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188 Cards in this Set

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When does implantation occur?
Day 6 after fertilization.
Describe the primary, secondary and tertiary villi of the placenta:
primary- cytotrophoblast core surrounded by synctiotrophoblast shell
secondary- mesodermal core developing inside the cytotrophoblasts, still surrounded by synctiotrophoblast shell.
tertiary- arteriocapillary network forming inside the cytotrophoblast-mesoderm core. Arterioles grow from the umbilical vessels.
Describe the prelacunar, lacunar/trabecular and villous stages of placental development.
prelacunar (day 6-8) placenta begins forming following implantation at day 6. Outer layer forms multinucleated synctiotrophoblast. Inner layer layer is a single cell layer of cytotrophoblast.
Lacunar/Trabecular (Day 9-12) vacuoles appear within the synctiotrophoblast forming lacunae, the endometrium begins to form into the decidua.
Villous Stage (day 13-18)- development of the 3 stages of villi. cytotrophoblasts proliferate and invade the trabeculae.
How far does the placenta invade?
The placenta invades through the decidua basalis (aka the basal plate) and 1/3 of the way through the mother's myometrium. Hence placental bleeds can be very bad.
How is the mother's blood delivered to the placenta?
Mom's blood comes in the singular oxygenated vein going to baby and exits via two smaller deoxygenated arteries. There is no direct mixing of maternal or fetal blood as the capillaries are separated by a placental membrane.
What is a normal amniotic fluid volume and where does it come from?
Amniotic fluid is mostly an ultrafiltrate of maternal plasma, and after 12 weeks baby's kidneys start producing fetal urine with some lung secretions. Normal fluid ranges from 250 ml at 18 weeks to 1L at 34 weeks (max).
Oligohydramnios is abnormally low amniotic fluid. What are 3 causes?
rupture of membranes is most often cause. Also if mom pre-gestational diabetes, HTN or preelampsia all of which cause poor placental perfusion. Also placental causes can be due to twin twin transfusion. Fetal causes- congenital anomalies ie GI system dysfunction.
Drugs- nephrotoxic medications (ie ACEI)
Polyhydramnios is supernormal value of amniotic fluid. What are 3 causes?
contenital abnormalities of the fetus such as an inability to swallow, blind pouch esophagus, MT defects. Hydrops can occur associated to hemolysis and CHF or infection. Also polyhydramnios is commonly seen with gestational diabetes.
Contrast diffusion limited transport and flow limited transport.
Diffusion limited- damage to synctiotrophoblast ie scaring will impair oxygen delivery to the fetus
Flow limited- aortic stenosis will cause reduced CO leading to IUGR fetus.
The placenta is an organ of transport. Contrast facilitated diffusion and active transport and give examples of each.
Facilitated diffusion is due to a concentration gradient and requires carrier proteins ie glucose and GLUT2
Active transport is transport against the maternal fetal concentration gradient ie AA transport.
Fetal hemoglobin (2 alpha 2 gamma chains) exhibits characteristics of a left shift on the hemoglobin saturation curve. What chemical in erythrocytes influences this?
Fetal erythrocytes have a lower 2,3 diphosphoglycrate concentration causing a left shift. Thus the fetus holds on to oxygen more strongly then the mom and is able to retrieve oxygen from her blood
What cells in the placenta make hCG?
The trophoblasts make hCG
This hormone is the earliest marker of pregnancy, it is highest at week 10 and maintains the corpus luteum and progesterone production for the placenta.
This hormone is secreted by sCTB, causes insulin resistance and may cause gestational diabetes.
hPL (human placental lactogen) . Secreted by the synctiotrophoblast just like hCG.
This hormone increases from week 12 to term, it controls maternal IGF-1 and low levels are indicative of IUGR.
Placental growth hormone
What chorionic/amniotic combinations can monozygotic or dizygotic twins have.
monozygotic- any combination. Depends on when split occured, the later the higher the risk. Twins must be the same sex as their genetic makeup is identical. Monochorionic/Monoamnionic is the highest risk for umbilical cord entanglement and TTT.
Dizygotic twins- dichorionic and diamnionic.
If the blastocyst does not split by day 15 what is the inevitable result?
Conjoined twins. If the egg does not split by day 15 there will be no viable pregnancy.
Describe Twin Twin Transfusion.
Requires monochorionic diamniotic twins. The blood from one twin drains into the second. The first twin doesn't end up getting enough nutrients (olioghydramnos) and can die while the other twin gets polyhydramnios, hypoxia and CHF from fluid overload.
Contrast placenta previa with placenta accreta.
placenta previa- internal os is partially covered by placenta, baby needs to come out first! Will present with painless bleeding and obstruction to passage of the fetus during labor.
Placenta accreta- trophoblast invades through myometrium resulting in postpartum hemorrhage. Usually due to previous scar from C section or placenta previa.
You note amnion nodosumon the fetal side of the placenta. What is this due to?
Amnion nodosum is due to oligohydramnios
Contrast pathological findings with chorioamnionitis with villitis.
chorioamnionitis- infiltration of PMNs into the fetal membranes. Indicates an ascending infection via the birth canal. Mostly bacterial. Can be associated with premature rupture of membranes.
Villitis- is transplacental infection of the villi from the mother, usually viral. Villi may be swollen, necrotic, calcified, infiltrated by lymphocytes and plasma cells.
Define the symptomology of preeclampsia.
common 6% of pregnancies
occurs in the 2nd half of pregnancy, usually 3rd trimester
Young age
first pregnancy
multiple gestation
black, obese
chronic HTN
proteinuria >300 mg mild >5g severe
HTN >140/90 mild, severe > 160/110
visual changes
RUQ pain, hemolysis, low platelets
What is a circumvallate placenta.
placenta free edge is folded under. Slightly increased morbidity. More central attachment.
What is a velamentous insertion of the cord into the placenta?
Velamnetous insertion means that vascular branches are exposed near their insertions increasing the risk of a ruptured vessel. Often causes irregular fetal heart beat.
What is a succenturiate (accessory) placental lobe?
A small segment of the placental disc is only attached by blood vessels, these vessels are at high risk to tear and cause post partum bleeding.
Why is preeclampsia so worrisome?
