Boards and Beyond: Reproductive A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 3-10-2017 3 -10-2017
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Table of Contents Embryonic Genes Embryogenesis Embryogenesis Germ Layers Errors in Morphogenesis Morphogenesis Teratogens I Teratogens II Pharyngeal Arches Cleft Lip and Palate Pharyngeal Pouches/Clefts Pouches/Clefts Reproductive Embryology Embryology
1 4 6 9 11 16 20 24 25 27
Spermatogenesis and Oogenesis Placenta Twins Pregnancy Maternal-Fetal Disorders HTN in Pregnancy Placental Complications Complications Gestational Tumors TORCH Infections
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31 34 38 40 44 48 51 54 57
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Embryonic Genes •
•
Sonic Hedgehog FGF
•
Wnt-7a
•
Homeobox ( Hox) genes
Embryonic Genes Jason Ryan, MD, MPH
Sonic Hedgehog Gene
Patterning •
SHH Gene
Development of body pattern •
•
Head, arms, legs
•
•
•
Sonic Hedgehog Gene •
•
•
Formation forebrain
•
Signaling separates right and left brain Establishes midline Mutations: Holoprosencephaly •
Holo = “whole”
•
Prosencephalon = forebrain
Many embryonic roles: limbs, brain, eyes Keyroles: •
CNS development
•
Limb development
Holoprosencephaly
CNS Development •
Makes Sonic Hedgehog protein Embryonic signaling protein
•
•
Failure of cleavage of prosencephalon Left/right hemispheres fail to separate Single-lobedbrain •
•
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No left/right hemispheres
Facial abnormalities •
Cleft lip/palate
•
Cyclopia
Limb Development •
•
Limb Development
Limb “patterning” Limbs develop along three planes
•
Proximal to distal
•
Dorsal-ventral Dorsal-ventral axis
•
•
Limb Development
Humerus radius wrist
•
Dorsal: Extensors
•
Ventral: Flexors
Anterior-posterior axis •
Anterior: towards head
•
Radius and thumb
•
Ulna fingers
Apical Ectodermal Ridge
Dorsal
Ventral
•
Critical for proximal to distal development
•
Ectodermoverlying Ectodermoverlying mesoderm
•
•
Area of limb bud formation Removal: Limb stops growing
AER Mesoderm Limb Growth
Apical Ectodermal Ridge •
•
Influences underlying mesodermal growth •
“Progress zone” forms in mesoderm with with growing cells
•
Mesoderm also influences ectodermal r idge
Key transcription factor: Fibroblast Growth Factor •
•
Dorsal-Ventral Development
From expression of FGF gene
Ridge removed, replaced with FGF: Normal growth
•
Flexors/extensors
•
Depends on multiple genes •
Radial fringe (dorsal)
•
Engrailed1 (ventral)
•
SER2 (border)
•
Wnt-7a
Dorsal (extensors) AER
FGF
Mesoderm Limb Growth
AER Mesoderm
Ventral (flexors)
Limb Growth
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Dorsal-Ventral Development •
Wnt-7a key for dorsaldevelopment dorsal development •
•
Wnt Genes •
Activates LMX-1 gene in mesoderm
•
•
“Dorsalizes” mesoderm
•
Gene deletion: Two ventral sides to limb
•
Mouse embryos: sole sole on both surfaces surfaces of paws
Family of genes Originally described in Drosophila •
•
•
Ventral side: Engrailed1 represses Wnt-7
•
Winged integration gene
Found in many species including humans Early embryo: regulators ofdorsal-vent of dorsal-ventral ral axis Later embryogenesis:anteroposterior embryogenesis: anteroposterior axis
Dorsal (extensors) AER Mesoderm Limb Growth Hikasa H and Sokol S. Wnt Signaling in Vertebrate Axis Specification. Cold Spring Harb Perspect Biol. 2013 Jan (5(1)
Ventral (flexors)
AP Development
Homeobox Genes
Anterior-Posterior
HOXGenes
•
•
•
•
Depends on zone of polarizing activity Posterior limb (near little finger)
•
•
Influences AER Major signaling molecule: SHH •
•
Sonic Hedgehog protein •
Code for transcription factors Regulators of AP of AP axis axis development development Homeotic genes •
Homeosis = transformation transformation of one structure into another
•
Homeotic genes = lead to formation formation of body segments
•
Mutation abnormal body part formation
All homeotic genes have same sequences ~180 bases •
Called the Homeobox Homeobox (part of gene)
Homeobox Genes
Embryonic Genes
HOXGenes
Summary
•
Family of genes: HOXA1, HOXB1, HOXD1, etc.
•
Rare mutations of some HOX genes described •
Most result in abnormal limb formations
•
Fruit flies: legs grow from head head instead of antenna!
•
Polydactyly (extra fingers/toes)
•
Syndactyly (fused fingers/toes)
•
Sonic Hedgehog •
Hemispheres of brain holoprosencephaly
•
Limb AP axis: zone of polarizing activity AER
•
FGF
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Wnt-7a
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Homeobox (Ho x) genes
•
•
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Limb proximal-distal axis apical epidermal ridge Limb dorsal-ventral axis
“dorsalizes” limb
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Limb AP axis
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Mutation abnormal digits/toes
Fertilization •
•
•
Haploid mature spermatozoon (1N, 1C) Haploidovum Haploid ovum (1N, 1C) Forms zygote (2N, 2C)
Embryogenesis Jason Ryan, MD, MPH
DNA Synthesis •
Maternal/paternal DNA in “pronucleus”
•
2N, 2C DNA synthesis chromatids 2N, 4C
•
Zygote divides into two cells (2N, 2C)
Fetal Development Development •
Morula
Two cell stage: first 1-2 days after fertilization
Blastulation
•
Cells continue to divide
•
Formation of blastulafrom blastula from morula
•
Morula = ball of cells cells
•
Blastula contains fluid cavity called blastocoel
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Blastulation •
•
•
Implantation
In humans, blastula called blastocyst Outer cells: trophoblast •
Polarized: one side different from other
•
Watery fluid of blastocoel blastocoel secreted by trophoblast cells
•
•
Blastocyst implants in uterus about day 6-10 secretionbegins β-hCG secretionbegins
Inner cell mass (apolar) •
Give rise to all tissues tissues of body
•
Embryonic stem cells derived from inner cell mass
Gastrulation
Gastrulation
•
Blastula 3 layered structure called gastrula
•
•
Three germ layers
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Two cell layers separated by basement membrane
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Epiblast andhypoblast
•
Ectoderm
•
Mesoderm
•
Endoderm
Primitive Streak •
•
•
Inner cell mass bilaminar disc
Gastrulation
Formed by invagination of epiblast cells
•
Creates a visible line (“streak”) in blastocyst Presence indicates start of gastrulation gastrulation
Epiblast three germ layers •
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Ectoderm, endoderm, mesoderm
Gastrulation •
•
Formation of gastrula Contains three germ layers •
Ectoderm
•
Mesoderm
•
Endoderm
Germ Layers Jason Ryan, MD, MPH
Nervous System Development
Ectoderm •
Epidermis
•
Nervous system
Nervous System Development •
Nervous System Development
Notochord arises in mesoderm •
•
Adult remnant: nucleus pulposus of spine
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Inducesoverlying ectoderm neural plate
•
Neural plate folds neural tube •
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Neural tube: CNS •
CNS neurons, oligodendrocytes, astrocytes
•
Retina
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Spinal cord
Neural crest: PNS •
Cranial nerves
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Dorsal root ganglia
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Autonomic ganglia
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Schwann cells
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Microglia (phagocytes): Mesoderm
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Meninges: Mesoderm
Endoderm
Mesoderm
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GI epithelium and derivatives
•
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Liver,gallbladder , pancreas
•
•
Alveoli, epithelium epithelium of trachea/br trachea/bronchi onchi •
•
Airway cartilage from mesoderm
•
•
Mesoderm •
Many congenitaldefects in mesoderm derivatives
•
Congenital heart defects
•
•
Muscle, bone, connective tissue Cardiovascular structures Kidneys Lymphatics Blood
Mesenchyme •
Embryonic connective tissue
•
Mostly derives from mesoderm
•
Limb deformities Renal defects
•
•
Cells surrounded by proteins and fluid Gives rise to most connective tissue •
•
•
•
•
Heart Development
First 8 weeks after fertilization Organogenesis occurs Must vulnerable period to teratogens Followed by fetal period •
Most adult structure established
•
Organs/structures grow
Bones, cartilage, lymphatic and circulatory circulatory systems
Mesenchymal tumors = sarcomas
Embryonic Period
Embryonic Period •
Not found in adults adults except for mesenchymal stem stem cells
•
Week 4
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Week 6
•
•
7
Heart begins beating
