Week 7 Flashcards
Labor
effective uterine contractions leading to dilation and effacement of the cervix and delivery of the fetus
Clinical Stages of Labor: (4)
1) Effective contractions to complete dilation of cervix
2) Complete dilation to delivery of fetus
3) Delivery of fetus to delivery of placenta
4) First 6 hours after delivery
The first clinical stage of labor is made up of what 2 sub-phases?
First stage = Effective contractions to complete dilation of cervix
- Initial latent phase → contractions without cervical change
- Active phase → acceleration and deceleration phase in cervical dilation
Uterus during pregnancy:
undergoes 3 main changes
1) Growth by hyperplasia and hypertrophy
- Weight increases from 50g → 1000g
2) Increased connectivity of myocytes (connexins)
3) Increased oxytocin receptors (modulate calcium movement)
- Receptors most concentrated at fundus (top of uterus)
What is the function of the gap junctions between myocytes in the uterus?
Increased connectivity of myocytes (connexins)
Cells connected by gap junctions via connexin 43
Electrochemical and mechanical coupling
Molecular/Cellular mechanisms of myometrial quiescence: (5)
LOW Ca2+, LOW PG, LOW oxytocin
1) Membranes: produce prostaglandin dehydrogenase (breaks down PG)
2) Myometrium: myosin and actin not arranged properly for contraction
3) Progesterone secreted → anti-inflammatory and NO production → increase cGMP → reduce MLCK activity
4) CRH → receptor mediated increase in cAMP signal → PKA → shut down MLCK activity
5) K+ channels open (maintain negative potential in cell) and Na/K+ ATPase
Molecular/Cellular mechanisms of myometrial ACTIVATION phase (5)
1) Add gap junctions
2) Express L-type calcium channels to allow Ca2+ in
3) Express oxytocin receptors
4) Express COX (increase PG production) - BUT still have PGDH, so no increase in PG yet
5) Express prostaglandin receptors
Molecular/Cellular mechanisms of myometrial CONTRACTION phase (4)
1) New CRH receptor that promotes CONTRACTION
CRH → PKC → promote contractility
2) Stop production of PGDH → increase PG
3) PG → internal Ca2+ release
4) Oxytocin binds → depolarize cell and allow Ca2+ in
Myometrial phases (4)
Phase 0 = Quiescence (includes 90% of pregnancy)
Phase 1 = Activation
Phase 2 = Stimulation
Phase 3 = Involution
Phase 0 = Quiescence
Hormones present at this time?
PROGESTERONE
Progesterone
- source
- function?
- expressed during what phase?
myometrial inhibitor, quiescence factor in early pregnancy
Source = placenta
Function:
- Block myosin light chain kinase
- Inactivates prostaglandins, decreases inflammation signaling
Expressed during quiescent phase (also expressed during contraction but acts on a different receptor)
Phase 1 = Activation
what is the purpose of this phase?
-what is hormones and signals are modulating this? (3)
Molecular changes in myometrium without labor - getting ready to contract
Hormones and modulators:
1) ESTROGEN mediated activation factor
2) Uterine stretch
3) Fetal signals
Phase 2 = Stimulation
what happens?
what hormones do this (3)
LABOR
Hormones:
Prostaglandins
Oxytocin
CRH
Prostaglandins (role in labor?)
Source?
Function?
stimulates contractions (PGE2, PGF2a)
Source = myometrium and placental membranes
Mechanism:
- Paracrine function
- Increases intracellular calcium
- Facilitates weakening of amnion and chorion
Oxytocin
source?
function?
mechanism?
myometrial stimulant
Source = maternal anterior pituitary
- Stimulates contractions
- Differential distribution on uterus - highest concentration at fundus
Mechanism: increases intracellular Ca2+, activates myosin light chain kinase
CRH
function in labor? source?
myometrial inhibitor (maintains quiescence) AND induces labor acting as a myometrial stimulant
Source = Placenta
Shift between quiescence and contractile function due to shift in receptor isoforms
Important for pulmonary maturation on fetal side
Fetal CRH system
POSITIVE feedback system:
CRH produced by baby pituitary → ACTH → fetal adrenal → fetal cortisol → feed FORWARD to have exponential increase in fetal CRH
Driven by fetal maturation
Phase 3 = Involution
what happens?
what two hormones do this?
Get uterus back to normal size and prevent bleeding
Hormones:
Oxytocin
Inflammatory cell activation
Structure of Cervix:
what happens to this structure as you approach labor?
