LC Unit 2 Flashcards

Question

describe atypical lobular hyperplasia

Answer 1

Atypical lobular hyperplasia: - some lobules look normal (2 cell epithelium, lumen, normal size) - acini are filled w/ more cells than normal - >2 cell layers; look filled - involving <50% of lobules = atypical lobular hyperplasia - >50% of lobules= LCIS - risk of malignancy is bilateral

Answer 2

risk of breast carcinoma in FCC: minimal/no risk: -duct ectasia, cysts, apocrine met adenosis, mild hyperplasia, fibroadenoma w/o complex features slight risk: 1.5-2x -moderate- florid hyperplasia, papilloma, Serous adenoma, fibroadenoma w/ complex features moderate risk: 4-5x - atypical hyperplasia - atypical ductal hyperplasia - atypical lobular hyperplasia significant risk: 8-10x - DCIS: risk of invasive ductal carcinoma - LCIS: risk of both ductal and lobular carcinoma and can be ipsilateral or other side FHx of breast cancer increases risk in all groups

Answer 3

Metastatic: rare - melanoma (most common) - renal cell carcinoma - papillary thyroid carcinoma Primary breast tumors: - epithelial (by far most common; incl DCIS and LCIS) - stromal (stromal mesenchymal, vascular, fibroblastic, etc) - mixed (epithelial + stromal) - lymphoid tumors

Answer 4

Carcinoma in situ general: - one particular cell that has made an entire clonal process; expanded duct/lobule; caused havoc - has NOT invaded through basement membrane Squamous cell CIS: - acanthosis (increased epithelial thickness) - huge/ugly cells (increased N/C ratio, size, mitotic activity) - tongues of tumor coming down Bladder CIS: (normally transitional/urothelial epithelium) - urothelial CIS- increased mitoses; going above the basal layer of the tissue - cells are increased, big, N/C ratios, lighter chromatin (open chromatin pattern- denotes active proliferating cell) and discrete nucleoli Breast CIS: - DCIS: - LCIS:

Answer 5

Paget's disease = special DCIS - starts as crusty/infectious looking process of nipple - often misconceived as eczema - need to biopsy - proliferation of monotonous cells; increased N/C ratio, increased size; cleared-out cells; acanthosis, abnormal cell proliferation within the epidermal layer - doesn't break through basement membrane - often mistaken morphologically for melanoma

Answer 6

DCIS: - an epithelial CIS - increasing size of proliferation within ducts - numerous cells (all coming from same clone) - cribiform variant (looks like sieve) - papillary variant (fingerlike projections w/ fibrovascular core) - solid variant (duct is filled w/ cells) - micropapillary variant (do not have fibrovascular core; little tufts of cells coming out into lumen; hobnail looking cells) - camedo type (high-grade; very magenta-pink center; camedo-type necrosis like a zit) - risk of invasive carcinoma (mostly ipsilateral breast) - excision is often curative (no invasion through basement membrane/ into blood vessels) - risk factors for recurrence: histo grade, extent of breast involvement, and positive surgical margins - tend to be difficult to treat (vs invasive carcinoma...?) - low grade DCIS often expresses HORMONE RECEPTORS (ER, PR) but HER2 negative - high grade DCIS often over expresses HER2/NEU protein LCIS: - epithelial CIS - looks very monotonous- 1 solid type of morphologic appearance - look like discrete/evenly placed ants - expand and fill lobules - lobules and acini lose the dual cell layer - no crossing of basement membrane - can look similar to DCIS; use immunohistochemical staining to differentiate - does not typically form masses or calcifications - often multi centric and bilateral (hard to chase surgically) - increased risk for invasive carcinoma in BOTH breasts E-cadherin: - cell-cell adhesion marker - LCIS is defined by its LACK of E-cadherin expression (via IHC stain) - DCIS DOES have E-cadherin expression