Can lead to HELLP and DIC, stroke, eclampsia (seizures) and pulmonary edema. Leading cause of maternal death worldwide.
To treat deliver the placenta!
Describe a complete mole
A placenta growing without a fetus. Comes to pass by an empty egg being fertilized by two sperm or by one sperm that goes on to immediately divide. Most are 46 XX 2N. Very high levels of B-hCG.
Can progress to choriocarcinoma (10% progress)
No fetal tissues present, appears as grapelike chorionic villi. Placenta has a uniform appearance without blood vessels, show premalignant atypia.
Describe a partial mole.
Karyotype is instead triploid 69 XXY, alternating areas of normal chorionic villi and molar tissue. Some fetal tissue present.
stillbirth is after 20 weeks, miscarrage before then.
newborn- up to 1 month postpartum
peripartum- from 20 weeks prepartum to 4 weeks postpartum
What percentage of women vs men have been abused?
25% of women 8% of men
T/F 1/3 of female homicides are from intimate partners.
Name a few clinical presentations suspicious for IPV
non vehicular repeated trauma often with delayed presentation.
recurrent non specific complainta (HA, chronic pain. sleep disturbances)
poor control of chronic conditions
pelvic trauma and pain.
How do you determine EGA? Define preterm, term and postterm.
Estimated Gestational Age is from the first day of last menses.
Preterm <37 weeks
Term 37-42 weeks
Postterm >42 weeks
What is the difference between an embryo and a fetus?
embryo first 8 weeks
fetus after eight weeks till birth.
Contrast definitions for and causes of SGA and LGA.
Small for gestational age is IUGR <10%, caused by chronic hypoxemia, poor nutrition, maternal HTN, preeclampsia, bilateral renal disease, smoking, drugs.
LGA, macrosomnia >90th%tile
diabetes melitus - not the same as edema weight
Define Congenital Hydrops Fetalis and name two causes.
Hydrops is anascara- a general edema of the head, limbs and organs with effusions within the body cavity.
Causes are either immune based ie blood incompatabilities such as Rh or ABO group with mom's Ab attacking baby. Other non immune causes include parvovirus B19 with destruction of RBC precursor cells resulting in severe enema causing high output cardiac failure.
You just delivered a newborn with a large skin covered mass that protrudes posteriorly from the base of the spine. This is the most common tumor of the newborn. What do you tell mom.
Baby has sacrococcygeal teratoma. Can be surgically removed. Benign.
How does an ectopic pregnancy present?
Severe acute unilateral abdominal pain, usually at about 6 weeks EGA. Medical emergency, crossmatch and prepare for surgery.
Fill in the blank:
The umbilical chord has ___ vessels, ___ artery(s) and ____ veins(s). ___ contains oxygenated blood.
The umbilical chord has 3 vessels, there are 2 arteries and 1 vein. The vein contains oxygenated blood
How does the CV system change during pregnancy?
-RBC mass
- Plasma volume
Plasma volume expands by 50% starting at 6-8 weeks, peaking at 34 weeks. This is due to progesterone leading to decreased sm muscle tone and increased volume capacity.
RBC mass increases by 20-30% causing a dilutional anemia with HCT now around 32-36%.
BP decreases until 22 weeks and then returns to baseline. Decreased systemic vascular resistance, decreased MAP and diastolic of about 5-10 mm Hg (due to NO). BP should never be higher then baseline.
How does the heart change during pregnancy?
- CO?
-Cardiac muscle
Cardiac output increases 40% due to increased SV
HR increases 10-20 bpm
vascular resistance/ BP decreases
Ventricular muscle hypertrophies, increased preload due to increased venous return. Decrease in afterload due to decreased vascular resistance.
What is preload and what effects it?
Preload is the muscle legth preior to contractility. It is dependent on ventricular filling ie EDV. The value is related to right atrial pressure. The most important determining factor for preload is venous return and thus is related to vasodilation.
What is afterload and what effects it?
Afterload is the tension (aka the arterial pressure) against which the ventricle must contract. If the arterial pressure increases the afterload must also increase. Afterload for the left ventricle is determined by the aortic pressure. Afterload for the right ventricle is determined by pulmonary artery pressure.
Describe the influence on SV of preload, afterload and contractility.
Preload gives the vol of blood that the ventircle has to pump as well as the EDV. The contractility is the force that the muscle can make at a given length. The afterload is the arterial pressure against which the muscle is contracting. These factors establish the SV and recall that CO = HR X SV
Why do women become hypotensive while lying on their back during pregnancy?
The fetus will compress the vena cava leading to decreased preload causing a decrease in CO.
Describe the following perinatal changes:
ventircular wall muscle mass
cardiac compliance
myocardial contractility
ventricular wall muscle mass enlarges- hypertrophy
increased end diastolic volume due to lower SVR.
no change in end systolic volume.
Increased cardiac compliance
increased in myocardial contractility.
There is up to a 50% increase in CO during pregnancy but it is not distributed evenly. Where is it the highest.
No increase to brain or liver. Increase to kidneys the most. Also increase to skin, uterus and breasts.
What are the top 3 causes of maternal morbidity?
1. peripartum hemorrhage as blood flow to the uterus is 15% of CO at term up to 700cc/min.
2. infectious disease
3. pulmonary embolism
4. eclampic seizure, stroke, renal/liver
How does pregnancy change:
-acid base balance
-RR unchanged
-TV increases
-progesterone makes respiratory center more sensitive to CO2 resulting in hyperventilation
-PaCO2 decreases.
-oxygen consumption increases
-PaO2 increases
Acid-base balance
-pH increases (less CO2)
-serum HCO3 decreases
What is the causal factor to hyperventilation of pregnancy?
-recall that baseline RR doesn't change.
Progesterone, makes respiratory center hypersensitive to carbon dioxide.
How do the following change during pregnancy:
-Expiratory reserve
-Vital capacity
-Inspiratory reserve
-minute ventilation (RR x TV)
RR= same
TV= increases up to 40%
Expiratory reserve decreases to allow for increased TV
Vital capacity = same
inspiratory reserve = same
minute ventilation = increased by 40% due to increased TV, RR same.
