resulting in ambiguous genitalia. -Presentation includes the absence of phallus elongation, bifid scrotum, and hypospadias, lasting until puberty. -Labs show a Testosterone:DHT ratio >20, XY karyotype, and normal estrogen levels. -Autosomal recessive inheritance.
• Androgen Insensitivity Syndrome: -Occurs in individuals with an XY karyotype due to a defect in the androgen receptor preventing the body from responding to androgens. -Y chromosome presence results in testes. -Leydig cells produce testosterone but no mesonephric ducts develop. -Sertoli cells produce AMH but no paramesonephric ducts develop. -Presentation includes female presenting, rudimentary vagina, primary amenorrhea, cryptorchidism, absent mesonephric duct structures, female breast development, and absence of pubic hair. -Labs show XY karyotype, increased LH, increased testosterone, and increased estrogen. -X-linked recessive inheritance.

Disorders of Sexual Development Part 2

• Placental Aromatase Deficiency: -Caused by an autosomal recessive mutation leading to an absence of aromatase. -Inability to convert androgens to estrogen leads to fetal masculinization due to increased androgen levels. -Presentation: In female infants, ambiguous genitalia and primary amenorrhea; mothers may experience voice deepening, hair growth, and acne. -Labs show decreased estrogen and increased testosterone.
• Kallman Syndrome: -Occurs due to failure of GnRH neurons to migrate to the hypothalamus, affecting the olfactory bulb and preoptic nucleus. -Failure is caused by GnRH neurons failing to stimulate gonadotropin hormones, resulting in hypogonadotropic hypogonadism. -Presentation includes lack of secondary sex characteristics, primary amenorrhea, decreased sperm count, cryptorchidism, decreased height, and anosmia. -Labs show decreased GnRH, FSH, LH, testosterone (in males), and estrogen (in females).

Male Anatomy

• Organs include the testis, seminal vesicle, ejaculatory duct, epididymis, ductus deferens, prostate, and penis.
• Blood flow: The testicular artery branches from the abdominal aorta to supply the testicles. -The Pampiniform plexus is present. -Internal iliac branches supply portions of lower anatomy -Nutcracker syndrome: Trapping of the left renal vein causes backflow of blood and symptoms including left varicocele, hematuria, and flank pain; can be caused by renal cell carcinoma or massive weight loss.
• Lymphatics: -The testis drains to the para-aortic nodes. -The scrotum drains to the superficial inguinal nodes. -The prostate/corpus cavernosa drain to the internal iliac nodes.
• Sexual Response: -Erection is caused by parasympathetic nerve stimulation. -Emission is caused by hypogastric nerve stimulation. -Expulsion is caused by pudendal nerve stimulation.
• Anterior Urethral Injury: -Damage to the bulbar urethra. Resulting from a straddle injury, which causes blood to appear at the urethral meatus and scrotal hematoma (Dartos fascia).
• Posterior Urethral Injury: -Damage to the membranous urethra caused by a pelvic fracture -Fluid leak into retropubic space -Presentation: Blood at urethral meatus and high riding prostate.

Female Anatomy

• Organs: ovaries, oviduct, uterus, vagina, labia majora, labia minora, greater Bartholin gland.
• Blood Flow: Ovarian artery branches from abdominal aorta. Rest are supplied by branches of the internal iliac artery i.e. uterine and vaginal arteries.
• Lymphatics: Ovaries drain to para-aortic nodes. Labia majora/minora drain to superficial inguinal nodes. Uterus/Cervix drain to external/internal iliac nodes.
• Nerves: The peritoneal fold contains the pelvic pain line- pelvic sympathetics are above , and parasympathetics (S2-S4) below. -Ischial spine provides landmark which leads to the ischioanal fossa which leads to the Pudendal block: Pudendal nerve is the primary sensory innervation to the genitalia
• Ligaments: The suspensory ligament contains The ovarian vessels and damaging the ureter is a risk during hysterectomy.
• The Broad Ligament consists of Mesometrium, mesosalpinx, and mesovarium Cardinal Ligament: goes from Cervix to lateral pelvic wall Round Ligament: Goes from Uterine horn to labia majora, travels through inguinal canal, and causing round ligament pain.

Pregnancy and Menstruation

• Gametogenesis: Includes spermatogenesis, folliculogenesis, and oogenesis.
• Pregnancy Hormones: Focus on estrogen, prolactin, β-hCG, and human placental lactogen.
• Menstrual Cycle: Involves ovarian and uterine cycles.
• Menstrual Cycle Disorders: including primary and secondary amenorrhea, dysmenorrhea, and mittelschmerz.
• Pregnancy Physiology: Focus on fertilization, changes by systems.
• Placenta and Umbilical Cord: Covers anatomy of the placenta, umbilical cord disorders.
• Fetal Circulation: Includes ductus venosus, foramen ovale, and ductus arteriosus and their blood circulation.
• Childhood Development: Describes use of the Tanner Stages.