Answer 7

INVASIVE epithelial carcinoma: -most commonly in UOQ (spread first to axillary lymph nodes) 2 main clinical presentations: - Palpable mass - mammographic abnormality uncommon presentations: - enlarged erythematous breast ("inflammatory carcinoma"; diffuse involvement of dermal lymphatics; very poor prognosis) - metastatic disease (usually in an axillary lymph node) signs of locally advanced disease: - fixation/pinning of tissue to underlying chest wall - dimpling of the overlying skin (carcinoma is more adherent and invading into skin- retracting skin) - numerous histologic subtypes, but we focus most on Invasive ductal carcinoma, not otherwise specified (NOS) and invasive lobular, and tubular carcinoma, metaplastic carcinoma, medullary carcinoma, and mucinous carcinoma Invasive Ductal Carcinoma (NOS) - 3 different degrees of differentiation help determine histo and clinical prognosis - well-differentiated degree: forms glands; cells aren't terribly ugly but still monotonous; glands aren't forming discrete lobules like usual - poorly differentiated: individual cells, lack of gland formation, infiltrated, large cells, high mitotic activity, big/ugly cells; have apoptotic debris; discrete nucleoli; open chromatin (high proliferation); not forming luminal/glandular structures - tends to metastasize to lungs and pleura Invasive Lobular Carcinoma: - 2nd most common histo type - tumor cells lose E-cadherin - tend to express hormone receptors but do not overexpress HER2/Neu - frequently assoc w/ LCIS - same prognosis as invasive ductal carcinoma - metastasizes more to CSF, GI, ovaries - very monotonous appearance; cells are large; increased N/C ratio, but they infiltrate; "Indian filing"- individual cells stacked and infiltrating through the glands Tubular carcinoma: - subtype of ductal carcinoma - very GOOD prognosis (has to have strict criteria for it- entire tumor has to be well-differenitaed) - 1 cell layer (lost myoepithelial layer), but forming nice tubules - cells are bigger, but not crazy ugly Mucinous carcinoma: - well-circumscribed mass - older aged groups - relatively favorable prognosis - usually express hormone receptors ER, PR (do not overexposes HER2/neu) - more frequent in pts w/ BRCA1 mutation - a lot of mucin; very few epithelial cells floating in pools of mucin; pale/white/grey Medullary carcinoma - often presents as well circumscribed mass - typically negative for hormone receptors - does NOT overexposes HER2/Neu (triple negative) - more frequent in pts w/ BRCA1 mutation - do slightly better than typical IDC - 3 main features: - --indistinct cell borders (AKA syncytial growth) - --prominent lymphoplasmacytic infiltrate at periphery (T cells and IgA plasma cells) - --pushing borders/ well circumscribed - not encapsulated, but well defined; brisk proliferation of lymphocytes around the tumor cells Metaplastic carcinoma: - any carcinoma w/ non-glandular growth - usually restricted to carcinomas demonstrating squamous, spindle cell, or heterologous (pseudo sarcomatous) differentiation - arise in assoc w/ poorly differentiated ductal carcinoma most commonly - usually ER/PR negative - Clinical: age range is similar in other types of breast carcinoma; seem to grow FASTER than other types; no specific mammography features (may have circumscribed contours) - no differentiation, except ugly/high mitotic rate cells; pleomorphic; can have squamoid appearance; very different than the others we've looked at INVASIVE STROMAL CARCINOMA: Angiosarcoma: - can be de novo or post radiation (more common) - often show up close to surface - proliferation of vascular cells - ugly spindle cells; extravasation of RBCs in stromal components; well delineated blood cells MIXED: - Phyllodes tumor: - --can be mistaken for benign fibroadenoma (more glandular proliferation and some stromal proliferation) - pretty much all stromal proliferation - leaf-like projections LYMPHOID: - can arise because there's lymph cells in beast (like other places in body) - can get mantle cell, marginal, CLL-associated, diffuse large B cell lymphoma, small lymphocytic lymphoma, etc