What is FEV1 and FVC? What does the ratio tell you?
Do these values change in pregnancy?
FEV1 = forced expiratory volume at 1 second.
FVC = forced vital capacity, the total volume of air expired after a full inspiration
FEV1/FVC ratio should be 70%.
obstructive disease = decreased ratio, ie asthma, constriction of bronchioles decreases the speed that air can exit the lung.
Both FEV1/FVC are both unchanged in pregnancy. However the Functional residual capacity does decrease due to the elevation of the diaphram.
restrictive disorder = normal ratio.
You are counseling your pregnant patient regarding her asthma. She wants to d/c her meds as she is afraid of the effects on the fetus. What do you say.
Important to maintain meds for asthma during pregnancy. Dypsnea of pregnancy is common. Effects of beta agonists and steroids on fetus are minimal. More important to make sure baby is not hypoxemic.
Quickly summarize changes in pulmonary function during pregnancy.
The tidal volume increases during pregnancy, decrease in the residual volume. vital capacity stays constant. Recall that the diaphram is pushed higher there is a smaller residual volume and total lung capacity. No change to IRV during pregnancy. RR stays constant. Increase in progesterone causes increased sensitivity to CO2 so often tachynapnea occurs and increased secretion of bicarb keeps mom's ph normal.
Your asthmatic mother is having an acute attack. The ABG show a PCO2 of 40 (normal for non pregnant). Does this concern you? What is your next step.
Imperative to get ABGs.
PCO2 of 40 is bad, normal during pregnancy is much lower 27-32. Make sure O2 sat is >95%.
Know that albuerol can increase FHR.
May need extra steroids during labor due to adrenal suppression.
Treat any underlying cause of the flare ie infection/pneumonia.
Your pregnant mom has a right ureter that is large at 2 cm. Are you concerned?
No ureteral dilation occurs due to relative hydronephrosis of pregnancy with the R more then the left. Caused by compression by uterus. Kidneys and renal pelvis will also enlarge. Dilation up to 15mm on right and 5 mm on left.
What Creatine clearance values indicate mild vs moderate vs severe risk to the obstetric outcome.
Mild Cr <1.4
Moderate Cr 1.4-2.8
Severe Cr >2.8
How does the immune system respond to pregnancy? How does this change at labor?
WBC actually increase to 20-30 k at labor without any sign of infection (stress).
Immune tolerance is necessary as the fetus is a semi allograft. Change of TH response from TH1 and NK cells to autobody mediated responses and TH2 cell responses.
What is Virchow's Triad for coagulation.
1. endothelial damage
2. stasis
3. changes in local clotting factors
How does coagulation change during pregnancy? What does this put the mom at risk for?
Coagulation factors are increased in total amounts although concentration in the serum stays about constant. This puts mom at a higher risk for DVT/PE during pregnancy.
How do you treat a pregnant woman with a DVT/PE?
Give un-fractionated heparin or LMW heparin and switch to un-fractionated at 36 weeks (shorter half life)
Warfarin (coumadin) counterindicated during pregnancy.
Postpartum can give Coumadin for 3 months, although it can cross into breast milk
Your pregnant patient has a cc of itching over palms and soles of feet. Elevated serum bile acids and mild jaundice are present. What is the diagnosis.
Cholestasis of pregnancy. Associated with Hep C and multiple gestations. Elevated serum bile acids causes itching. Give antipruretics and ursodiol.
What hormone is responsible for the darkening pigmentation of the skin during pregnancy.
hCG stilmulates melanocyte stimulating hormone causing skin darkening.
Melasma is common in up to 70% of women mostly malar rash, more pronounced in brunettes with dark skin pigmentation at baseline.
What is HELLP and what is it associated with?
Hemolysis Elevated Liver enzymes and Low Platelets and is associated with severe preeclampsia.
What are the risk factors for preeclampsia?
chronic hypertension
chronic renal disease
lupus/ diabetes
APA syndrome
prior disease
family history
multiple gestation
At what point do you begin meds for HTN or IV Mag Sulfate for seizure prophylaxis in a preeclampic?
HTN if DBP > 110 and SBP >160.
IV Mg Sulvfate if highest risk. Must monitor closely.
Complicaitons of preeeclampsia?
acute renal failure oliguria for 3 hrs.
pulmonary edema
hepatic rupture
eclampais/ seizure
DVA- due to BP and vasospasm
How does pregnancy effect coagulation factors/proteins?
Protein C stays Constant while protein S Sinks.
AT III unchanged
plasminogen activator decreases causing decreased fibrinolysis.
PT/PTT stay the same.
Increased factors I, VII, VIII, IX and X.
Most common benign neoplasm of the breast?
a phyllodes tumor
b intraductal papilloma
c fibroadenoma
d lactating adenoma
c fibroadenomas are the most common benign neoplasm of the breast. Most often found in young women, solitary, discrete mass made of proliferating ducts (adenoma) and fiborus tissue. Not associated with any increased risk of breast cancer
Which of the following has a significant risk for breast cancer?
a atypical ductal hyperplasia
b fibro adenoma
c apocrine metaplasia
d duct ectasia
Atypical ductal hyperplasias and atypical lobular hyperplasia both moderatley increase risk for breast cancer up to 4x.
ADH- appears similar to carcinoma in situ
ALH- less then 50% of lobules are filled by epithelial cell proliferation. Usually both epithelial and myoepithelial cells. No atypia.
Lobular carcinoma in situ is associated with increased risk for what?
Increase risk for invasive lobular and ductal carcinoma associated with lobular carcinoma in situ.
LCIS: >50% of lobules are filled and distended by epithelial proliferation (much more then atypical lobular hyperplasia)
Fat necrosis may mimic breast cancer on exam and mammogram and is caused by what with what histological changes?
Fat necrosis is due to trauma resulting in ischemia and narrowing of arteries. Collection of neutrophils and histiocytes acutely and then giant cells later. Appears as a hard mass suspicious for carcinoma.
What is the significance of hCG?