Transvaginal ultrasound detects detects fetal heart movement
Embryonic Period
Embryonic Period
Limbs
Genitalia
•
Week 4 •
•
•
Limbs form
•
Week 8 •
Week 10
Baby begins moving •
SRY gene (Y chromosome)
•
Lack of SRY gene clitoris development
•
•
From Rathke’s pouch of ectoderm
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Outpouching of upper mouth
Usually week 15 to 20
•
Cortex:Mesoderm Cortex:Mesoderm
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Medulla: Neural crest
•
Posteriorpituitary (neurohypophysis) (neurohypophysis) •
penis development
Adrenal Gland
Anterior pituitary (adenohypophysis) •
Ultrasound identification of gender •
Pituitary Gland
Prior to week 10 genitalia look similar similar for males/females
•
•
From neural tube
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Aldosterone, cortisol, androgens Epinephrine, norepinephrine
Morphogenesis •
Process of embryo taking shape
Errors in Morphogenesis Jason Ryan, MD, MPH
Errors in Morphogenesis Morphogenesis
Errors in Morphogenesis •
•
Intrinsic Errors
Intrinsic
•
Agenesis
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Failure of embryo to develop
•
Missing organ caused caused by missing embryonic tissue
•
Abnormal genes or other internal processes
•
Renal agenesis
•
Agenesis, Aplasia, Hypoplasia, Malformation
Extrinsic •
External force impacts normal development
•
Disruption, Deformation
Errors in Morphogenesis
Errors in Morphogenesis Morphogenesis
Intrinsic Errors
Intrinsic Errors
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Aplasia
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Hypoplasia
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Missing organ due to growth failure failure of embryonic tissue
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Incomplete organ development
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Thymic aplasia (DiGeorge syndrome)
•
Microcephaly
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Errors in Morphogenesis Morphogenesis
Errors in Morphogenesis
Intrinsic Errors
Extrinsic Errors
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•
•
•
•
Malformation Neural tube defects defects Cleft lip or palate
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Classic example: amniotic band syndrome
Congenital heart defects
Errors in Morphogenesis
•
Disruption •
Deformation •
External force leads to abnormal abnormal growth (not arrest)
•
Deforms or misshapes misshapes structure
•
•
•
Classic example: Potter’s syndrome
•
Potter’s Syndrome •
External compression of the fetus
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Alteration in lung liquid content
•
Also called Potter’s sequence
•
•
Normal tissue growth arrested due to external force
•
Fetal structures entrapped entrapped by fibrous bands in utero
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Often involves limbs or digits
Potter’s Syndrome
Extrinsic Errors •
•
Abnormal developmentof developmentof structure
Abnormal face/limb formation Abnormal lung formation
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Fetus exposed to absent or ↓ amniotic fluid Amniotic fluid = fetal urine Severe renal malfunction = ↓ amniotic fluid Loss of fetal cushioning to external forces
Teratogens •
•
Teratogens I
Substances that cause abnormal fetal development development Common effects: •
Fetal loss
•
Growth restriction
•
Birth defects
•
Impaired neurologic function
Jason Ryan, MD, MPH
Teratogens •
•
Teratogen Timing
Many mechanisms:
•
Cell death/apoptosis
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“All or none” period
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Disrupted metabolism
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Spontaneous abortion or no effect
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Disrupted cell growth/proliferation
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Greatest risk of fetal exposure 1st trimester •
Embryonic period
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Formation of organs
•
Teratogens •
Drugs
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Substances of abuse •
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•
•
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First two weeks
•
•
•
Radiation Chemicals (mercury) Maternal illness Diabetes
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Phenylketonuria (PKU)
Infectious agents •
•
Organogenesis
•
Structural defects
After week 8 •
Decreased growth
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Central nervous system system dysfunction
•
Usually no birth defects
Drug Testing
Alcohol, cocaine, smoking
•
Weeks 2-8
TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes
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Animals •
FDA requires all drugs drugs be tested in animal models
•
Often rodents (rats)
Case reports
Drug Categories •
•
•
•
•
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ACE Inhibitors and ARBs
FDA labels drugs during pregnancy in categories Category A: no risk to fetus in human studies
•
•
Category B: no risk to fetus in other studies Category C: risk cannot be ruled out
•
Category D: positive evidence of risk Category X: contraindicated in pregnancy •
Drugs known to be teratogenic in animals and humans
•
Risks clearly outweigh outweigh benefits
Seizure Drugs •
Women with epilepsy may require drugs in pregnancy
•
All anti-seizure drugs may affect fetus
•
Decreased fetal kidney function
•
Fetal renal failure
•
Can lead to Potter’s syndrome
•
Pulmonary hypoplasia, limb/skeletal deformities
High risk drugs •
Valproic acid (↑↑ neural tube defects)
•
Phenytoin
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Congenital heart disease
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Phenobarbital
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Cleft palate
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Carbamazepine
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Short fingers
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Abnormal facial features
•
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Fetal Hydantoin Syndrome
•
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Seizure Drugs
•
•
2nd/3rd trimester: Oligohydramnios
Neural tube defects defects
•
•
Pregnancy Pregnancy class D 1st trimester: numerous congenital malformations
Many anti-seizure drugs associated with ↓ folic acid ↓ folic acid neural tube defects High dose folic acid supplementation
Chemotherapy
Associatedwith phenytoin use in pregnancy Growth deficiency Abnormal facial features
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Rarely women develop malignancy while pregnant
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Ideally chemotherapy deferred
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Hodgkin lymphoma
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Broad, short nose
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After birth
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Wide-spaced eyes
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2nd/3rd trimester
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Malformed ears
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Microcephaly
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Classically cleft lip and cleft palate
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Fetal malformations 15% with therapy in 1st trimester
Chemotherapy •
•
Isotretinoin
Highest risk: alkylatingagents and antimetabolites Adverse effects on fetus: •
Spontaneous abortion
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Missing digits
•
Many other fetal abnormalities
•
•
•
•
•
Derivative of vitamin A Used to treat acne Pregnancy class X Spontaneous abortions (~20%)
“Embryopathy”: 20-30% of live births •
•
Vitamin A Excess •
•
•
•
•
Congenital heart disease
•
Hydrocephalus
Birth control mandatory
Methotrexate
Teratogenic in first trimester Spontaneous abortions
•
•
Microcephaly Cardiac anomalies
Inhibits folate metabolism Used as anti-inflammatory
•
Pregnancy class X
•
May cause neural tube defects
•
Occurs at doses several times RDA
Aminopterin/me Aminopterin/methotrex thotrexate ate embryopathy embryopathy Neural tube defects
•
Abnormal skull/face shape shape
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Cleft palate
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Hydrocephalus
•
Limb anomalies
Methotrexate
Folate
Warfarin
Methotrexate •
Used to induce induce abortion in ectopic ectopic pregnancy
Methotrexate
Vitamin A
•
Abnormal facial features features (low ears, wide-spaced eyes)
•
•
•
•
•
•
Folate