Connective tissue (made up of collagen and proteoglycans)
Proteases degrade collagen and proteoglycans + edema later in pregnancy during cervical ripening
Smooth muscle of internal os (holds baby in)
→ Dilates passively with contractions
Uterine tocolytics: (6)
1) Calcium antagonists (Nifedipine)
2) Oxytocin receptor antagonists (Atosiban)
3) Inhibitors of PG synthesis (indomethacin)
4) NO donors (nitroglycerin)
5) Beta-mimetics (Fenoterol, terbutaline, ritodrine)
6) Magnesium
Uterine tocolytics
“treatment” for preterm labor - only delay about 48 hrs, done so that full course of steroids can be given
PGE2-PGE1: targets in labor? (2 receptors and what happens when they are stimulated?)
EP1 (myometrium) → Gq → increase Ca2+ → myometrial contraction
EP2,3,4 (cervix) → Gs → increase cAMP → cervix ripening-dilation
PGF2a
target in labor? (receptor and what happens when stimulated?)
FP → Gq → increase Ca2+ → myometrial contraction
Oxytocin binds what kind of receptor?
what happens when it is stimulated?
Oxytocin → Gq → increase Ca2+ → myometrial contraction
Epinephrine binds what kind of receptor on the uterus?
what happens when it is stimulated?
Epi → B2 → Gs → increase cAMP → myometrial relaxation
Dinoprostone
synthetic PGE2
ADRs: intestinal cramping, diarrhea, nausea
Stimulates cervical effacement (ripening) when applied vaginally
Misoprostol
synthetic PGE1
ADRs: fewer systemic side effects
Induces uterine contractions
Oxytocin (Pitocin)
- use?
- ADRs (2)
Augment uterine contractions
Used for labor induction AFTER cervical ripening
Also effective for postpartum hemorrhage
ADRs:
Water intoxication (similar to ADH)
Uterine rupture and impaired fetal oxygenation
Tocolytic Agents:
Prostaglandin synthesis inhibitors (indomethacin)
- mechanism?
- ADRs?
Inhibits COX1 and COX2
ADR: closure of ductus arteriosus in utero can lead to pulmonary HTN postnatally
Tocolytic Agents:
B2 adrenergic agonists (Terbutaline):
- effective for what?
- ADRs?
Higher incidence of maternal side effects (jitteriness, hypokalemia, hyperglycemia, hypotension)
→ infant hypoglycemia
Effective at suppressing contractions - treating premature labor
Less effective if cervix dilated and membranes have ruptured
Tocolytic Agents:
Magnesium sulfate:
- mechanism?
- use?
- ADRs?
Chemical antagonist of Ca2+
NO longer used at UCH as tocolytic
Still indicated for pre-eclampsia and eclampsia
Tocolytic Agents:
Calcium channel blockers (nifedipine)
- mechanism?
- use?
- ADRs?
Used at 32-34 weeks
Fewer maternal side effects than MgSO4 or B-agonists
Potential concern that fall in maternal BP may reduce blood flow between uterus and placenta
Tocolytic Agents:
Ethanol
-mechanism?
Inhibits pituitary release of oxytocin
No longer used to potential adverse side effects in both mother and fetus
Erectile Dysfunction Drugs
phosphodiesterase inhibitors, increase cGMP
Sildenafil
Vardenafil
Tadalafil
Malformations
morphologic or structural abnormalities due to an INTRINSICALLY abnormal development process
EX) Polydactyly, Syndactyly, single gene/chromosomal disorders
Deformations
morphologic or structural abnormalities due to a mechanical force, EXTRINSIC or INTRINSIC
EX) Arthrogryposis and club feet secondary to oligohydramnios
Disruptions
morphologic or structural abnormalities due to destruction of normally developing tissue
Principal causes of human birth defects: (7)
1) Chromosomal aberrations = 10-15%
2) Mendelian inheritance = 2-10%
3) Maternal/placental infections = 2-3%
- (Toxoplasmosis, Rubella, CMV, HIV, Syphilis)
4) Maternal disease states = 6-8% - (Diabetes, PKU, Endocrinopathies)
5) Drugs and chemicals = 1% - (Alcohol, folic acid antagonists, androgens, phenytoin, thalidomide, warfarin, 13-cis-retinoic acid)
6) Multifactorial = 20-25%
EX) Neural tube defects
7) Unknown = 40-60%
how timing of exposure of teratogens impacts human development
Each system has a different critical time period of development
Exposure to same teratogen at different times during gestation can cause different effects
EX) Congenital Rubella and timing of exposure
First trimester → congenital heart defects, deafness, neuro defects, retinopathy
Second or third → more likely to avoid serious systemic defects and only get localized inflammatory and destructive lesions
Phenocopies
similar birth defect phenotype resulting from a genetic versus an environmental/teratogenic cause
EX) Isotretinoin exposure very similar to 22q11.2 deletion
Development field
groups of embryonic structures that respond as a single developmental unit
- Tissue sharing gene expression (hedgehog signaling pathway)
- Tissues related to each other through location (branchial arches)
- Tissues sharing developmental timing (embryonic inner cell mass)
- Tissues affected by interacting processes (cell proliferation and apoptosis)
Hierarchical pathways in human development
Cascades of genes that all has to happen at the right time and in the right tissue
Involves cell migration, cell division, interaction between tissue types, controlled cell death
Threshold theory of environmental/genetic interactions for birth defects
Liability = all genetic and environmental factors that influence the development of a multifactorial disorder
Influenced by genetic predisposition, sporadic gene causes, mechanical disruption, etc.