Human chorionic gonadotropin
similar alpha subunit to LH, FSH, TSH. Produced by the placenta- the syncytiotrophoblast. Production begins 8 days after fertilization. Peaks at 10 weeks and is gone by 17 weeks. Maintains the corpus luteum and therefore progesterone production. Helps with immune tolerance by causing apoptosis in endometrial T cells. Decreases myometrial contractility by decreasing Connexin 43 to down regulate gap junctions and decrease Ca++. Has TSH activity at high levels. Can stimulate testosterone secretion by Leydig cells of fetal testes to produce testosterone acting like LH, to begin sexual differentiation.
Causes hyperemesis.
Stimulates relaxin (increases GFR, PRF)
How does the molecular mimicry of hCG become problematic during pregnancy?
How can hCG be a warming sign?
hCG can mimic TSH such that 15% of women have suppressed TSH. Can also cause hyperthyroidism by activating thyroid receptors.
if hCG >1500 and no gestational sac= ectopic pregnancy
if hCG >9000 with absent FHS consider missed abortion.
hCG increased with molar pregnancy and for multiple gestations.
What is the role of human placental lactogen?
HPL is secreted by the synctiotrophoblast at day 5-10 and peaks at 34 weeks. Its role is metabolic and it stimulates insulin secretion and lipolysis. It may be cause insulin resistance in pregnancy. New research shows it has pro and anti insulin effects.
Facilitates mobilization and utilization of free fatty acids for energy. May cause gestational diabetes.
What is the role of human placental growth hormone?
hPGH is not regulated by GHRH.
Secreted tonically replacing pituitary GH in fetus. Doesn't cross the placenta but increases IGF-1 which regulates transplacental glucose and aa transport.
Stimulates gluconeogenesis and may cause insulin resistance.
low hPGH in growth restricted fetus
if high cause larger and more insulin resistant fetuses with hyperinsulinemia.
Increases nutrient availability to the fetus.
What is the role of relaxin?
Relaxin is made by the trophoblast and the corpus luteum.
Relaxin increases GFR and renal plasma flow and decreases SVR.
Is increased by hCG.
Decreases the effects of angiotensin II
Softens the cervix and promotes partuition.
What is the role of PTH-rp
PTH-rp is made by the placenta, decidua, fetal parathyroids and mammary glands.
Regulates calcium transport and increases the synthesis of active vit D for fetal skeletal formation.
What is the role of inhibin?
Inhibin inhibits FSH and decreases hCG and progesterone.
It is high in Downs syndrope and molar pregnancies.
It is low in ectopic pregnancies and with abortions.
What hormone does the placenta have that the fetus does not that protects the fetus from high levels of progesterone?
3 beta hydroxysteroid dehydrogenase
This hormone is made in large quantities 1-2g by the synctiotrophoblast and determines the placental weight. It peaks at 34 weeks but is detected as early as day 5.
Human Placental Lactogen
This hormone facilitates the mobilization and utilization of FFA for energy, stimulates insulin secretion and promotes growth of mammary tissue.
What is the major insulin resistance hormone of pregnancy?
hPGH is the insulin resistance hormone of pregnancy. It is needed to make mom slightly insulin resistant so she shuttles nutrients to her fetus.
This hormone is initially made by the corpus luteum till week 10. It inhibits uterine contractions, stimulates minute ventilation, promotes lobular development of the breast but inhibits milk secretion, is a substrate for cortisol and aldosterone synthesis and modulates the immune system.
This hormone stimulates growth of the myometrium, induces hypercoagulable stage, induces protein synthesis, induces lactotrophs and PRL at the breast. It also increases CO, uterine blood flow, blood volume and perfusion and increases pituitary size.
Estrogen. Primarially estradiol , high levels of placental aromatase and DHEAS turning into E by the palcenta.
Increases risk of thrombosis and PE, increases retinopathy and pituitary growth from prolactin macroadenomas are all promoted by what hormone?
What are the 4 polypeptide hormones released by the placenta
-too large to actually cross the placenta
gonadotropin releasing hormone
growth hormone releasing hormone
thyrotropin releasing hormone
CRH- releases prostaglandins to start labor.
What are the steroid hormones produced by the placenta- mostly transferred to the maternal circulation.
Progesterine, estrogen, 1,2 OH VIt D
Your patient has a low TSH and a high T4, do you suspect Graves?
What if she's pregnant?
Know that hCG mimics TSH and thus will suppress it and cause a hyperthyroid like state for a few weeks that is not pathologic.
Your patient has a very high hCG what are you worried about? What about a very low hCG?
high hCG = ectopic pregnancy or missed abortion, Downs syndrome or multiple gestation.
What are the 4 stages of labor:
Stage 1: onset of effective contractions, complete dilation of the cervix
Stage 2: complete dilation of the cervix and delivery of the fetus
Stage 3: delivery of the fetus until delivery of the placenta
Stage 4: first 6 hours post delivery.
What hormones are responsible for myometrial quiescence during pregnancy?
progesterone- blocks myosin light chain kinase via NO. Late in pregnancy progesterone receptors become less sensitive and stop this inhibition.
CRH- in early pregnancy promotes quiescence (blocks myosin LC kinase via cAMP) late pregnancy contributes to contractions (activates Protein Kinase C) due to shift in receptor subtype.
Describe the contraction activated proteins and how they contribute to myometrial contractility.
Calcium channels open to facilitate stronger contractions.
Gap junctions make the contraction wave like.
oxytocin/prostaglandin receptors become more sensitive.
What are the 4 phases of myometrial activation during parturition?
phase 0 = quiescence (passively expanding)
phase 1: activation, preparation for contractions
phase 2: stimulation - contractions beginning
phase 3: involution after labor.
What 3 hormones increase myometrial calcium and what are their MOAs.
CRH- activates protein kinase C pathways late in pregnancy
oxytocin- increases Ca by sensitizing calcium channels and increasing myosin light chain kinase
prostaglandins- sensitize calcium channels and weaken amnion and chorion preparing for labor.
What is the role of progesterone in labor?
progesterone keeps the uterus quiescent. Then late in pregnancy the receptors become less sensitive. As a result intracellular calcium levels increase and labor is able to proceed after the CRH signal to begin is received.
What is complete dilation of the cervix and what stage of labor does this occur in?
complete dilation = 10cm.
Cervix is effacing and thinning in stage 1 of clinical labor. (subdivided into latent and active stages)
Would weak acids or bases be more likely to pass the placenta?