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Anticoagulant Pregnancy class D Fetal hemorrhage, spontaneous abortion Optic atrophy (vision loss) Warfarin Embryopathy •
Bone and cartilage abnormalities
•
Stippled epiphyses: small, round densities on X-ray
•
Nasal hypoplasia
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Limb hypoplasia
Methimazole •
•
•
•
•
Lithium
Treatment for hyperthyroidism Pregnancy class D
•
•
May cause fetal and neonatal hypothyroidism Aplasia cutis: cutis: absence of epidermis on scalp •
Solitary defect on scalp ~70% of cases
•
Missing patch skin/hair
•
•
•
Antibiotics
Aminoglycosides •
•
•
•
Trimethoprim
•
Sulfonamides
•
May disrupt folate metabolism in fetus neural tube defects
•
Accumulate in fetal fetal teeth and long bones
•
Displace bili rubin from albumin
•
May permanently discolor fetal teeth
•
Can cause kernicterus
Fluoroquinolones Fetal cartilage damage
Thalidomide •
•
Reports of permanent deafness in fetus
Tetracycline
•
•
Teratogenic effects primarily involve heart Ebstein’s anomaly most common
Propylthiouracil Propylthiouracil (PTU) used in 1st trimester
Antibiotics •
Used in psychiatric disorders Pregnancy Pregnancy class D
Diethylstilbestrol
Pregnancy class X
•
Rarely used for treatment of multiple myeloma Used in 1950s as sedative in pregnancy Limb deformities •
Amelia: absence absence of li mb
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Micromelia: short limbs
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Phocomelia: abnormal limb
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•
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Nonsteroidal estrogen Used to prevent miscarriage, premature birth Removed from US market 1971 Slightly increased risk of breast cancer for mothers Female babies: Reproductive tract abnormalities
Diethylstilbestrol •
•
•
Hypoplasticuterus Cervicalhypoplasia Vaginal adenosis •
Metaplasia of cervical or endometrial epithelium in vagina
•
Persistent Müllerian tissue after birth
•
Vaginal clear cell adenocarcinoma
•
High rate of infertility
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Teratogens •
•
Drugs Substances of abuse •
•
•
Teratogens II
•
Jason Ryan, MD, MPH •
Chemicals(mercury) Maternal illness •
Diabetes
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Phenylketonuria (PKU)
Infectiousagents •
•
Facial Features
Neurotoxin •
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Smooth philtrum
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Short palpebral fissures fissures
•
Thin vermillion border
Multiple mechanisms: mechanisms: Cell death, failure of cell migration
•
May cause fetal alcohol syndrome (FAS) •
Characteristic facial features
•
Congenital heart defects
•
Skeletal anomalies
•
Intellectual disability
TORCH: Toxoplasmosis, Other, Rubella, CMV, Herpes
Alcohol
Alcohol •
Alcohol, cocaine, smoking
Radiation
•
•
Groove from base of nose to upper lip
Small opening of eyes
Upper lip
Alcohol
Alcohol
Heart Defects
Growth/Skeletal
•
Congenital heart defects •
Atrial septal defect
•
Ventricular septal defect
•
Tetralogy of Fallot
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•
Below average height, weight
•
Limb defects •
Finger contractions
•
Congenital hip dislocations
Alcohol
Alcohol
CNS •
•
•
•
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Structuraldefects
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First trimester
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Microcephaly
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Facial abnormalities
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Small corpus callosum, cerebellum, basal ganglia
•
Brain abnormalities
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Congenital heart disease
Abnormal reflexes Hypotonia Cranial nerve deficits
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Third trimester •
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Intellectual impairment (reduced IQ)
Intellectual impairment: •
Smoking Two toxins: Nicotine and carbon monoxide
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Impaired oxygen delivery to the fetus •
Nicotine-induced vasoconstriction
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CO competes with O2
•
•
•
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IUGR/Low birthweight
•
Placental anomalies
•
↓ placental blood flow
↓ oxyhemoglobin
•
Cocaine •
May occur without facial or brain anomalies
Smoking
•
•
Mostly affects size of baby, brain growth
20% cases cases associated with smoking Abruption
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Previa
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Premature rupture of membranes
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Preterm labor
•
Well-documented association with SIDS
Mercury
Vasoconstriction
•
IUGR/low birthweight Placental abruption Preterm birth
Methylmercury found infish/seafood in fish/seafood •
Not removed by cooking
•
Highest levels: swordfish, swordfish, shark, shark, tilefish, Mackerel King
•
Fetal brain highly sensitive to mercury
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Delayed milestones
•
Rarely blindness, deafness, or cerebral palsy
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Miscarriage
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Mother not usually usually affected
CH3 - Hg Methylmercury
X-rays •
•
•
No evidence of harm at small doses Threshold for harm not definitively determined
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Higher dosages 8-15 weeks may cause: •
•
Maternal Diabetes
Intellectual disability
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Microcephaly
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Growth restriction
•
•
•
•
•
•
Blood sugar alterations
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Congenital heart disease
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CNS disorders
Adverse effects related to severity of diabetes
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Neonatal Hypoglycemia
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Baby born large for gestational age
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Baby makes excess insulin (“hyperinsulinemic state”)
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Weight >90 th percentile is common
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Blood glucose levels below 40 mg/dL
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Babies often >9lbs at birth
•
Transient: usually the first 24 hours of of life
•
Close glucose monitoring after delivery is essential
Can lead to birth injury Shoulder dystocia (shoulders cannot pass through birth canal)
Caudal Regression Syndrome
Maternal Diabetes •
Increased growth
•
Maternal Diabetes
Macrosomia(large Macrosomia(large baby)
•
•
•
Lead shielding used to protect fetus
Maternal Diabetes •
Multiple effects on fetus:
Sacral Agenesis
Congenital heart defects: 3-9% of babies Transposition of the great arteries (TGA) Ventricular septal defects (VSDs) Truncus arteriosus
•
Classically associated with maternal diabetes
•
Incomplete development of sacrum
•
May include sirenomelia
•
Tricuspid atresia Patent ductus arteriosus (PDA) •
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Usually children of insulin-dependent mothers
•
“Mermaid syndrome”
•
Fusion of legs
Often includes a neural tube defect
Phenylketonuria
Phenylketonuria Phenylalanine
•
Maternal PKU
•
High levels of phenylalanine acts as a teratogen
•
•
•
•
Occurs in women with PKU who consume phenylalanine
•
•
Serum phenylalanine monitored in pregnancy Dietary restriction of phenylalanine essential
•
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IUGR Microcephaly
Phenylalanine
Intellectual disability (mental retardation) Congenital heart defects •
Coarctation of the aorta
•
Hypoplastic left heart syndrome
Pharyngeal Apparatus •
•
Embryonic structure Key for development of head and neck
Pharyngeal Arches Jason Ryan, MD, MPH
Terminology •
•
•
•
Pharyngeal Apparatus
Branchia: Greek word for gills “Branchial”: relating to gills Humans: similar embryonic structures Branchial or pharyngeal
•
Pharyngealclefts Pharyngealclefts Pharyngealpouches Pharyngealpouches
First Pharyngeal Arch Bones •
Gives rise to cartilage/bone and muscles
Neural crest cells migrate to center •
•
Pharyngeal arches
•
Core of mesenchyme (connective tissue) •
Three components
•
•
Pharyngeal Arches •
•
Gives rise to cranial nerves
•
Artery forms aortic arches
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“Maxillaryprocess” “Maxillary process” •
Maxilla
•
Zygomatic bone
“Mandibularprocess” “Mandibularprocess” •
Mandible
•
Meckel’s cartilage incus and malleus
First Pharyngeal Arch
First Pharyngeal Arch
Muscles
Trigeminal Nerve