Answer 8

Hormone receptor expression = better prognosis HER2/neu expression = worse prognosis Prognostic factors: - lesion characteristics - regional lymph node involvement - examination for metastatic disease - not to be confused w/ risk factors (likelihood of developing vs progressing cancer) Major prognostic factors: - lymph node metastasis - tumor size - presence of invasion - distant metastasis - locally advanced disease - inflammatory carcinoma Used in the staging systems: TNM system - Tumor size and local growth characteristics - Node involvement extent - Metastasis presence of distant metastasis - used to separate pts into 5 categories, stage 0 up to stage 4 Minor prognostic factors: - tumor biology (hormone receptor or HER2 expression; histologic the; lymphovascular invasion, proliferative rate) - histologic grade (degree of differentiation- well differentiated = better prognosis) - amount of tubule formation - mitotic rate - degree of nuclear atypia - add points to give a combined score/GRADE (well differentiated - poorly differentiated) Biomarkers (ER, PR, Her2) are prognostic and have strong predictive value (how well pt will fare, and how well pt will respond)

Answer 9

- most common incidence of F cancer - 2nd most common death of F cancer - incidence rapidly increased in 1980 w/ screenings - slightly decreased recently

Answer 10

Risk factors: assoc/ w/ MORE estrogen exposure - age - age at menarche - age at menopause - age at first live birth - 1st degree FHx - prior biopsy results - race - exogenous estrogen exposure - radiation exposure - cancer of opposite breast or endometrial cancer - obesity - breast-feeding (protective) ``` 70-80% sporadic 10-15% Hereditary (BRCA1/2 mutation) 20-25% Familial (FHx, but neg for BRCA) -CHEK2 gene mutation -Tumor suppressor gene mutation (LOF) -Li-Fraumeni Syndrome (TP53 mutation) -Cowden Syndrome (PTEN mutation) -Peutz-Jeghers Syndrome (STK11/LKB1 mutation) ```

Answer 11

Carcinoma sequence: -Hyperplasia --> dysplasia --> CIS --> invasive cancer Molecular pathway of pathogenesis: -acquired mutations will eventually lead into the invasive carcinomas to some degree ER positive, HER2 negative cancers arise via dominant pathway (>50%) - same genetics found in: Atypical Ductal Hyperplasia, flat epithelial atypia, low grade DCIS - assoc w/ better prognosis of tumors HER2 positive (Chr 17q) cancer pathway: - 20% of all breast cancers - most common subtype of Li-Fraumeni syndrome - same genetics found in: DCIS (assumed precursor lesion) - assoc w/ worse prognosis ER negative, HER2 negative (triple negative): - 15% of all breast cancers - most common subtype assoc w/ BRCA1 mutation - precursor lesion is still unknown

Answer 12

rare disease in males risk factors are similar to F (incl hereditary and hormonal) BRCA2 mutations significantly increase the risk for males also assoc w/ Klinefelter's syndrome, likely related to altered testicular hormonal function often present as a subareolar mass often involve chest wall and skin expression of ER is more common tend to present at higher stage, but prognosis is same stage for stage

Answer 13

Sperm head: - haploid - nucleus contains highly condensed chromatin - protamines --> specialized basic histone tightly held together by disulfide bond cross-linking - shape of the sperm head is species-dependent - contains DNA and acrosome Sperm tail: - designed for maximum transport through fluid - narrow flagellum w/ tons of of mitochondrial content - microtubules 9+2 axoneme structure for motility Failure of sperm motility: Kartagener's (primary ciliary dyskinesia)