Gene/environment interaction “shifts” threshold of liability
Can “shift” the threshold with supplementation of folic acid
Screening Tests
assess risk, quick, noninvasive, widely accessible, high NPV, low false positives, first step only - pre and post test counseling
Done to reassure families at risk and prepare for the birth of a baby with anomalies
Develop plans for monitoring and for neonatal care
Provide data to allow continuation decision making
**Cannot known positive predictive value unless you know the PREVALENCE of disorder
MOST screening is _______
Most anomalies occur in ____________
MOST screening is NORMAL
MOST anomalies occur in low risk patients
Who should you NOT give a screening test to?
Do NOT give screening test for patient if they do not want to accept risks of diagnostic follow up of a positive result
Diagnostic Tests
as close to truth as possible, maybe longer or invasive, may require special training, gives a diagnosis if completed
Last or first step
Risks and pre/post test counseling
Targeted screening
Screen with history, exam, routine labs, or other data
Examine highest risk subgroups, especially for rare diseases
Could be screen-in or screen-out
Counseling issues are the same
Population Screening
Everyone screened to identify disease or disease risk
Can be opt-out
EX) neonatal metabolic screening
Offer screening or diagnosis to all for fetal evaluation - can opt out
First trimester screening (11-14 weeks) (3 things)
1) Ultrasound
2) Serum biochemistry: hCG, PAPP-A
3) Maternal factors: age, prior history of aneuploidy, weight, race, number of fetuses
First trimester ultrasound looks for what?
1) 82-87% detection of Down Syndrome
- 5% screen positive
- Larger NT is higher risk and higher risk of other anomalies
- Nasal bone adds additional sensitivity
2) Crown → rump length helps determine age*
+/- 1 week in first trimester = MOST ACCURATE
Second trimester:
-Cervical length measurement
After 16 weeks: transvaginal US to measure cervical length and determine risk of preterm delivery
3 tests that can estimate gestational age in the second trimester
1) Biparietal Diameter
2) Abdominal circumference
3) Femur length
Take all of these things and use them to estimate fetal weight
+/- 2 weeks in second trimester
+/- 3 weeks in 3rd trimester
Maternal serum analytes: (4)
AFP
Unconjugated estriol
hCG
Dimeric Inhibin A
Alphafetoprotein
made in fetal liver, predominant blood protein in fetus, and cleared by maternal renal function
Marker for NTDs (high), Down Syndrome (low)
Neural tube defect:
AFP? unconjugated estriol? hCG?
*AFP - INCREASED
Unconjugated estriol = normal
hCG = normal
Trisomy 21
AFP? unconjugated estriol? hCG? inhibin A? PAPP-A?
AFP - LOW
Unconjugated estriol = low
hCG = INCREASED
Inhibin A = INCREASED
PAPP-A = decreased
Trisomy 18
AFP? unconjugated estriol? hCG? PAPP-A?
Trisomy 18 (everything is LOW)
AFP - low
Unconjugated estriol = low
hCG = low
PAPP-A = decreased
Trisomy 13
what lab value?
PAPP-A = DECREASED
Screening tests for fetus: (4)
Maternal serum biochemical screening
Ultrasound (1st trimester with nuchal translucency)
Ultrasound (fetal anatomy survey)
Maternal serum cell free fetal DNA + microarray
Maternal serum cell free fetal DNA
Noninvasive test with no miscarriage risk
High sensitivity and specificity
Available early in gestation
Used for patients at increased risk for aneuploidy
Diagnostic tests for the fetus: (2)
Chorionic villus sampling (around 10-13 weeks)
Amniocentesis (performed after 15 weeks)
Chorionic villus sampling
(around 10-13 weeks)
Detects genetic, metabolic, and DNA abnormalities
Done earlier than amniocentesis