•
Muscles of mastication •
Temporalis, masseter, pterygoids
•
Anterior digastric
•
Mylohyoid
•
Tensor tympani (ear)
•
Trigeminal mandibular and maxillary divisions
•
Sensory to face
•
Motor: muscles of mastication
First Pharyngeal Arch
Second Pharyngeal Arch
Aortic Arch
Bones
•
Portion of maxillary artery
•
•
•
•
“Reichert’scartilage” “Reichert’s cartilage” Stapes (ear) Styloid process of temporal bone Lesser horn of hyoid hyoid
Second Pharyngeal Arch
Second Pharyngeal Arch
Muscles
Nerve
•
•
•
•
•
Stapedius (ear)
•
Auricular muscles (ear) Stylohyoid Posteriordigastric Muscles of facial expression
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Facial nerve
Second Pharyngeal Arch
Third Pharyngeal Arch
Artery
Cartilage/Bones
•
•
Stapedialartery •
Embryonic vessel
•
Usually involutes in development
•
Hyoid bone •
Body and greater horn
Hyoid artery •
Embryonic vessel
•
Develops into small branch of internal carotid
Third Pharyngeal Arch
Third Pharyngeal Arch
Muscles
Nerve
•
Stylopharyngeus
•
Third Pharyngeal Arch
Glossopharyngeal nerve (IX)
Fourth and Sixth Arches
Artery •
Common carotid
•
Fifth arch does not persist in humans
•
Proximal internal carotid
•
4th/6th: both innervated by vagus nerve branches
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•
4th: superior laryngeal
•
6th: recurrent laryngeal
Fourth and Sixth Arches
Fourth and Sixth Arches
Cartilage
Muscles
•
Both arches fuse to form larynx cartilage •
Thyroid
•
Cricoid
•
Arytenoid
•
Corniculate
•
Cuneiform
Fourth and Sixth Arches
•
•
•
•
Cricothyroid
•
Levator palatini
•
Pharyngeal constrictors
6th Arch •
Intrinsic muscles of larynx
•
(except cricothyroid)
4th Arch •
Left: aortic arch
•
Right: proximal right subclavian artery
(“pulmonaryarch”) 6th Arch (“pulmonaryarch”) •
Left: proximal pulmonary artery
•
Left: ductus arteriosus
•
Right: proximal pulmonary artery
Tongue
First arch syndrome
•
Failure of neural crest cell migration Underdeveloped facial bones •
•
4th Arch
Pharyngeal Arches
Treacher Collins Colli ns Syndrome •
Laryngeal muscles
•
•
Arteries •
•
Small mandible (mandibular hypoplasia) •
Anterior two thirds: 1st and 2nd arches •
Lingual swellings and tuberculum tuberculum impar
•
Sensation: CN V (1st arch)
•
Taste: CN VII (2nd arch)
Posterior third: 3rd and 4th arches
•
Small jaw (micrognathia)
•
Absent/small ears
•
Sensory: GP Nerve (IX) of 3rd arch
•
Glossoptosis (retraction of tongue)
•
Some posterior taste via CN X (4 th arch)
May lead to difficulty breathing
•
Motor:
•
Underdeveloped lower jaw
•
Hypoglossal (XII)
•
Obstruction of airway by tongue
•
One exception: palatoglossus (CN X)
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Cleft Lip and Palate •
•
•
Cleft lip: most common craniofacial malformation Often occurs with cleft palate Multifactorialetiology Multifactorialetiology •
Environmental, genetic
Cleft Lip and Palate Jason Ryan, MD, MPH
Cleft Palate
Cleft Lip •
Primary palate (front of palate)
•
Secondary palate (back of palate)
•
Formed by fusion of structures
•
Lateralstructures:palatal structures: palatal shelves (processes)
•
•
•
•
Nasal prominences fuse: form philtrum Maxillary prominences from 1st pharyngeal arch
•
•
Fuse with medial nasal prominences to form 1° palate Failure of this process leads to cleft lip Maxillary Prominence
Nasal Prominences
24
Fusion to form 2° palate Failure leads to cleft palate
Pharyngeal Apparatus •
•
Pharyngeal Pouches and Clefts
Three components Pharyngealarches Pharyngeal arches
•
Pharyngealclefts Pharyngeal clefts
•
Pharyngealpouches Pharyngealpouches
Jason Ryan, MD, MPH
1st Pharyngeal Pouch
Pharyngeal Pouches •
Four pharyngeal pouches
•
Forms many portions of inner ear
•
Composed of endoderm
•
Eustachian tube
•
•
2nd Pharyngeal Pouch •
•
•
•
Middle ear cavity Contributes to tympanic membrane
3nd Pharyngeal Pouch
Lining of palatine tonsils (back of throat)
•
2nd pouch forms buds Invaded by mesoderm
•
•
Invaded by lymphatic tissue
25
Thymus (mediastinum) Left and right inferior parathyroid glands (neck) Forms two “wings” •
Dorsal (back): Thymus
•
Ventral Ventral (front): Parathyroid
DiGeorge Syndrome
4th Pharyngeal Pouch •
•
•
Thymic Aplasia
Superiorparathyroid glands Ultimobranchial body •
Incorporates into thyroid gland
•
Forms C-cells (calcitonin)
•
Dorsal (back): Parathyroid
•
Ventral Ventral (front): Ultimobranchial body
Four pharyngeal clefts
•
Lined byectoderm by ectoderm
•
1st cleft develops into external auditory meatus •
•
Most cases: 22q11 chromosomal chromosomaldeletion deletion
•
•
Also contributes to tympanic membrane
Temporary cavity
•
Obliterates in development
•
•
Often occur in children Mass does not move with swallowing Contrast with thyroglossal duct cyst •
Midline neck mass
•
Moves with swallowing
•
Loss of thymus (Loss (Loss of T-cells, recurrent infections)
•
Loss of parathyroid glands (hypocalcemia, tetany)
•
Congenital heart defects (“conotruncal”)
Present as neckmass •
2nd through 4th clefts form cervical sinus •
Abnormal thymus, parathyroid function Classic triad:
Branchial Cleft Cyst
Branchial Cleft Cyst •
•
Also forms two “wings”
•
•
Failure of 3rd/4th pharyngeal pouch to form
•
Pharyngeal Clefts
•
•
26
Location based on cleft of origin
•
2nd cleft cysts are most common
•
Below angle of of the mandible
•
Anterior to sternocleidomastoid sternocleidomastoid muscle
Often noticed when become infected Fistula to skin may develop
Genital System •
Chromosomal sex determined at fertilization
•
Later development: development:
•
Genital Embryology
XX (female) or XY (male)
•
Gonads (ovaries/testes)
•
Internal genitalia
•
External genitalia
Jason Ryan, MD, MPH
Gonads
Testis
Testis/Ovaries •
•
•
•
Gonadal ridges form about 7 weeks Derived frommesenchyme from mesenchyme (mostly mesoderm) Germ cells derived from epiblast Invade gonadal ridges
•
SRY gene (Y chromosome)
•
Codes for testis determining factor
•
•
Forms Sertoli and Leydig cells Leydig cells producetestosterone produce testosterone
•
Failure to reach ridges : gonads do not develop
•
Testosterone male development
•
Male/female gonads initially identical
•
Medullary (testis) cords form
•
Expand out of testis connect to genital ducts
•
“Indifferent gonad”
Ovary •
•
•
•
Genital Ducts
Medullary cords regress
•
Cortical cords develop form clusters Surround germ cells •
Oogonia and follicular cells form primordial follicles
27
Two pairs of genital ducts in embryo •
Mesonephric (wolffian)
•
Paramesonephric (müllerian)
Mesonephros: interim kidney 1st trimester •
Associated duct: mesonephric duct
•
Paramesonephric duct: formed near mesonpehric duct
Genital Ducts
Genital Ducts •
Male
Develop into internal genital tracts
•
Sertoli cells: Müllerian inhibitory factor (MIF)
•
Male: epididymis, vas deferens, seminal vesicles
•
Suppress development of paramesonephric paramesonephric ducts
•
Female: fallopian tubes, uterus, upper vagina
•
Male remnant: appendix testis (tissue at upper testis)
•
Leydig cells: Androgens Androgens Stimulate development development of mesonephric ducts
•
Testosterone
Genital Ducts
Genital Ducts
Male
Male
•
Mesonephric ducts elongate to form:
•
Epididymis
•
Epididymis
•
Duct behind testis
•
Ductus (vas) deferens
•
Transport sperm from seminiferous seminiferous tubules to vas vas deferens
•
Seminal vesicles
•
Ejaculatory ducts
•
Ductus deferens (vas deferens) •
Transport sperm from epididymis epididymis to ejaculatory ejaculatory ducts
Testosterone
Genital Ducts
Genital Ducts
Male
Female
•
•
Seminal vesicles •
Glands behind bladder
•
Secrete about 75% of fluid in semen
•
Connect with ejaculatory ducts Collect sperm/fluid from from seminal vesicles and vas deferens
•
Pass through prostate
•
Connect to urethra
Paramesonephric ducts form internal structures
•
Fallopian tubes
•
Ejaculatory ducts •
•
28
Only occurs in absence of MIF and androgens
•
Uterus
•
Upper 2/3 vagina
Gartner's Duct •
•
•
Urogenital Sinus
Wolffian/mesoneph ric remnant in females Found on vaginal walls May form cyst
•
Upper portion: bladder
•
Pelvic (middle) portion: prostate and prostatic urethra
•
Phallic portion: penile urethra
•
Urogenital sinus forms male/female structures
Forms urogenital sinus and anal canal
•
“Lateral fusion defects” most common
•
May cause infertility, pregnancy loss
•
Failed fusion of two two sides of uterus
Females •
Upper portion: bladder
•
Pelvic portion: Inferior vagina
•
Connects with paramesonephric ducts
Uterine Anomalies •
•
Uterine Anomalies
Males •
Cloacadivides Cloaca divides •
Urogenital Sinus •
•
Uterine Anomalies
Most common: septate uterus •
Septum divides uterus
•
Two endometrial cavities
•
Defect in resorption of septum between Müllerian Müllerian ducts
•
Bicornuate: Fundus is indented
•
Unicornuate: Uterus connects to one ovary