Answer 14

``` color viscosity volume >1.5mL pH concentration >15 million /mL motility >32% rate of progression morphology 4% ```

Answer 15

Zona pellucida: - shell; barrier to most diffusion surrounding oocyte - glycoprotein sheet w/ several microns thick - composed of 3 glycoproteins: ZP1, ZP2, ZP3 - glycoproteins play a role in fertilization (mutant/inactive zona proteins = infertility; clinically could be used as contraception)

Answer 16

Oocyte quantity and quality both determine reproductive potential -DNA damage, radiation, infection, chemical exposure, polyglandular endocrine failure, etc can affect the oocytes

Answer 17

Fertilization: -the process involving union of male and female germ cells that result in formation of a pronuclear zygote or once-cell embryo Fertilization requirements: - ovulation and oviductal collection of oocytes - deposition of sperm with sufficient number and motility - sperm capacitation - sperm traversal of cumulus oophorus - sperm interaction w/ zona pellucida and acrosome rxn - sperm penetration into zona pellucida - sperm-oocyte fusion - oocyte activation - male pronuclei formation Sperm capacitation: - spermatozoa acquire the capacity to undergo the acrosome reaction and fertilize eggs - capacitated sperm display hyperactive motility (increased flagellar beat frequency and amplitude; decrease in progressive movement), bind to zona pellucida, and area able to undergo acrosome rxn Acrosome reaction: - ZP3 receptor on tip of it - process of exocytosis Zona reaction: - prevents polysperm fertilization - as soon as first sperm binds, it alters cortical lumen and forms a barrier - 1st sign of fertilization: 2 pronuclei Sperm-egg interaction: - sperm activated by F reproductive tract - sperm goes through Cumulus layer and binds zona pellucida - acrosomal rxn - sperm lyses hole in zona - sperm and egg membranes fuse Sperm-oocyte fusion: - occurs between sperm's plasma membrane in the postacrosomal region and the oolemma - Fertilin: sperm protein responsible for sperm-oocyte fusion - lack of species specificity (sperm penetration assay SPA: zona-free hamster oocyte fusing w/ human sperm)

Answer 18

oocyte activation: - reawakening of the oocyte in regard to 2nd meiotic division - morphological indicator: exocytosis of cortical granules preimplantation: - 2 pronuclei w/ 2 polar bodies - 24 hours to get to 4 cell stage - good embryo morphology= 2 blastomeres w/ ground glass appearance (not lumpy bumpy) - 3 days after fertilization to get to 4-cell - variable quality of embryos- look for uniform/similarity in size and granulation of cells - rough correlation between quality and implant ability - day 4: morulae (cluster of grapes) - early blastocyst formation; zona thinning; cells move to one pole - a lab can look at polar body to get some chromosomal abnormality help (less invasive to the eggs)

Answer 19

within first 6 days after conception/fertilization, implantation of the blastocyst occurs ("blastocyst sticks at day 6") -hCG secretion begins around this time - implantation requires a direct and coordinated interaction between blastocyst, (outer trophectoderm) and the hormonally primed lining of the uterine cavity - primary processes for the preparations for implantation are blastocyst hatching and decidualization

Answer 20

-primary processes for the preparations for implantation are blastocyst hatching and decidualization Blastocyst hatching: -process when blastocyst "escapes" from zona pellucida -occurs around day 6-7 after ovulation (20-21 from LMP) -zona pellucida has been serving as a protective shell for the developing zygote -products of blastocyst likely activate the lytic factor(s) in the uterine fluid, as an unfertilized egg does not hatch (egg can be hatched in vitro via mechanical disruption or enzymatic digestion) -once hatched, the trophectoderm can come into direct contact w/ the endometrial epithelium Decidualization: - process where the endometrial stromal cells (fibroblasts) are transformed into round decimal cells - process is dependent on progesterone and cAMP - process begins in the secretory phase of the menstrual cycle - pre-decidualization takes place where stromal cells immediately adjacent to the spiral arteries begin to transform into rounded decimal cells - if fertilization takes place, then this process expands and includes the remaining stromal cells - depending upon the location of the decidua, it has different names - decidua basalis: resides under implanting embryo - decidua capsularis: overlies embryo - decidua parietalis: covers the remainder of the uterine surface