Weak bases get trapped in fetal blood. This is because the fetal blood pH is lower than the maternal pH.
Note that drugs that are given orally are more likely smaller, uncharged and lipid soluble. Since they can traverse the gut membrane they are also more likely to get into the placenta, ie warfarin. Give IV drug like heparin instead if you can.
What antithyroid drug is best for a pregnant female?
PTU is better then methimazole as it is more protein bound.
Can you give a pregnant female steroids? Will they cross the placenta? How do you ensure baby gets steroids for lung development if needed?
Placenta has enzymes that inactivate cortisol, cortisone and prenisolone. Thus you can give mom steroids. If you want to target the fetus give betamethasone as it will cross the placenta.
What drugs are most likely to make it into breast milk?
Breast milk is acidic pH = 6.5 so weak bases like opioid analgesics get trapped. Also small. lipid soluble, no protein bound drugs are more likely to make it thorough. Keep in mind that drugs must get through mom's GI tract, through her liver and into her breast milk to get passed to baby.
What is the MOA of a PDE inhibitor, give examples.
What is a severe side effect if given with nitrates.
PDE Inhibitors like viagra are used for the treatment of erectile dysfunction.
Nitric oxide is released from endothelial cells. Increases cGMP levels which relax smooth muscle allowing vascular congestion. PDE breaks down cGMP and PDEIs inhibit this process so increased l time for the erection.
Don't take viagra when you are taking nitrates. Nitrates increase cGMP and PDE inhibit its breakdown possibly leading to severe vasodilation and hypotension.
What is the best steroid drug to give to mature fetal lung development?
Betamethason crosses into the placenta while prednisone and cortisol do not.
What timing methods can a breast feeding mother implement to minimize baby's exposure to drugs?
Mom can breast feed at the end of her dosing interval and administer her next dose at the end of breast feeding. Also administer a dose prior to infant's longest sleep time. Feed for shorter periods as late milk has more fat and thus more drug.
Your patient has a low serum AFP. What disease does this worry you about?
What if her AFT was high, what 2 conditions could this indicate?
Low AFP: Downs Syndrome
High AFP: omphalocele/gastrochecesis, or Spina Bifida
What 5 serum markers are analyzed in non invasive population screening of the pregnant female?
maternal alpha fetal protein (low=downs, high = omphalocele/ spina bifida)
unconjugated Estriol- low with trisomy 21 and 18
hCG- increased with Downs syndrome
Inhibin A- low with trisomy 18
PAPP-A (pregnancy associated placental protein A)- decreased with trisomies 21, 18, 13
Increased AFP indicate what?
Neural tube defects- anencephaly or spina bifida or omphalocele.
Describe 3 methods of estimating EGA:
EGA is determined by the first day of the last menstrual cycle.
Also by using the crown to rump length in the first trimester.
Also by taking the fetal weight in the second trimester- BPD, the transverse image of the head gives the biparietal diameter and head circumference.
Abdominal circumference also helps give an estimate of EGA in 2nd trimester.
Your prenatal tests show an elevated hCG but a decreased AFP and estriol. What trisomy do you suspect?
Down Syndrome, trisomy 21.
decreased estrogen sugests a dysfunctional placenata as the placenta takes DHEA from fetal adrenals and converts it to estrogen.
At 6 weeks you are told you have 1 fetus and you are given its crown to rump length. Then at 13 weeks you come back for a measurement of nuchal transluency. You have increased nucal thickness in your fetus. This indicates the possibility of what?
Increased nuchal thickness indicates higher possibility of trisomic features.
What is an amniocentesis, how early can it be done and what cells does it analyze.
Amniocentesis can be done between 14-20 weeks gestation. Needle removes amniotic fluid with fetal cells aka amniocytes which can be grown for analysis. Risk is increased by 0.5%.
What is chorionic villus sampling, how early can it be done and what cells does it analyze.
CVS: catheter is passed into developing placenta under u/s guidance to collect trophoblast cells from chorionic villi. Done between 9.5-12.5 weeks gestation. only 1% higher risk to fetus. Limitation is difficulty telling if there is only a confined placental mosaicism as the fetus and the placenta may have different karyotypes.
Contrast progesterone and CRH in their role in uterine quiescence.
progesterone "progestation" role is to block smooth muscle contractions via NO increasing cGMP which blocks myosin light chain kinase. Later in labor receptors become less sensitive.
CRH - receptors change isoforms and become inducers of labor. Early pregnancy also blocks myosin light chain kinase via cAMP but in late pregnancy activates protein kinase C instead initiating contractions.
Your patient has just finished having contractions and her uterus is now begining to involute. What phase of labor has she just transitioned into?
Transition from contractions (stimulation) during stage 2 into involution, stage 3.
What 3 hormones are responsible for increasing intracellular calcium leading to contractions?
CRH (via protein kinase C)
oxytocin (increased # receptors, sensitize Ca channels)
Prostaglandins (increase Ca channels)
Oxytocic agents like oxytocin and misoprostol do what?
promote labor. Prostaglandins and oxytocin both induce contractions. prostaglandins also ripen the cervix.
What is the difference between dinoprostone and misoprostol?
Both are oxytocic agents and are prostaglandins. However dinoprostone is a gel put on the cervix to ripen it while misoprostol is po which initiated contractions as well as cervical effacement.
What is the MOA of ergot alkaloids like methylergonovine/ergonovine? What are they used for?
Ergot alkaloids are oxytocic drugs that act through adrenergic/ serotoninergic receptors to contract smooth muscle. They are used after oxytocin if there is still hemorrhaging.
What is the tocolytic agent of choice to delay labor?
What is 2nd line therapy and what is the major side effect?
CCB: Nifedipine relaxes uterine smooth muscle by inhibiting calcium entry.
2nd line therapy is B2 Adrenergic agonist Terbutaline. Terbutaline relaxes uterine smooth muscle via adenylate cyclase but can cause jitteriness, hyperkalemia in mom and hypotension in teh infant.
What is the NSAID indomethacin used for?
NSAIDs help close the ductus arteriosis by inhibiting COX2. It can help prolong labor as it is a prostaglandin synthesis inhibitor but is no longer used due to PDA closure.