•
Uterine didelphys (double uterus)
•
•
Treatment: septoplasty
•
29
Partial fusion of the Müllerian ducts Other ovary not connected connected to uterus
Müllerian ducts fail fail to fuse
External Genitalia
External Genitalia •
•
Male
Begins with indifferent stage Four ke ystructures •
Genital tubercle
•
Urogenital sinus (from cloaca)
•
Urogenital folds (from cloaca)
•
Labioscrotal (genital) swellings
•
Genital tubercle elongates phallus
•
Urogenital folds close penile urethra
•
Urogenital sinus glands
•
Hypospadia
•
Prostate gland
•
Bulbourethral glands (of Cowper)
Labioscrotal swelling scrotum
Epispadia
•
Congenital anomaly of male urethra
•
Urethral opening on dorsal side of penis
•
Ventral opening of urethra
•
Much less common than hypospadia
•
•
Failure of urethral folds to close Cryptorchidism in ~10% of patients
•
•
Abnormal position/formation of genital tubercle Commonly occurs with bladder extrophy
External Genitalia
External Genitalia
Male
Female
•
•
Requiresdihydrotestosterone Requires dihydrotestosterone •
Testosterone DHT
•
Enzyme: 5α-reductase
•
•
•
5α-reductase deficiency •
Ambiguous genitalia until puberty
•
At puberty: ↑ testosterone
30
Genital tubercle elongates clitoris Urogenital folds (no fusion) labia minora Urogenital sinus glands •
Paraurethral glands (Skene)
•
Bartholin glands
•
Labioscrotalswelling labia majora
•
Requires estrogen >> androgen
Gametogenesis •
Spermatogenesis and Oogenesis
Development of haploid gametes •
Male and female sex cells
•
Sperm
•
Oocytes
Jason Ryan, MD, MPH
Primordial Germ Cells •
Common origins of spermatozoa and oocytes
•
Derived from epiblast cells
•
•
Spermatogenesis •
Migrate to reside among endoderm cells of yolk sac During 8th week: migrate to genital ridge
•
Meiosis •
Diploid cells give rise to haploid cells (gametes)
•
Unique to “germcells” “germcells”
•
•
Spermatocytes
•
Oocytes
Begins at puberty •
Sex cords in testes develop a lumen
•
Become seminiferous tubules
Spermatogenesis occurs in seminiferous tubules
Meiosis Blue = Paternal Red = Maternal
Meiosis I
Chromosome content of cells: •
2n 2C (diploid)
•
2n 4C (diploid)
•
1n 2C (haploid)
•
1n 1C (haploid)
Meiosis II
2n 4C
2n 2C DNA Synthesis
1n 2C 1n 1C
31
Spermatogonia •
•
•
Spermatogenesis
2n 2C cells Derived from primordial germ cells
•
•
Precursors of spermatozoa •
•
•
Haploid (1n 1C)
Undergo spermiogenesis •
Form spermatozoa (sperm)
•
Singular: spermatozoon
•
•
•
Sertoli Cells •
•
•
•
•
•
DNA synthesis completed
•
Starting meiosis I
2° spermatocytes spermatocytes •
Meiosis I completed
•
Starting meiosis II
•
1n, 2C cells
Formation of spermatozoa
Spermatids •
2n, 4C cells from spermatogonia
•
Spermiogenesis
Spermatogenesis •
1° spermatocytes spermatocytes
Formation of acrosome •
Cap of sperm
•
Contains enzymes to assist in fertilization
Condensation of nucleus Formation of neck and tail Shedding of most of cytoplasm
Sertoli Cells
Line walls of seminiferous tubules
•
Support and nourish developing spermatozoa Regulate spermatogenesis Stimulated by FSH Supported by Leydig cell testosterone (paracrine) Need FSH and LH for normal spermatogenesis
32
Formblood-testis Form blood-testis barrier •
Tight junctions between adjacent adjacent Sertoli cells
•
Apical side (toward tubule): meiosis, spermiogenesis
•
Basal side: spermatogonia cell division
•
Isolates sperm; protection from autoimmune attack
Seminiferous Tubules •
•
Spermatogonia •
Germ cells
•
Behind blood-testis barrier
•
Separated from tubule by Sertoli cells
•
•
•
•
Sertoli cells •
•
Oogenesis
Support/regulate spermatogenesis
•
Form blood testis b arrier
•
•
Found in interstitium (between tubules)
•
Secrete testosterone
Oogenesis
Primary oocytes: diploid cells formed in utero •
•
•
About 7 million
Surrounded by cells primordialfollicle
Leydigcells
Oogenesis •
Oogonia 1° oocytes (2n 4C) Maximum number formed by 5th month in utero •
Line tubules
•
Primordial germ cells oogonia (2n 2C) Oogonia divide in utero
•
2° oocytes (1n 2C)
•
No fertilization: oocyte degenerates
Beginning meiosis I
•
Arrested in prophase prophase of meiosis I until puberty
At puberty •
Menstrual cycles begin
•
A few primary oocytes oocytes complete meiosis 1 each each cycle
•
Some form polar bodies degenerate
•
Some form 2° oocytes
33
Meiosis II begins
arrests in metaphase
•
Fertilization completion of meiosis II
•
Forms ovum (1n 1C)
Placenta •
Nutrient and gas exchange between mother/fetus
Placenta Jason Ryan, MD, MPH
Decidual Reaction •
Endometrium reaction at implantation
•
Decidua = altered uterine lining during pregnancy
•
Decidua basalis •
•
•
•
Uterus at site site of implantation •
Interacts with trophoblast Surrounds fetus
Decidua parietalis •
•
•
Inner membrane that that covers fetus
•
Holds amniotic fluid
•
Protects embryo
Chorion Membrane that surrounds amnion/embryo
•
Derived from trophoblast
•
Supports fetus and and amnion
Opposite wall of uterus
Placental Terminology •
Amnion
•
Decidua capsularis •
•
Membranes
Trophoblast
Basal plate •
Maternal side of placenta
•
In contact with uterine wall
•
Includes maternal decidua basalis
Chorionicplate •
Fetal side of placenta
•
Chorion at placenta
•
Gives rise to chorionic chorionic villi
34
•
Outer layer of blastocyst
•
Develops into placenta
Trophoblast •
•
•
•
Chorionic Villi
Proliferates into two cell layers Syncytiotrophoblast :: outer layer Syncytiotrophoblast •
Invades endometrium
•
Finger-like projections: projections: villi
•
Form lacunae (spaces) for maternal maternal blood
•
•
•
•
Proliferates cells migrate into syncytiotrophoblast
•
Secretes proteolytic enzymes to aid invasion
Chorionic villi: villi: projections of both layers •
Contact with maternal maternal blood
•
Nutrient/gas exchange
•
Fetal mesoderm invades villi
•
Branches of umbilical artery/vein grow
•
Eventually connects to umbilical cord
Placental Circulation
•
•
•
•
•
Maternal side
•
Fetal side
•
Placental Barrier •
Contact area with maternal blood
Cytotrophoblast : inner layer
Chorionic Villi
•
Outerlayer: syncytiotrophoblast syncytiotrophoblast Innerlayer: cytotrophoblast cytotrophoblast
Endometrial (spiral) art villous space endometrial vein
•
Umbilical arteries (deoxygenated blood)
•
Umbilical arteries
•
Capillaries umbilical vein (oxygenated blood)
chorionic arteries capillaries
Umbilical Cord
No mixing of maternal/fetal blood
•
Oxygen and carbon dioxide diffuse Facilitated transport of glucose Active transport of amino acids
•
•
•
IgG antibodies (not IgM) Some other nutrients, drugs, infectious agents
Connection between embryo and placenta Derives from fetus Contains umbilical arteries and veins Yolk sac •
•
Allantois •
35
Cavity (sac) formed in early embryogenesis Outpouching of hindgut
Pharyngeal Pouches
Allantois •
Esophagus
•
•
Celiac Trunk
Foregut
•
Yolk Sac SMA
Outpouching Outpouching from wall of gut Walls formumbilical form umbilical blood vessels Lumen occludes in development Becomes urachus •
Fibrous remnant of allantois
•
Connects bladder to umbilicus
Midgut
Allantois IMA
Hindgut
Cloaca
Umbilical Cord •
Two umbilical arteries •
•
Single Umbilical Artery •
Deoxygenated fetal blood to placenta
One umbilical vein •
•
•
Associated with fetal anomalies
•
Contains mucopolysaccharides
•
Similar to vitreous humor
•
•
•
Allantoic duct
•
Connects fetal fetal bladder to umbilical cord
•
Obliterates in development
•
Becomes urachus
•
Duct sometimes seen in umbilical cord
•
Aneuploidy
•
Congenital malformations
Urachus
Wharton jelly
•
Often identified on prenatal ultrasound
•
Oxygenated fetal fetal blood from placenta
Umbilical Cord
Abnormal variant
•
36
Remnant of allantois Connection between bladder and umbilical cord In adult: median umbilical ligament May cause adenocarcinomaof adenocarcinomaof bladder
Urachus Anomalies •
Immunology of Pregnancy
Patent urachus •
•
Vesicourachal diverticulum
•
Urachal cyst
•
•
Urine discharge from umbilicus Diverticulum of bladder bladder
Fetus: foreign antigens •
Half of genes from father
•
HLA proteins differ from mother
•
Protected from maternal immunity by placenta
•
Several mechanisms
•
Partial obliteration
•
Trophoblast cells do not express many MHC class I antigens
•
Fluid-filled cavity
•
Placenta secretions secretions block immune response
•
May become infected
37
Twins •
•
Twins
•
Jason Ryan, MD, MPH
Twins •
•
Resorption of fetus/embryo
•
Delivery of single baby
•
•
•
More fetuses = shorter pregnancy •
•
Single fetus ~ 40 weeks
•
Twins ~ 37 weeks
•
Triplets ~ 33 weeks
Monozygotic Twins •
•
•
•
Two zygotes
•
Two separate ova fertilized by two separate sperm
•
Two siblings born from single single pregnancy
•
“Fraternal twins”
Monozygotic twins •
One zygote divides in two
•
One ova fertilized by one sperm
•
“Identical twins”