Answer 21

prep: - fertizlied egg will be in fallopian tube for 3 days; undergoes cell division - corpus luteum begins to secrete estrogen and P soon after fertilization - P and E start deciddualization of stroma - by the time it arrives in uterine cavity = morula - very quickly after uterine cavity = blastocyst window of implantation: - only a finite period of time that the epithelium lining of uterus is prepared to accept a blastocyst implantation - occurs day 20-24 during cycle - pinopodes (small finger-like projections) form on the apical surface of the endometrium - this is dependent on progesterone, and can be suppressed by estrogen - endometrium is becoming more vascular and edematous - endometrial glands have enhanced secretory activity Stages of implantation: - Apposition: 1st stage - --loose unstable connection between the trophectoderm and the endometrial lining - --trophoblast microvilli interdigitate w/ the pinopodes - Adhesion: 2nd stage - --stronger connection created by ligand-receptor interactions - --integrins (cell surface receptors) and intracellular cytoskeleton and L-selectin expression likely play a role - --heparin or heparin sulfate proteoglycans and their receptors are also important for implantation - --thought to dislodge and allow access of trophoblast to the basal lamina (asymmetric blastocyst positioned such that inner cell mass is embedded first) - Invasion: 3rd stage - --trophoblastic cells rapidly proliferation once the blastocyst adheres to epithelium - --cells differentiate into syncytiotrophoblasts and cytotrophoblasts - syncytiotrophoblasts: extend long protrusions and secrete TNF-alpha, which interferes w/ expression of cadherins and beta-catenin (assisting in dislodgment of the epithelial cells); secrete autocrine factors and proteases that promote invasion through the basement membrane and the endometrial stroma (decidua) - --other sub's: prostaglandins, CSF-1, LIF, IL-1 - blastocyst invades and is completely buried into the endometrium - no longer in direct contact w/ uterine cavity - occurred by the 10th day after fertilization

Answer 22

some infertility may be the result of defects in the ability to transform the endometrial lining or impaired decidualization - progesterone (via corpus luteum) is a critical player for both of these - the trophectoderm of the blastocyst produces hCG, which maintains the corpus luteum, and therefore progesterone - hCG is closely related to LH, and has immunosuppressive properties and growth-promoting properties likely critical for implantation implantation most frequently occurs in upper posterior wall in the midsagittal plane, but it can occur anywhere - implant near cervix = placenta previa - implant over site of prior uterine scar = placenta accreta - viable pregnancy can still occur, and are still considered intrauterine pregnancies Abnormal implantation leading to ectopic pregnancies: - ectopic = pregnancy outside uterine cavity - MOST common site = fallopian tube (mostly ampulla) - others: ovary, cervix, within abdominal cavity - not a viable fetus; life-threatening to mother - main risk: rupture and hemorrhage - present: vaginal bleeding, abdominal pain, hypotension, lack of US confirmation of intrauterine pregnancy - 2nd leading cause of maternal mortality Tx: - medical: methotrexate - surgical: laparotomy vs laparoscopy (salpingectomy, salpingostomy) - expectant

Answer 23

Screening test: -no symptoms allowed (symptoms = diagnostic testing) -screening advances time of dx of cancers destined to cause trouble -early tx is superior to tx initiated after pt already has symptoms -an effective screening program: increase the dx of early-stage cancer and decrease the amount of ate-stage cancer -hope to find bear cancers- detect it early enough to catch it before it gets too bad (length time bias)- slower growing--> better prognosis

Answer 24

lead time bias: - early detection is confused w/ increased survival - "screening always increases survival- even if death is not delayed by early detection" over diagnosis bias: -benign natural history --> best prognosis

Answer 25