Gametogenesis

• Spermatogenesis occurs in the seminiferous tubules. -Spermatogonia undergo mitosis to form one 1° spermatocyte. -1° spermatocyte undergoes meiosis I to form two 2° spermatocytes. -2° spermatocytes undergo meiosis II to form four spermatids.
• Spermiogenesis is the maturation process where spermatids become spermatozoa, this happens in the epididymis.
• Folliculogenesis maturation of ovarian follicle from primordial follicle to secondary and tertiary.
• Tertiary follicle’s oocyte component is releases. -The empty tertiary follicle becomes the corpus luteum which releases progesterone. with ↑ hCG sustaining the corpus luteum if fertilization occurs.
• Oogenesis: Immature oocyte → 2° oocyte or mature ovum -In fetal development a oogonium turn into a 1° oocyte while in the fetal stage. -1° oocyte arrested in Prophase I until puberty -During ovulation, a oocyte is released and arrested in Metaphase II. -If unfertilized, menstruation. If fertilized, zygote. -Post-fertilization, the secondary oocyte finishes Meiosis II to become a mature ovum with a 2nd polar body.

Hormones of Pregnancy

• Estrogen: A steroid hormone with intracellular receptors synthesized in ovaries (granulosa cells), placenta, and adipose tissue. -Converts androgen to estrogen via aromatase with estradiol (ovary) > estrone (fat) > estriol (placenta) -Stimulates growth of breast, endometrium, and vagina, and ↑ clotting factors, HDL, and osteoclast apoptosis.
• Progesterone: steroid hormone → Intracellular receptor. Synthesized by corpus luteum + placenta. -Endometrial spiral artery and glandular development, inhibits prolactin and cervical mucus thickening; raises body temperature, inhibits estrogen receptors .
• βhCG: GPCR → cAMP that maintains the corpus luteum → continued progesterone production. Peak during secretion at Day 6 post-fertilization, around 8-10 weeks.
• Human Placental Lactogen: Contributes to insulin resistance.

Menstrual Cycle

• Normal cycle lasts around 28 days, with menses lasting 3-7 days and menopause after 12 months without menstruation.
• Ovarian Cycle: -Follicular Phase (Days 1-14): FSH stimulates ovarian follicle development, granulosa cells produce estrogen which decreases FSH, and increased estrogen increases FSH and LH which leads to ovulation. -Luteal Phase (Days 15-28): LH surge causes ovulation/rupture of tertiary follicle. -Tertiary follicle remnant becomes corpus luteum. Increased -CG maintains corpus luteum until late in pregnancy so progesterone increases. Corpus luteum decreases if there is no fertilization making progesterone decrease.
• Uterine Cycle: -Menstrual Phase (Days 1-7): triggered by no fertilization, this cause decreased progesterone, vasospasm spiral arteries to cause bleeding. -Proliferative Phase (Days 7-14): endometrium grows due to estrogen which is produced by follicles. -Secretory Phase (Days 14-28): Corpus luteum produces progesterone to lead to the preparation of endometrium. This Causes spiral arteries to extend along endometrium and endometrial glands to lengthen.

Menstrual Cycle Disorders

• Primary Amenorrhea: absence of menarche by age 15 of the following causes: -Hypogonadotropic hypogonadism (Kallmann syndrome): decreased GnRH leads to decreased LH, FSH, and estrogen. -Hypergonadotropic hypogonadism (Turner’s): increased GnRH, LH, and FSH, with decreased estrogen. -Anatomical Abnormalities -Mullerian Agenesis → Normal GnRH, LH, FSH, estrogen -Imperforate hymen = non patent hymen -Enzymatic/Receptor dysfunction -Complete Androgen Insensitivity causes increased LH, testosterone, and estrogen -Congenital Adrenal Hyperplasia
• Secondary Amenorrhea: absent menses for 3 months in an individual with a regular cycle or 6 a previously irregular cycle. Uterine Disorders: such as asheman syndrome ovarian disorders (PCOS, premature ovarian failure) Pituitary/Functional hypothalamic amenorrhea is low GNRH due to Eating disorders/Disordered eating, increased / cortizal
• Dysmenorrhea: painful menses with primary and Prostaglandin increases as an trigger.
• Mittelschmerz: Ovulatory pain due to a ruptured follicular cyst during from overstimulation of the oviduct

Pregnancy Physiology

• Fertilization occurs when flagellum of the sperms whip around and allow the sperm to penetrate the oviduct.
• Acrosome reaction penetrates with its enzymes help the sperm to penetrate the zona pellucida, for the cortical reaction to prevent polyspermy.
• Changes by System increases cardiac output, respiratory to dyspnea due to increase of pre/afterload, which causes tidal volume + low TLC. Elevated Renal plasma flow increases to increase GFR which lowers Creatinine with Glycosuria. Also decreases Motility through decreased Lower Esophageal Sphincter, and constipating the Colon. Increases Insulin and triggers Insulin Resistance.
• Lactation: Suppressed during pregnancy by progesterone then it is increased with Prolactin with the release of the placenta. Also Suckling inhibits Dopamine release to further prolactin + which causes ↑ Oxytocin release from supraoptic and paraventricular nuclei with leads to the Milk ejection

Placenta & Umbilical Cord

• The Placenta has Anatomy Decidua Basalis, Intervillous Space, Choronic Plate and which have hormone production.
• Hormone protection occurs through βhCG, HPL, and Progesterone Derived from the allantois which later become the Median umbilical ligament.
• There are 2 arteries that transfer deoxygenated blood and then 1 vein: Oxygenated blood and 1 -Vitelline duct: Connects yolk sack to midgut lumen
• Diseases such as Vitelline fistula: Where the vitelline duct persists allowing Meconium to escape from umbilicus, otherwise Partial obstruction of vitelline duct = Cyst around umbilicus is. If it is completely obliteration of vitelline duct = Small bowel obstruction creating what's called Meckel diverticulum.
• A Single umbilical artery increases chromosome abnormalties leading to Patent and partially blockage of the Urachus.