Dizygotic Twins
Often one twin dies in utero •
One pregnancy: two babies Dizygotic twins
Each baby has own amnion and chorion “Dichorionic diamniot ic” ic” Two separate placentas Common in mothers using IVF
Monozygotic Twins
May have a single shared placenta
•
Variable number of amnions, chorions Depends on when zygote divides •
•
•
38
Days 1-3 •
May have two placentas
•
Dichorionic, diamniotic
Days 4–8 •
Chorion already under under development
•
Monochorionic diamniotic
Days 9-12 •
Chorion and amnion amnion already under under development
•
Monochorionic monoamniotic
Day 13+ •
Also monochorionic monoamniotic
•
May results in conjoined twins
Twin Pregnancies •
•
•
Increased risk of maternal/fetal complications Fetus •
Growth restriction
•
Congenital anomalies
•
Preterm delivery
Maternal •
Gestational hypertension/preeclampsia
39
Pregnancy Dating •
Embryonicage
•
Gestational age
•
Age dated to fertilization
•
Age dated to to last menstrual period
•
Embryonic age plus two weeks
Pregnancy Jason Ryan, MD, MPH
Fertilization
Implantation
•
Occurs within 1 day of ovulation
•
Occurs about 6 days after ovulation
•
Usually occurs in the ampulla of fallopian tube
•
Syncytiotrophoblast secretes hCG
HCG
HCG
Human chorionic gonadotropin
Human chorionic gonadotropin
•
•
Similar structure to luteinizing hormone (LH) •
Two glycoprotein subunits (“heterodimeric (“heterodimeric glycoprotein”)
•
α and β subunits
•
LH and hCG: same α subunit
•
Also same α subunit in FSH and TSH
•
•
•
•
Binds LH receptors in corpus luteum
40
Maintains corpus luteum Corpus luteum continues progesterone release Prevents menstruation Maintains pregnancy for first 10 weeks
HCG
HCG
Human chorionic gonadotropin
Human chorionic gonadotropin
•
Used to detect pregnancy
•
Usually antibody based tests (ELISA variants)
•
•
Detect β subunit of hCG •
Serum tests •
Most sensitive method for detecting hCG
•
Can detect very low levels 1-2mIU/mL
•
May be positive within 1 week week of conception
Urine tests •
hCG threshold 20 20 to 50mIU/mL
•
May not be positive until 2 weeks weeks or more
Human placental lactogen
Syncytiotrophoblast
Chorionic somatomammotropin
•
Secretes hCG
•
Protein hormone
•
Begins progresterone synthesis about 10 weeks
•
Producedby syncytiotrophoblast syncytiotrophoblast
•
Placenta maintains pregnancy going forward
•
•
•
•
•
•
Decreased maternal response to insulin Diabetes mellitus
•
•
Worsened by pregnancy
•
Gestational diabetes •
Raises blood glucose glucose level (good for baby)
•
Promotes breakdown of fatty acids by mother for fuel
•
Promotes breakdown of proteins for fuel
Plasma Volume
Pregnancy is an insulin-resistant state
•
•
Physiologic Changes
Diabetes in Pregnancy •
Higher levels as placenta grows during pregnancy Blocks effects of insulin
Onset of diabetes diabetes during pregnancy
41
Total body volume expands Blood fills placenta Diverted from maternal circulation
↑ renin salt/water retention
Physiologic Changes
Physiologic Changes
Red Cell Mass
Hemodynamics
•
Red cell mass expands
•
Increased maternal EPO
•
•
•
•
Dilutional anemia •
Rise in volume > rise in red cells
•
Result: ↓ Hct
•
Physiologic Changes
•
Peripheral Peripheral resistancefalls •
Placenta is a low resistance system
•
Also maternal maternal vasodilation
Occurs in later stages of pregnancy
•
Large baby compresses IVC when lying flat
•
•
1 =
1
Rtotal
R1
Maternal heart rate rises slightly
•
•
Blood pressure normally falls
Parallel
Preload increased by rise in blood volume Afterload reduced reduced due to fall in systemic systemic vascular resistance
Supine Hypotension
Hemodynamics •
Cardiac output rises
Decreased venous return (preload) Fall in cardiac output Reflex tachycardia may produce symptoms
Series 1 +
R2
Rtotal = R1 + R 2
Physiologic Changes
Physiologic Changes
Coagulation
Pulmonary
•
•
Pregnancy is a hypercoagulable state
•
Ventilation increases
•
Probably evolved to protect against blood loss at delivery
•
More CO2 to exhale
•
Many clotting factor levels change
•
Also hormone-induced
•
Increased fibrinogen
•
Decreased protein S
Fetus also obstructs venous return DVTs common
42
•
Mostly due to increased tidal volumes
•
Respiratory rate minimally changed
Labor •
•
•
•
•
Terbutaline/Ritodrine
Regular uterine contractions Progressive dilation of cervix
•
•
Descent and expulsion of fetus Normally occurs at 40 weeks
•
Inhibit contractions
Preterm labor <37 weeks
Apgar Score •
Used to access newborn immediately after birth
•
10 point score at 1 and 5 minutes after birth
•
Value of 0, 1, or 2 for five categories: •
•
•
β-2 agonists ↑ cAMP Relax uterine (smooth) muscle
Pregnancy Termination •
Heart rate •
Respiratory effort
•
Muscle tone
•
Reflex irritability
•
Skin color (pink, blue)
5-min score ≤3 associated with neurologic damage •
Cerebral palsy
43
Mifepristone •
Anti-progesterone
•
Blocks progesterone effects on uterus
•
Prevents implantation
Misoprostol •
Synthetic prostaglandin E 1 analog
•
Induces uterine contractions
•
Combination: Medical abortion in >90% women
•
NOTE: Methotrexate used only in ectopic pregnancy
Ectopic Pregnancy •
•
Maternal-Fetal Disorders
•
Pregnancy outside the uterus 98% occur in fallopian tube Most commonly ampulla (mid portion)
Jason Ryan, MD, MPH
Ectopic Pregnancy
Ectopic Pregnancy
•
Symptoms in 1st trimester
•
Diagnosis: ultrasound
•
Vaginal bleeding
•
Treatment:
•
•
Abdominal pain (may mimic appendicitis) Abnormal ↑hCG based on dates
•
Methotrexate
•
Surgery
Ectopic Pregnancy
Ectopic Pregnancy
Risk Factors
Risk Factors
•
•
•
Damage to fallopian tube Prior ectopic pregnancy Tubal disorders •
Tubal surgery (tumor)
•
Pelvic inflammatory inflammatory disease (Chlamydia, Neisseria)
Infertile women: higher incidence
•
Kartagener syndrome (1° ciliary dyskinesia) •
Tubal ligation (rarely pregnancy occurs)
•
•
44
Fallopian tubes: ciliated epithelium
Spontaneous Abortion
Spontaneous Abortion
Miscarriage
Risk Factors
•
Pregnancy loss before 20 weeks •
After 20 weeks: weeks: stillbirth or fetal demise
•
Maternal smoking, alcohol, cocaine
•
Maternal infection (TORCH)
•
Presents as vaginal bleeding
•
Hypercoagulable states
•
Often requires D&C to remove all tissue
•
Lupus/antiphospholipid
•
50% cases due to fetal chromosomal chromosomal abnormalities abnormalities
Amniotic Fluid •
Primary sources: fetal urine and lung secretions
•
Major source for removal: fetal swallowing
•
Oligohydramnios
•
•
Decreased amniotic fluid
•
Often a fetal fetal kidney problem
Oligohydramnios •
•
Polyhydramnios •
Excessive amniotic fluid
•
Often a swallowing/GI swallowing/GI problem
syndrome
•
Fetalrenal abnormalities •
Bilateral renal agenesis
•
Posterior urethral valves (males)
Placental insufficiency •
Preeclampsia
•
Maternal vascular diseases
Premature rupture of membranes
•
Oligohydramnios •
Polyhydramnios
Can lead to Potter’s sequence
•
Fetal swallowing malformations
•
Loss of fetal cushioning to external external forces
•
Esophageal/duodenal atresia
•
Compression of the fetus
•
Anencephaly
•
Limb deformities
•
Flat face
•
Pulmonary hypoplasia
•
Maternal diabetes
•
Fetal anemia
•
•
•
Leads to high fetal cardiac cardiac output
•
Increased urine production
•
Can occur in parvovirus infection
Multiple gestations •
45
Fetal hyperglycemia polyuria
More fetal urine
Low Birth Weight
Low Birth Weight •
•
•
•
Selected Risk Factors/Causes
Less than 2500 grams (5.5lbs) Caused by: •
Premature delivery
•
Intrauterine growth restriction (IUGR)
•
Congenital abnormalities of fetus
•
Multiple gestation
•
Maternal conditions
Increased risk of:
•
Preeclampsia
•
Abruptio placenta Alcohol
•
Neonatal mortality
•
•
Newborn complications
•
Smoking
•
Cocaine use
Lower birth weight greater risk complications
Low Birth Weight
Low Birth Weight
Newborn Problems
Newborn Problems
•
•
•
Hypothermia •
Less white adipose tissue (insulation)
•
Less brown adipose adipose tissue (heat (heat generation)
•
Large ratio surface area to weight (lose heat easily)
•
•
•
Loss of maternal maternal glucose
Transient tachypnea of the newborn
•
Pneumonia
•
Insufficient fetal generation of glucose
•
•
Hyperbilirubinemia •
↑ unconjugated bilirubin
•
May lead to newborn jaundice
•
Persistent Fetal Circulation In utero: high PVR
•
•
Blood shunted right left
•
•
•
•
Via foramen ovale ovale and ductus arteriosus
•
At birth oxygen to lungs PVR falls Persistent high PVR shunting hypoxemia Abnormal development of pulmonary vasculature •
Small vessels
•
Thickened walls
•
Excessive vasoconstriction
Inadequate lung fluid clearance
Respiratory failure Need for ventilator ventilator support
Immune Function
•
•
Deficiency of surfactant surfactant
•
Hypoglycemia •
Respiratory distress Neonatal RDS
46
Cellular immunity impaired ↓ T-cells and B-cells at birth Some babies have neutropenia