-ethanol and Mg Sulfate are both also non longer used for their tocolytic effects.
What is the MOA of the abortificant misoprostol?
Misoprostol is a prostaglandin analogue. It helps instigate cramps to expell the aborted fetus (usually synergistically with mifepristone Ru485)
PDE inhibitors prevent the degradation of this compound resulting in penile erection maintenance.
cGMP levels stay elevated without PDE degradation.
What can be done first, CVS or Amniocentesis?
CVS done at 9.5 weeks while amnio must be done after 14 weeks. Both are very invasive.
Contrast population based/ targeted/ highly targeted prenatal screening.
population based- NT defects, Down's
Targeted- ethnic predisposition- sickle cell (MCV), thalassemias (hemoglobin electrophoresis), cystic fibrosis (deletion in codon 508/ DF508), Tay-Sachs (hexosaminidase A deficiency causing accumulation of gangliosides, AR)
Highly targeted- known family Hx, look for gene sequence.
Your amniocentesis shows an elevated alpha feto protein. What test do you do to determine if the baby does indeed have a NT defect?
Confirm elevated aFP with AChE being elevated. (acetyl cholinesterase)
What is the difference between a screening test and a diagnostic test?
screening- simple, inexpensive, sensitive and specific test but often low PPD as most +s are false +s due to low prevalence of the disease.
Diagnostic test- after positive screening test do confirmatory test with better PPD. Weed out the false +s.
Your patient is young child with cataracts, MR, hepatosplenomegaly. This disorder is autosomal recessive with the accumulation of galactitol. What is the disorder and what is the defective enzyme?
The disorder is galactosemia. The enzyme that is absent is galactose 1 phosphate uridyltransferase, so galactose 1 -P can't be made into glucose 1-P.
Galactokinase enzyme deficency causes similar disease but has accumulation of galactose instead of galactose 1-P
Which BRCA gene is associated with increased risk of ovarian cancer and which is associated with breast and ovary.
BRCA 1(17q21): breast and ovarian cancer risk are increased
BRCA 2 (12q): less frequent, only associated with ovarian cancer.
How do the 3 types of fat differ in the lactating vs the non lactating gland.
lactating gland has increased glandular fat and decreased intraglandular fat. Subcutaneous and retro fat stay constant.
What hormone is responsible for differentiation of dermal mesenchyme to mammary mesenchyme... which leads to nipple development. What happens in its absence?
Parathyroid hormone-rP is responsible for differentation of mammary mesenchyme. In the absence of PTHrP blomstrands chondropasia (aka amastia) occurs where there is no mammary development.
PTH-rP is responsible for mammary development but what hormone is needed for
1. milk synthesis and secretion
2. milk ejection
milk synthesis and secretion = prolactin
milk ejection = oxytocin
The neonatal breast of both males and females will occasionally lactate "witch's milk," what causes this phenomenon?
High PRL and decreased progesterone at partruition can induce this temporary milk production.
Recall that progesterone and estrogen levels, if high, suppress milk production
What hormones during puberty induce elongation and branching of the ductal network by increasing IGF-1 production by the stroma?
What hormone causes side branching and alveolar development?
Estrogen and GH induce branching of the ductal network.
Then progesterone of the menstrual cycle brings about side branching and lobular alveolar development.
What is the role of the following hormones in breast growth and milk production?
GH and Estrogen increase IGF1 which regulates breast growth and primary ductal branching during puberty
Progesterone causes side branching and lobularalvolar formation during the LH phase and then regresses during menses. During pregnancy progesterone and prolactin are required for alveolar maturation.
Lactogenesis I: differentiation of milk secreting glands during pregnancy is regulated by what 2 hormones?
prolactin and placental lactogen induce the differentiation of milk secreting cells during lactogenesis I.
Milk protein expression is initiated during pregnancy by PRL and placental lactogen but women don't lactate until after birth due to what hormone?
High progesterone levels keep the milk in check.
The fall in progesterone (no more placenta) and elevated prolactin maintain synthesis and secretion of milk.
What hormone is high and what hormone is low in order for lactogenesis II (onset of copious milk secretion) to take place?
progesterone = low (no placenta)
prolactin (high) = milk production in high gear.
What 2 hormones are high and what hormone is low in order for lactogenesis II (onset of copious milk secretion) to take place?
progesterone = low (no placenta)
prolactin and oxytocin (high) = milk production in high gear.
prolactin = milk secretion
mil ejection = oxytocin/suckling stimulus
Name 2 factors that can negatively impact lactation by influencing the neuroendocrine reflex (which may mean increased DA inhibition of oxytocin).
Stress and Obesity both reduce prolactin response to suckling.
Also note that premature infants without good sucking reflex often are unable to nurse as by the time they are able to suck the nipple the sensitivity of the pituitary to the response has lessened and less oxytocin/prolactin is released.
What is special about the first 2 days of breast feeding before the tight junctions close?
Increased release of IgG is transferred into the breast milk transferring more of mom's immunity to protect baby.
What is special about the first 2 days of breast feeding before the tight junctions close?
Increased release of IgA is transferred into the breast milk transferring more of mom's immunity to protect baby.
What are the two cell types in the terminal ductule units?
myoepithelium = muscular contractions to expell milk (signaled by oxytocin)
secretory epithelium = glandular structures
What type of fat is most prevalent during lactation?
Glandular fat is most prevlent in the lactating breast.
Contrast the role of estrogen and progesterone in breast development during puberty.
estrogen- ductal development
progesterone- alveolar formation, side branching. (fall at end of LH surge causes regression and breast tenderness at the time of menstruation)
Contrast the role of estrogen and progesterone in breast development during puberty.
estrogen- ductal development
progesterone- alveolar formation. (fall at end of LH surge causes regression and breast tenderness at the time of menstruation)
During pregnancy prolactin is responsible for more side branching.
Deficency of what hormone causes the absence of nipples (Blomstrands chondroplasia)?
Deficiency of PTH-rP
How does suckling impact dopamine levels?
Suckling removes the tonic inhibition of PRL by DA and promotes the secretion of oxytocin from the Post pituitary.