BRCA1 mutation screening breast MRI ideal candidate for prophylactic tamoxifen: -high risk pt w/ no personal or family hx of endometrial cancer or VTE's

Answer 26

2x2 table: - "the truth is on top"- disease or no disease - screening pos/neg is on the side- true or false Sensitivity: TP/(TP+FN) -about pts w/ the disease; how often is this test right? -how often a metal detector beeps when you have metal -test for the guilty; to rule something out -SNOUT- Negative rules it out (high sensitivity = low false negatives) Specificity: TN/(TN+FP) -about the pts without the disease; how often is this test right? -how often a metal detector doesn't beep when you don't have metal -SPIN- positive rules it in (high specificity = low false positives) Likelihood ratio: LR= probability a test result in pt w/ disease / probability of the same test result in a pt without disease -disease is always in numerator -without disease is always in denominator -moves us from a pretest to a posttest predictive value -LR moves towards infinity- more likely pt has disease; LR >10 rules in (rapid strep test pos) -LR=1; test has no impact -LR moves towards 0- more likely pt does not have disease; LR <0.1 rules out (neg HIV test) -use Fagan's nomogram: -start w/ prevalence on pretest probability; draw a line through the LR in the center; then you get post-test probability -LR + = sensitivity / (1-specificity) -LR - = (1-sensitiivty) / specificity Relative risk: RR = (a/(a+b)) / (c/(c+d)) 1-RR = RRR Absolute risk: AR = (a/(a+b)) - (c/(c+d)) Risk difference: AKA absolute risk reduction ARR -ARR = difference (decrease) in risk between groups- risk of death in screened pop's vs unscreened pop's RRR les than avg risk 8% less (RR 0.92) than 0.35% = 0.32% ARR = (0.35% - 0.32%) = 0.03% NNS: AKA NNT NNS = 100 / ARR (where ARR is expressed as %) or NNS = 1 / ARR (where ARR is expressed as a decimal) -number needed to screen in order to prevent one death -NNS decreases as the prevalence increases: RRR increases with age; and ARR further increases since risk of breast cancer mortality increases w/ age NNH: NNH = 1/AR

Answer 27

Positive and Negative Predictive Values- ``` PPV= TP/(TP+FP)- chance you have dz when test is positive NPV= TN/(TN+FN)- chance you do not have dz when test is negative ``` to fill in 2x2 box: - need prevalence: total number of all 4 boxes - need sensitivity: TP/FN - need specificity: TN/FP False negatives are more common with increased prevalence - NPV's vary inversely w/ prevalence or pretest probability - --high Pretest probability = low NPV Prevalence goes up: PPV goes up; NPV goes down Prevalence goes down: PPV goes down; NPV goes up

Answer 28

Use the online Breast Cancer Screening Tool to determine if you should screen for BRCA additional testing and counseling when BRCA+ likely no more testing or counseling is

Answer 29

higher false positives and treating pts who don't need it- cancer under a microscope but is unlikely to cause harm - unnecessary surgery, radiation, or chemo (over diagnosis) - increasing the breast cancer screening has a very small effect on avoiding death from cancer

Answer 30

encourages pts to get screened, perhaps unnecessarily -increases 5 yr survival rate, but it's also because you're catching it sooner and it wasn't going to hurt you anyway Summary: -Goal of screening is to identify/treat disease before symptoms start as a means to reduce morbidity/mortality - Breast cancer screening and prevention strategies most beneficial in women at highest risk (high age//FHx/BRCA) - Evidence-based tools and guidelines exist to facilitate breast cancer screening and prevention - Breast cancer screening guidelines are all pretty similar (screen periodically starting around middle age) - Patients and physicians generally overestimate benefits and underestimate harms of screening - Basic understanding of EBM principles enhances our ability as physicians to optimize patient care

Answer 31