Low Birth Weight
Low Birth Weight
Newborn Problems
Newborn Problems
•
Polycythemia of the newborn
•
Necrotizing Enterocolitis
•
Excessively elevated hematocrit at birth (>65)
•
Intestinal necrosis and obstruction
•
Newborns normally have increased red cell mass
•
•
•
•
Fetus in a relatively hypoxic environment in utero
•
Increased hemoglobin production
•
Placental blood may may transfer to baby baby at birth
•
•
Usually terminal ileum or colon Can lead to perforation Major risk factor is prematurity, low birth weight
Usually asymptomatic Rarely may cause symptoms •
Hypoglycemia (excessive RBC glucose utilization)
•
Hyperbilirubinemia
Low Birth Weight
Low Birth Weight
Newborn Problems
Long Term Outcomes
•
Intraventricular Hemorrhage •
•
•
•
•
•
Hemorrhage i nto lateral ventricle
•
Hypotonia Loss of spontaneous movements Seizures, coma Germinal matrix problem •
Highly vascular area area near ventricles
•
Premature infants: poor autoregulation autoregulation of blood blood flow here
•
In full term infants, infants, this area has decreased vascularity
•
SIDS Sudden Infant Death Syndrome •
•
•
Sudden death of infant < 1 year of age Unexplained by other causes Risk factors •
Stomach sleeping
•
Maternal smoking during pregnancy
•
Very young maternal age (<20)
•
Bed sharing (infant/parent)
•
Prematurity/low birth weight
SIDS
47
Sudden infant death death syndrome
•
Leading cause infant mortality 1 month month to 1 year year in US
•
Increased risk with preterm birth or low birth weight
Increased risk of neurocognitive problems •
Cognition
•
Social skills
•
Behavioral and emotional skills
Hypertension in Pregnancy •
Pre-existing hypertension
•
Gestational hypertension
•
Preeclampsia-eclampsia
•
Hypertension in Pregnancy
•
Jason Ryan, MD, MPH
Gestational Hypertension
Elevated BP prior to pregnancy Elevated BP that that develops during pregnancy
•
Hypertension in pregnancy
•
Proteinuria
•
End-organ damage
Preeclampsia
•
Elevated BP after 20 weeks
•
Multi-system disorder of pregnancy
•
No proteinuria or evidence of preeclampsia
•
Hypertension
•
Safe drugs in pregnancy
•
•
α-methyldopa
•
Labetalol (β1β2α1 blocker)
•
Nifedipine (calcium channel blocker)
•
Proteinuria End-organ dysfunction
Preeclampsia
Preeclampsia
Pathogenesis
Pathogenesis
•
•
•
•
Disorder of theplacenta the placenta
•
•
Normally trophoblast invades/transforms spiral arteries
•
Abnormal invasion/transformation
preeclampsia
•
Placental under-perfusion Leads to release of circulating substances Diffuse maternal endothelial dysfunction
•
Vasospasm and coagulation
•
Resolves with delivery (placental removal)
•
•
48
Extravillous trophoblast fails to penetrate penetrate myometrium Spiral arteries do not develop normally Remain narrow placental hypoperfusion Placentalbiopsy: fibrinoidnecrosis of vessels
Preeclampsia ClinicalFeatures • •
•
Preeclampsia HTN Proteinuria
Usually occurs 3rd trimester New onset hypertension •
In mother with no known HTN
•
First pregnancy
Clinical Features •
Edema
•
•
Proteinuria low oncotic pressure
•
Increased salt/water retention
Proteinuria or end-organ damage •
Often presents with edema Endothelial dysfunction
Renal failure (vasospasm (vasospasm of renal vessels)
•
CNS (headache, (headache, visual changes, confusion)
•
Liver failure
Preeclampsia
Preeclampsia
Clinical Features
Risk Factors
•
•
•
•
Often involves the liver Edema of the liver
•
•
Ischemia/necrosis Elevated liver enzymes common
•
•
Prior preeclampsia First pregnancy Familyhistory Multiple gestations
Preeclampsia
Preeclampsia
Risk Factors
Complications
•
Maternal conditions (prior to pregnancy)
•
Placental insufficiency
•
Diabetes
•
Growth restriction
•
Hypertension
•
Oligohydramnios
•
Obesity
•
Chronic kidney disease
•
Lupus/Antiphospholipid syndrome
•
49
Placental abruption
Preeclampsia
Eclampsia
Complications •
Pulmonary edema
•
•
Heart failure
•
•
•
•
•
•
Liver hematoma with/without rupture Liverfailure
•
•
Disseminated intravascular coagulation Stroke
•
•
•
Exact etiology of seizures unclear Related to blood flow/endothelial dysfunction
HELLP Syndrome
Anticonvulsive of choice: magnesium sulfate •
Most effective drug
•
Often given for prevention in preeclampsia
Schistocytes
•
Elevated bilirubin
•
Low haptoglobin
•
Thrombocytopenia
•
Treatment: delivery of baby
Variant of preeclampsia
•
Hemolysis
•
Microangiopathic hemolytic anemia •
•
•
Definitive treatment: delivery of baby
HELLP Syndrome •
May lead to coma/death Often complicated by DIC, respiratory failure
Dialysis (advanced renal failure)
Eclampsia •
Seizuresin Seizures in a mother with preeclampsia Generalized, tonic-clonic seizures
(consumption)
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Elevated Liver enzymes Low Platelet count
•
Complication of preeclampsia (severe form)
•
Coagulation activation and liver infarction
Placental Abruption Abruptio Placentae Placentae •
Placental Complications
•
Placental detachment prior to delivery of baby •
Normally implanted placenta
•
Partial or complete early separation
Blood loss from maternal vessels •
•
•
•
Jason Ryan, MD, MPH
Rupture of maternal vessels in decidua basalis
Blood separates decidua from uterus Loss of gas and nutrient exchange Life-threatening to mother and fetus
Placental Abruption
Placental Abruption
Clinical Presentation
Complications
•
•
Occurs in 3rd trimester Abrupt onset of painful vaginal bleeding •
•
•
•
•
•
•
Posterior abruption may have minimal/no bleeding
•
•
•
•
•
•
Disseminated intravascular coagulation (DIC)
Abdominal or back pain Uterine contractions Often diagnosed clinically Ultrasound not reliable
Placental Abruption
Cortical Necrosis •
Maternal shock Fetal distress/demise
Risk Factors
Ischemic necrosis of renal cortex
•
Rare cause of acute renal failure Related to ischemia and DIC Can lead to permanent renal failure
•
•
•
Often associated with placental abruption Clinical presentation •
•
Acute renal failure
•
Anuria
•
Hematuria (may (may be gr oss)
•
Flank pain
•
51
Previous abruption Maternal hypertension/preeclampsia Smoking Cocaine Abnormal uterus •
Bicornuate uterus
•
Prior C-section
Trauma (motor vehicle accident)
Placenta Previa •
Placenta Previa
Previa = “going before” •
•
Placenta before baby
•
•
Placenta attached to lower uterus
•
•
Over or close to cervical os
•
Velamentous Umbilical Cord
May cause painless bleeding during pregnancy May lead to preterm birth May require C-section delivery Risk factors •
Prior placenta previa
•
Prior C-section
•
Multiple prior pregnancies
Vasa Previa
•
Normal umbilical cord: inserts into central placenta
•
Fetal blood vessels in membranes near cervical os
•
Velamentous cord: inserts into fetal membranes
•
Rupture of membranes at birth bleeding
•
Usually requires C-section delivery
•
•
Attaches to chorion Fetal vessels travel with membranes to placenta
•
Vessels exposed
•
No protection from Wharton’s jelly
•
Risk of rupture/bleeding
Abnormal Attachment •
•
•
•
Abnormal Attachment
Normal placenta attaches to decidua Abnormal decidua abnormal attachment Placenta attaches directly to myometrium Three forms •
Placenta accreta accreta (most common)
•
Placenta increta
•
Placenta percreta
•
Caused by defective uterine decidualization
•
Most important risk factor: prior C-section
•
Other risk factors:
•
•
52
Especially with placenta previa
Prior uterine surgery surgery or D&C
Abnormal Attachment
Abnormal Attachment •
•
Placenta accreta •
Placenta attached attached to myometrium
•
No penetration into myometrium
•
Usually diagnosed on routine ultrasound
•
Undetected: placenta fails to detach after birth •
Placenta increta •
•
Clinical Presentation
Placenta penetrates penetrates myometrium
Placenta percreta •
Placenta penetrates penetrates through myometrium
•
Invades uterine serosa serosa (outer layer)
•
Can attach to bladder/rectum
•
•
•
•
Postpartum Hemorrhage •
•
•
•
•
Massive bleeding
Maternal hemorrhage Shock, DIC, ARDS Delivery usually by C-section Often requires hysterectomy
•
Coagulopathy
•
Uterus contracts after delivery constricts spiral arteries
•
Blood loss may consumes clotting factors
•
Lack of contraction = atony
•
Some obstetric conditions may cause DIC
•
Often treated with oxytocin
•
Abruption, amniotic fluid embolism, preeclampsia preeclampsia
•
Also treated with uterine massage
•
Trauma Lacerations from delivery
•
Especially if instruments used
•
Surgical incisions
Amniotic Fluid Embolism •
Breaks into pieces
•
Postpartum Hemorrhage
Urine atony (most common cause)
•
•
Part/all of placenta remains attached attached to uterus
•
Retained tissue •
Placenta expelled expelled by uterine contractions
•
Retained tissue bleeding
Amniotic Fluid Embolism