How is the role of oxytocin in the breast similar to its role in the uterus?
Oxytocin promotes phospholipase C which increases calcium. This causes contractions. In the breast the myoepithelium contracts for milk ejection. In the uterus oxytocin is used to initiate contractions and induce labor.
What is the single most important factor in preventing deaths in children < 5yr worldwide?
breast feeding!
How does the nutritional content of breast milk compare to that of cow milk?
There is a high fat content with a lipid blend of long chain polyunsaturated fatty acids. Protein in breast milk has a high whey content vs. cow casein content, curd is better absorbed, low renal solute load helps immature baby kidneys. Also contains immunologic protection and helps long term with neurodevelopmental benefits.
What are some of the benefits of breast feeding for the infant and for the mother?
infant: bonding, increased cognitive performance 5 IQ points, 20% reduction in obesity, less chronic disease (celiac).
For mother there is less chance of postpartum hemorrhage, enhanced uterine contraction, increased weight loss, lactational amenorrhea helping space children.
How does breast feeding impact mom's future health?
protects against osteoperosis, protects against premenopausal breast and ovarian cancer. decreases steroid hormone levels. decreases overall illness/hospitalizations and medical expenses. Also saves money on formula.
How many calories per day does it take a lactating female to produce adequate breast milk?
500 kcal/day. Most from fat stores from pregnancy. If malnourished amount of milk will be reduced but nutritional content will be close.
What bioactive factors are there in breast milk?
lactoferrin- bacteriostatic by binding and lowering Fe
IgA- mucosal IgA given first 4 days
Oligosaccharides and glycoproteins- growth of healthy microflora
Immune cells
Nucleotides, hormones and growth factors
What is the AAP recommendation for breast feeding duration? How doest his compare to US Healthy People Goals for 2010?
AAP: Breast feed exclusively until 6 months, attempt to continue through 2 yrs.
US Healthy People Goals:
75% at hospital, 50% at 6 months, 25% at 12 months.
When should nursing be initiated?
Breast feeding should be initiated within the first hour of birth. There is a better 4 mo post partum health association, helps with thermoregulation and will help baby sleep.
How frequently are newborns breast fed?
When do solid foods begin?
Infants at first eat every 1 1/2 -3 hrs (about 8-12 x per day).
EBF until 6 months then begin rice cerials.
At first there is a decrease in baby weight for the first 2-4 days. Then by day 4-5 baby should start regaining weight. When should baby be back at birth weight?
If weight loss >7% and/or weight <birth weight at 2 weeks what is the problem?
At 7-10 days baby should have regained to its birth weight.
Insufficent milk syndrome is usually due to inadequate milk removal.
-stress, older age, mixed feeding, separation from infant
-baby problems with latching, sleepy, also eating formula.
What types of diseases may have a higher incidence with infants that are fed on cow milk based formula?
Atopy Diseases: triad of atopic dermatitis, asthma and food allergies.
Does maternal intake effect the vitamin or the mineral content of breast milk more?
Maternal intake affects mineral content more so notably iodine and selenium needed as supplements if deficent.
Summarize breast developmental changes through
and post menopause
puberty= estrogen and progesterone contribute to growth of the lactiferous ducts and intralobular duct system = non hormone sensitive after that.
follicular phase of menses- terminal duct epithelium proliferates and intralobular stroma is loose and edematous
during menses estrogen and progesterone decreased causing TDLU atrophy and increased lymphocyte infiltration
lactation= epithelial vacuolization and secretions from new acini
post menopause- increased fatty tissue and decreased intralobular stroma, TDLU atrophy
A newly nursing mother has cracked nipples, redness, swelling, pain and tenderness in the affected duct of the breast. What is the offending organism and what do you want to rule out?
S. aureus- Gram positive, cat positive, coag positive, cocci in clusters
Rule out inflammatory breast carcinoma (would be more common in older woman, presents as lymphatc obstruction by cancer cells- late stage cancer)
This disorder mimics breast carcinoma and is also called plasma cell mastitis and granulomatous mastitis. What histologic findings are characteristic.
plasma cell mastitis- plasma cells and lymphs
granulomatous mastitis- foamy histocytes and fibrosis
Nonbacterial cause in perimenopausa women due to obstruction of lactiferous ducts by residual secretions causing mammary duct ectasia (dilation).
Mimics breast carcinoma where there is a painless fixed mass (however this is painful with inflammation)
On breast exam you find a fibrotic calcified mass. Although this could be carcinoma if there is a prior history of trauma or ischemia it is probably what?
Fat necrosis. Collection of neutrophils and histiocytes around necrotic fat cells make painless calcified/fibrotic mass. Rule out carcinoma.
Also note that it could be an alveolar abscess/ or periductal mastitis but that is much more common in smokers (95%) and is associated with high recurrance.
What is the most common benign breast neoplasm? On exam it is solitary, discrete, mobile mass composed of proliferating ducts and stroma. Not associated with increased breast cancer risk.
Fibroadenoma- benign proliferation of ducts (adenoma) and fibroblastic stroma (Fibro). No increased risk of cancer.
This subareolar mass was discovered in a female complaining of bloody nipple discharge. What is it most likely?
Intraductal papillomas present with bloody nipple discharge. Usually a benign neoplasm growing in a major lactiferous duct near the nipple. Palpable as subaerolar mass. Histolocially note numerous delicate papillae with a fibrovascular core. Must distinguish from papillary carcinoma.
This neoplasm is rare, it demonstrates a spectrum of aggressiveness from low to high grade, and can grow to a massive size up to 16 cms. Tumors are composed of intralobular stroma and ductal epithelium appearing on cross section in leaf like clefts or slits.
This is a phyllodes tumor "leaf" like
benign < 5 mitoses
low grade 5-10 mitoses
high grade >10 mitoses with nuclear atypia and hypercellularity.
This benign neoplasm of the breast is a fibroadenoma in which lactational changes have caused a rapid increase in size during pregnancy (raising suspicion for carcinoma)
Lactating adenoma- subtype of fibroadenoma- painless
Fibrocystic change encompasses a group of changes that produce palpable lumps (cysts, epithelial proliferation and fibrosis). It is the single most common disorder of the breast. Two subtypes include proliferative and non proliferative. Contrast these 2 types and describe the cystic presentation.
nonproliferative- no hyperplasia, normal cell# present
proliferative- hyperplasia present
Both have cysts/fibroids and some increased risk of cancer.