Implantation: day 6-8 -blastocyst syncytiotrophoblasts has begun to invade uterine wall and come in contact w/ maternal vessels chorionic villi structure: day 13-18 - 3 stages: - --primary villi: cytotrophoblast core surrounded by syncytiotrophoblast; out-pedicles - --secondary villi: extra embryonic mesoderm forms villous core - --tertiary villi: formation of arteriocapillary network; maternal vessels have fused and formed pool of maternal blood (20 days gestation) Placental chorionic villi: - floating villi (majority of placental mass; main site of nutrient and waste exchange from the high SA/branching) - anchoring villi (attachment to uterus; site for invasive cytotrophoblast deployment; allows anchoring) Trophoblast invasion: - interstitial invasion (cytotrophoblasts invade the entire endometrium and the first 1/3 of the myometrium) - endovascular invasion (cytotrophoblasts invade the uterine spiral arterioles through their myometrial segments; only termini of veins are breached) 8 weeks gestation: - primordial placental tissue much larger than fetus and surrounding fetus - chorionic villi surround surface of sac (precursor to placenta) 11 weeks gestation: - more focused concentration of villous tissue that has focused into placenta - no longer surrounding fetus

Answer 32

full term placenta: - plakuos = flat cake - umbilical cord attaches to placenta - vessels branching out across surface - fetal side of placenta: umbilical cord, shiny - maternal side: embedded into wall of uterus - between the 2 sides: chorionic villi bathed in pool of maternal blood - amnion and chorion somewhat fused together on the surface collectively called chorionic plate - chorionic villi are tree-like structures in the middle - desidual layer on maternal surface = basal plate Term placenta: - fetal side: anchoring villi - maternal side: cytokeratin and basal plate

Answer 33

composed of ultra filtrate of maternal plasma, fetal urine, and fetal lung secretions ranges from 250mL at 16 weeks to 1 L at 32 weeks amniotic fluid is critical for lung development and proper MSK function oligohydramnios - not enough amniotic fluid - rupture of membranes (most common) - congenital anomalies (GU system) - nephrotoxic drugs (ACEI's, NSAIDs) - poor placental perfusion Polyhydramnios: - too much amniotic fluid) - congenital anomalies (neural tube defects, esophageal atresia) - gestational diabetes (most common)

Answer 34

support the growth and development of fetus bidirectional transport: - nutrients, O₂ - waste, CO₂ - via diffusion, facilitated diffusion, or active transport endocrine - steroid and peptide hormones - CRH - GnRH - TRH - SRFI - ACTH - hCG ("pregnancy hormone"- peaks around week 10 of pregnancy, then declines because placenta is now producing enough progesterone so that hCG doesn't need to support the corpus luteum; reason for morning sickness; elevated in trisomy 21 babies and multiple gestations (more placental tissue)) - hCT - hPL (produced by sCTB; shifts maternal sys to more fatty acid metabolism so carbs/glucose can be available to fetus for E; creates insulin resistance; partly responsible for dev of gestational diabetes) - pGH (similar to GH; increases from 12 weeks to term; controls maternal IGF-1; secretion regulated by glucose) respiration (O2/CO2 transfer) - Fetal Hgb has higher affinity for O₂ than maternal Hgb - Fetal Hgb has lower affinity for 2,3-DPG - Fetal Hgb has higher pH hepatic - produce glycogen, fatty acids - drug metabolism - excretion of waste products skin - involved in temp regulation (F feel warmer during pregnancy) - protective physical barrier to pathogens immune system - physical barrier to pathogens (Hofbauer cells in villous core) - transports maternal IgG to fetal circulation (fetal immune sys makes IgM; IgM does not cross placenta) - IgG transport (isoimmunization/immune hydrops; flu vaccination in pregnancy; Tdap vaccine in pregnancy; maternal autoimmune disease- neonatal lupus, etc) has a finite lifespan -not designed to live for 80-90yrs

Answer 35

trophoblasts secrete estrogens and progesterone at levels not reached in other mammals progesterone suppresses uterine contractions necessary for pregnancy maintenance estrogen production requires the maternal-fetal-placental unit placenta lacks P450c17 and 16-alpha-hydroxylase fetus lacks P450 aromatase and 3-beta-hydroxysteroid dehydrogenase mom-placenta-fetus is necessary to produce all of the estrogen and progesterone necessary to support a pregnancy

Answer 36