Fetal Circulation

• Oxygenated Blood flows from the Placenta → Umbilical vein → Ductus venosus → IVC → Right atrium the Ductus venosus connects the umbilical vein and IVC. After birth, Ductus venosus turns into Ligamentum venosum after birth. This causes Right atrium → Foramen ovale → Left Atrium → Left ventricle → Aorta → Systemic Circulation with the help of the Foramen ovale bypass the lungs.
  A patent is a result that fails the fusing of both in 25% to cause embolic risk.
• Deoxygenated Blood is now from Extremities → SVC → Right atrium → Right ventricle → Pulmonary artery→ Ductus arteriosus to avoid pulmonary artery issues and then that derivative turns to -->Ligamentum arteriosum after birth Closure of the Foramen Ovale happens after birth by increase left atrial pressure, when this fails we get an Failure of septum primum and septum secundum to fuse and turn into PFO this is can cause embolic risk is patent in 25% of
• the Ductus Arteriosus Derivative is from the 6th aortic arch and is Kept open during pregnancy by ↓ O2. In order to help a Alprostadil will help the Ductus arteriosus whereas an Indomethacin will close ductus arteriosus Machine is like murmur at is common when above happen with the
• Sinus Venosus is a Smooth portion of the right atrium

Childhood Development.

• Tanner Stages: The stages of development of the male and female sexual characteristics with stage 1 being the start of sexual development. While stage 5 is the maturation of their Penis/testis and pubic.
• Fetal alcohol syndrome causes Intellectual disability, thin upper lip, flat philtrum, down-slanting palpebral fissures

Pathologies of Pregnancy

• Includes ectopic pregnancy, molar pregnancy, hypertension in pregnancy, supine hypotension syndrome, polyhydramnios and oligohydramnios, twin-twin transfusion syndrome, placental pathology, postpartum hemorrhage.

Ectopic Pregnancy

• Etiology: Fertilized egg implants outside the uterine cavity and is most commonly in the Fallopian tube but can be also in less common regions like the abdomen or cervix. Risk factors include previous ectopic pregnancy, PID, IUD, IVF, ↑ age, and endometriosis.
• Presentation: Usually presents 4-6 weeks after the last period and comes with morning sickness/breast tenderness, Vaginal bleeding, varying/Acute Abdominal with signs of shock Diagnostics include urine pregnancy test which is + but with a ↑β-hCG and No evidence of intrauterine gestation on US
• Management: Methotrexate(contraindicated in breastfeeding mother), RhoGAM and surgery
• Differential Diagnosis: Appendicitis, Ovarian cyst rupture, Molar pregnancy, and Spontaneous abortion

Molar Pregnancy

• Etiology: Trophoblastic syncytiotrophoblast + cytotrophoblast disease of pregnancy. Complete moles consist of 46XX or 46XY which is when the Enucleated ovum (P57-) is Fertilized by 1 sperm that results in Paternal DNA duplication. Then the ↑↑↑ β-hCG that leads to ↑↑↑ Hydropic villi + Circumferential proliferation to then ↑↑↑ Risk of choriocarcinoma
• Partial Moles: 69XXX, 69XXY, or 69XYY normal -ovum (p57+) that is Fertilized by 2 sperm results in ↑ β-hCG which causes Minimal hydropic villi and proliferation (Minimal risk of choriocarcinoma)
• Presentation: ↑↑↑ β-hCG, pregnancy, and causes Pelvic discomfort. It is also diagnosed b first semester Vaginal bleeding (prune juice), and it is a ↑ Uterine fundus size for gestational age. US is when you see complete moles present through “Snowstorm” / “Grape cluster” / “Honeycomb appearance, " whereas partial moles: you would find Fetal part

Pregnancy Hypertension

• Stage Presentation Etiology Management
• Chronic: When you encounter -HTN prior to 20 gestational weeks or if -HTN persists post delivery with Obesity + Diabetes then the management is the prescribe -Antihypertensives(Hydralazine, Labetalol, Methyldopa, Nifedipine)
• Gestational: When -HTN presents after 20 gestational weeks with Normal BP 6 weeks post delivery and with a ↑ Risk with multiple gestations due to increased blood volume + circulatory load is treated with “Hypertensive Moms Love Nifedipine” but there is a prompt Delivery at 37-39 weeks
• Preeclampsia is when you can see -Gestational hypertension +(Proteinuria)or organ disfunction cause by Abnormal placental spiral arteries