During labor or shortly after Amniotic fluid, fetal cells, fetal debris Enter maternal circulation Inflammatory reaction
•
Phase I (respiratory/shock)
•
Phase II (hemorrhagic phase)
•
•
Often fatal •
53
Key features: respiratory distress, ↓O 2, hypotension Massive hemorrhage
•
DIC
•
Key feature: bleeding
Seizures also often occur
GTD Gestational Trophoblastic Disease
Gestational Tumors
•
Rare variant of pregnancy
•
Neoplasms of trophoblast (placenta)
•
Usually benign (molar pregnancy)
•
Rarely malignant
Jason Ryan, MD, MPH
Hydatidiform Mole
Complete Mole
Molar Pregnancy •
•
•
•
•
•
•
Most common form of GTD Hydatid = fluid filled cyst
•
Mola = Greek for “false pregnancy” Growth of trophoblast tissue
Fertilization of “empty” egg •
All chromosomes of paternal origin
•
No maternal chromosomes
Swollen chorionic villi Villi form clusters - “clusters of grapes” Ultrasound: “snowstorm appearance”
Complete Mole
Complete Mole
•
Cells usually 46,XX karyotype
•
•
Haploid sperm that duplicates
•
•
23 X 46 XX
•
46,YY does not occur
•
lethal
•
Rarely 46,XY moles occur
•
p57-negativeon p57-negativeon immunostaining
•
•
Empty egg fertilized by two sperm
•
Cyclin dependent kinase
•
Only expressed expressed by maternal chromosomes chromosomes (imprinted)
54
No f etal tissue Maternal chromosomes needed for fetal tissue No fetus to drain villi = massively swollen villi Most common form of molar pregnancy
Complete Molar Pregnancy
Partial Mole •
•
•
•
•
Less common form Some fetal tissue (maternal chromosomes)
•
Initially may appear to be normal pregnancy
•
Size/datediscrepancy of uterus
•
Painless uterine bleeding
•
These findings often lead to ultrasound
•
Fertilization of normal egg by two sperm Some villi drainage = less swollen villi
•
Cells usuallytriploid usually triploid •
•
Clinical Features
•
69,XXX
•
69,XXY
•
Rarely 69,XYY
Positive pregnancy test; uterine enlargement Uterus too big for stage of pregnancy Separation of molar villi from decidua
p57-positive (maternal genetic material)
Complete Molar Pregnancy
Complete Molar Pregnancy
Clinical Features
Clinical Features
•
Hyperemesis gravidarum •
•
•
•
Severe nausea and vomiting with weight loss
Maternal serum hCG
Hyperthyroidism •
Requires very high hCG
•
hCG stimulation of TSH receptor
•
Higher than normal normal for gestational gestational age
•
Low TSH
•
May be very high (>100,000 ) early in pregnancy
•
High T3/T4
Ovarian theca lutein cysts •
Ovarian stimulation by hCG
•
Often bilateral
•
Preeclampsia
Partial Molar Pregnancy
Molar Pregnancy
Clinical Features
Treatment
•
•
Uterine size •
May be normal (some villi drainage to fetus)
•
May be small for gestational age (slow growth of fetus)
•
•
•
Marked ↑hCG less common
55
Uterine suction curettage Rarely hysterectomy Chemotherapy: Methotrexate or Actinomycin D •
For high risk patients patients only
•
Features suggesting suggesting high likelihood of choriocarcinoma
Choriocarcinoma •
•
•
•
Choriocarcinoma
Rare malignant gestational neoplasm Can follow a normal pregnancy
•
•
Completemolar pregnancy •
15% develop locally locally invasive disease
•
5% develop metastatic disease
•
<5% develop any invasive invasive disease
Choriocarcinoma
Choriocarcinoma
Clinical Features
•
Syncytiotrophoblast and cytotrophoblast cells
•
•
No formation of villi
•
•
•
Early spread with extensive metastases Hematogenous spread
•
•
•
ElevatedhCG ElevatedhCG level Possible ovarian cysts, hyperthyroidism (hCG)
Non-Gestational Choriocarcinoma
Treatment
•
Vaginal bleeding Cough, hemoptysis
80% of case metastasize to lungs
Choriocarcinoma •
Plateau: indication of persistent disease
Partial mole •
•
Must monitor hCG level after molar pregnancy Should fall after treatment
Highly sensitive to chemotherapy
•
Methotrexate or Actinomycin D Most patients cured
•
•
•
56
Rare germ cell tumor May arise in the ovary or testes Germ cells differentiate into trophoblasts Histologically same as gestational choriocarcinoma
•
Produces β-hCG
•
More difficult to treat/cure
TORCH Infections •
•
TORCH Infections
Maternal infections fetal abnormalities TORCH •
Toxoplasmosis
•
Other (syphilis, varicella-zoster, varicella-zoster, parvovirus B19)
•
Rubella
•
CMV
•
Herpes
Jason Ryan, MD, MPH
Toxoplasma gondii
TORCH Infection
Toxoplasmosis
•
Maternal illness during pregnancy
•
•
Infection fetus
•
•
•
•
Miscarriage Stillbirth
•
•
Fetal abnormalities at birth
•
Protozoa Commonly lives in cats (felines) Oocysts shed in stool Infection from ingested oocysts (soil) Also meat from contaminated animal
Toxoplasma gondii
Toxoplasma gondii
Toxoplasmosis
Toxoplasmosis
•
Maternal 1° infection (immunocompetent mother) •
80 to 90% of infections asymptomatic
•
Lymphadenopathy
•
Fever, chills, sweats
•
Latent infection usually does not infect fetus
•
Diagnosis •
IgM antibodies in first week
•
IgG antibodies peak 6 to 8 weeks, fall over next two years
57
•
Most newborns appear normal
•
Classic triad in fetus: •
Hydrocephalus
•
Chorioretinitis (inflammation of choroid in eye)
•
Intracranial calcifications (often seen on prenatal US imaging)
Syphilis
Congenital Syphilis
Treponema pallidum
Early Findings
•
Spirochete (bacteria)
•
Maculopapular rash
•
Transmitted by sexual contact
•
Runnynose
•
Maternal symptoms
•
Abnormal long-bones
•
•
Primary syphilis: Chancre Chancre
•
More common in legs
•
Secondary syphilis: Maculopapular rash (palms/soles)
•
Many, many abnormalities reported
Findings in baby can be early or late •
Early (<2ys); Late (>2yrs)
Congenital Syphilis
Varicella Zoster Virus
Late Findings •
•
Ears/nose •
Saddle nose (no nasal bridge)
•
Hearing loss/deafness
•
Hutchinson teeth (notched, peg-shaped teeth) teeth)
•
Mulberry molars (maldevelopment of the molars)
Legs
•
Caused by scarring and gumma formation
•
Maternal infection
•
•
Primary: Chickenpox
•
Reactivation: Herpes Herpes Zoster (shingles)
Maternal 1° first trimester disease fetal infection
Saber shins (bowed legs)
Varicella Zoster Virus
•
Herpes virus (DNA)
•
Teeth
•
•
•
Parvovirus B19
Newborn signs and symptoms •
Scars in a dermatomal pattern
•
Microcephaly, hydrocephalus, hydrocephalus, seizures
•
Ocular abnormalities (cataracts, nystagmus)
•
Limb atrophy and hypoplasia
•
•
•
Non-enveloped, single-stranded DNA virus Found in respiratory secretions of infected persons Classic infection: Fifth disease in children •
Long term: learning disabilities, mental retardation
Adults often develop arthritis
•
Infects red cell progenitors progenitors
•
58
“Slapped cheek” appearance appearance of face
•
Hands, wrists, knees, and ankles
•
Mild ANEMIA in normal individuals
•
Severe in chronic anemia (sickle cell)
Parvovirus B19 •
•
Parvovirus B19
Fetus especially vulnerable to B19
•
Hydrops fetalis
•
Shortened RBC half-life half-life
•
Fluid accumulation in fetus
•
Expanding RBC volume
•
Ascites, pleural, etc.
•
Immature immune system system
•
Often diagnosed on ultrasound
•
“Immune hydrops” from Rh mismatch
•
Many non-immune causes including B19
Miscarriage, fetal death
Rubella
Congenital Rubella Syndrome
•
RNA virus
•
Sensorineural deafness
•
Found in nasal/throat secretions of infected persons
•
Cataracts
•
Cardiac malformations
•
Blueberry muffin baby
•
•
Maternal infection via respiratory droplets Mild, self-limited illness •
Maculopapular rash
•
Lymphadenopathy
•
Joint pain
•
Blueberry Muffin Baby
Classically a patent ductus arteriosus arteriosus (PDA)
CMV
•
Purpuric skin lesions
•
Herpes virus (DNA)
•
Extramedullary hematopoiesis
•
Several modes of maternal infection:
•
•
In utero hematopoiesis hematopoiesis occurs outside bone marrow marrow
•
•
Normally stops prior to birth
•
Close contact of infected individual (family member, daycare)
•
Persists in rubella infection
•
Blood/tissue exposure exposure (transfusion, (transfusion, organ transplant)
May also be seen in congenital toxoplasmosis, CMV
•
•
•
59
Sexual contact
1° CMV infection asymptomatic 90% cases May cause mild febrile illness “Mononucleosis-like”
•
Nonspecific symptoms
•
Rhinitis, pharyngitis, headache, myalgia, arthralgia
CMV •
•
CMV
Most infected newborns are asymptomatic Major consequence: sensorineural hearing loss
•
Other potential findings •
Small for gestational age, microcephaly
•
Most common consequence of congenital CMV
•
Hepatosplenomegaly
•
Many babies diagnosed diagnosed based only on failed failed hearing screen
•
Blueberry muffin baby baby
Most common ID cause cause of congenital congenital sensorineural deafness
•
Seizures
•
•
Herpes Simplex
Classic neuroimaging finding: •
Intracranial calcifications
•
Usually periventricular
Herpes Simplex
•
HSV 2 (DNA virus)
•
Vesicles: skin, near eyes, in mouth
•
Genital HSV fetus at birth via genital tract lesions
•
May spread to CNS
•
May disseminate to multiple organs
•
NOT transplacental
60