Cysts arise in the TDLU and are unilocular. The blue domed cyst contains brown fluid upon extraction and is the most common.
This FCC presents with microcalcifications mimicking carcinoma on mammogram. There is sclerosing and proliferation of acinar structures and stroma and distortion of the TDLU. Look for myoepithelial cells (if intact = benign).
Sclerosing adenosis- increased density of acini and fibrous tissue.
Contrast lobular carcinoma and situ and atypical lobular hyperplasia.
atypical lobular carcinoma in situ <50% lobules filled with epithelial hyperplasia/proliferation (moderately increased risk ~4x)
lobular carcinoma in situ > 50% of lobules are filled and are actually distended from epithelial proliferation (markedly increased risk of cancer ~10x
Ductal hyperplasia demonstrates a spectrum of changes from usual hyperplasia to atypical to carcinoma in situ. Contrast the 3 main types of hyperplasia and determine their increased risk for cancer as contrasted to atypical ductal hyperplasia and ductal carcinoma in situ.
mild hyperplasia- papillary tufts proliferating into the lumen (no increased risk)
moderate hyperplasia- epithelial cells may proliferate to bridge and create arcades (slightly increased risk 2x)
Florid hyperplasia- solid masses are formed that fill and distend the lumen. Overcrowding and nuclear overlap occur so it can be difficult to determine the 2 cell population. (slightly increased risk 2x)
Moderately increased risk (4x) comes with atypical ductal hyperplasia- more atypica.
Then Ductal carcinoma in situ- malignant cells confined within BM without invasion. Markedly increased risk (10x) just like lobular carcinom in situ.
What is unique about the increased cancer risk for lobular carcinoma in situ in comparison to ductal carcinoma in situ?
Both have markedly increased risk for cancer, 10x but lobular carcinoma in situ is a marker for increased risk of invasive carcinoma where the risk is equal for BOTH BREASTS and subsequent carcinoma can be either ductal of lobular.
What are the 3 most frequent cancers in males and females and what are the 3 most deadly.
males: prostate, lung, colon
females: breast, lung, colon
males: lung, prostate, colon
females: lung, breast, colon
Cancer of the stroma/mesenchyme is called?
Cancer of the epithelim is called?
stroma = sarcoma
epithelium = carcinoma
What type of carcinoma does acute mastitis mimic? What is unique about the presentation of these two disorders?
Pain is unique. Most lumps are painless. Acute mastitis mimics inflammatory carcinoma
Metastatic lesions of the breast are very uncommon (unless <20 yo), what is the most common type and how is it spread?
Most common type is clear cell from kidney with hematologic spread to breast.
Name 3 major and 3 minor prognostic factors for breast cancer survival.
lymph node metastasis
lymph node biopsy
tumor size
presence of invasion
distant metastasis, locally advanced disease with invasion of muscle or skin, inflammatory prognosis are all independently associated with especially bad outcome.
minor prognostic factors:
hormone receptor, HER2/neu overexpression (poor prognosis).
histologica type (tubular, mucinous, medullary have better prognosis then invasive ductal carcinoma.)
histological grade
lymphovascular invasion
proliverative rate
What are some risk factors for breast cancer?
Risk increases with age.
Young age of menarche (earlier E exposure increases risk)
Late menopause (more exposure = higher risk)
Earlier first live birth (decreased risk)
Family history
Prior biopsies
Estrogen exposure ie HRT
Cancer of other breast, personal history
Breast feeding (lowers risk)
BRCA1= ovarian and breast (BRCA2 = only increased risk for ovarian cancer, but also increased risk for male breast cancer)
What is the role of BRCA1/2 in breast cancer? What is their risk without prophylaxis? What other well known mutations increase the risk for hereditary breast cancer?
BRCA1= ovarian/breast risk increased
BRCA2 = male breast and ovarian
1/4 cases of breast cancer have association with mutations in this tuor suppressor gene. One inherited mutation and one sporadically mutated. Damage in facilitating DNA damage repair. If no prophylaxis 3/4 will develop breast cancer.
Other syndromes:
Li Fraumeni syndrome- get colon cancer and breast due to p53 mutation
Cowden syndrome- PTEN gene (skin tumors)
Peutz-Jeghers syndrome- mutation in STK11/LKB1 gene (lip pigmentation and hamartamous polyps)
In males breast cancer is more likely to express estrogen receptors and involve the chest wall. This attributes <1% of breast cancers but is associated with what mutation and what syndrome?
BRCA2 mutation 1/10 male breast cancer.
Kleinfelters syndrome 1/20 breast cancer incidence is attributed.
Also men usually present in a higher stage but prognosis by stage is similar to women.
What receptors are most commonly seen on low grade tumors vs high grade tumors.
low grade = estrogen/progesterone hormonal receptors
high grade= HER2/neu
Which is more common, invasive ductal carcinoma or invasive lobular carcinoma?
Invasive ductal carcinoma more common.
This cancer presents as single file rows of cells invading the stroma of the lobules. E-cadherin protein have been inactivated resulting in loss of adhesion function. Usually HER2/neu over-espression.
Invasive lobular carcinoma
-same prognosis as IDC but less common, different metastasis points (CSF, ovaries, GI- not long and pleura like IDC)
You note" small islands of tumor cells floating on lakes of mucin".
Tumor is associted with BRCA1. Good prognosis, shows hormone receptors.
Mucinous tumor.
This tumor looks more ugly then IDC but has a better prognosis. It's associated with BRCA1 mutation but is negative for hormone and HER2/neu expression. Well circumscribed with rounded border, high grade nuclei and marked inflammation on sheets of solid cells.
Medullary carcinoma.
How do you stage tumor growth?
Tumor size and growth
Nodal involvement
Stage = location/ spread
Grade = histology/ mitotic figures
How common is breast cancer? What is the mobidity/ survival?
Most common non skin cancer in women.
2nd most common cause of cancer mortality.
1/8 women get it.
1/5 of those women die in 10 years.