Dizygotic- "fraternal" - 2 ova fertilized by 2 sperm - not genetically identical - 70% of spontaneous twins - 95% of ART twins (assisted reproductive technology) Monozygotic- "identical" - 1 ovum fertilized by 1 sperm, fertilized oocyte divides - genetically identical - 30% of spontaneous twins Twin Placentation: - 2 cell stage- fertilized egg making its way through fallopian tube - if the egg splits within the first 4 days after fertilization (in morula stage), each develops its own trophoblast layer on outside and inner cell mass on inside when they become blastocysts- they develop their own placentas; different layers develop into own chorion, amnion, and placenta - can implant right next to each other or opposite sides of uterus, but each baby has its own amnion and own chorion - called diamnion and dichorion pregnancy - monozygotic diamniotic dichorionic pregnancy - can also get dizygotic diamniotic dichorionic pregnancy, but you don't have any egg splitting- you start with 2 eggs to begin with - if the fertilized egg makes it all the way to the uterine cavity, splits 4-8 days after fertilization (right before implantation)- there is only a single trophectoderm layer but 2 inner cell masses form, and only 1 placenta formed, but 2 separate sac's that are divided only by an amnion; only a single chorion around the entire sac; each baby has its own amnion- still in 2 separate sacs adjoining each other; monochorionic diamnionic (monozygotic) pregnancy - most common of the monozygotic twins (70%) - if fertilized egg does not split until 8-12 days after fertilization, then everything is shared- 1 chorion, 1 amnion, 1 placenta, and babies share 1 sac together - monochorionic mono amnionic (monozygotic) pregnancy -fertilized egg doesn't split until 13+ days- when splitting occurs this late- you get conjoined twins that don't completely separate; they are monochorionic mono amnionic conjoined (monozygotic) twins

Answer 37

Risks of twin pregnancies: - miscarriage - hyperemesis (increased hCG) - increased risk of aneuploidy and anomalies (increased 3-5x in monozygotic) - prenatal screening tests are less sensitive and diagnostic procedures are more difficult in twin pregnancies - maternal anemia - gestational diabetes (? higher hPL) - gestational HTN/preeclampsia (increased 2x) - intrauterine growth restriction - preterm birth--- (more likely to also need an iatrogenic preterm delivery) $$$ - higher chance of cesarean delivery - higher rate of postpartum hemorrhage - increased perinatal mortality- 5-7x rate in singletons - average twin gestational age is 36 weeks (1 week premature) Dizygotic twins: - 25% affected by fetal growth restriction (1 or both) - 40% deliver preterm - 10% perinatal mortality Monozygotic twins: - Di/di twins: - --30% growth restriction - --40% preterm - --18-20% perinatal mortality - Mo/di twins: - --50% growth restriction - --60% preterm - --30-40% perinatal mortality rate - Mo/mo twins: - --40% growth restriction - --60-70% preterm - --60% perinatal mortality rate* (cord entanglement) - conjoined twins: even higher rates

Answer 38

Zygosity: -number of originally fertilized eggs Chorionicity: -the number of placentas (layer surrounding the inner amnionic layer)

Answer 39

determining chorionicity: - ultrasound: thickness of membranes and how many layers are separating the 2 sacs - --Di/di: 4 layers; 2 chorions and 2 amnions; "thick dividing membrane"; "twin peak" or lambda sign- where membrane attaches to the placenta - --Mo/di: 2 layers; 2 amnions; thin dividing membrane; "T" sign - --Mo/mo: 0 layers - histology: - --dichorionic: by definition must be diamnionic; look at the dividing membrane morphologically; see twin A amnion; Twin A chorion; Twin B chorion; Twin B amnion - --monochorionic placentas: single trophectoderm so you only have single chorionic membrane surrounding the entire pregnancy; Amnion of Twin A and Amnion of Twin B; no intervening chorion down the middle (no purple cells going down the center) - --monoamnionic: single cavity that both babies are living in; no dividing membrane; single amniotic sac (and therefore single chorionic sac); very high risk for cords entangling at young gestational ages- demise of both fetuses due to cord entanglement; or can get babies develop to term (but high risk); cessation of blood flow to one or both twins

Answer 40

occurs exclusively in monochorionic-diamnionic twins (monozygotic twins that split 4-8 days post-fertilization) - 15-20% of monochorionic-diamnionic twins have unbalanced flow through connected vessels - recipient twin (larger) increases urine production to reduce blood volume - --larger bladder on US - --polyhydramnios - donor twin (smaller) reduces urine production to retain blood volume - --oligohydramnios - classification based on US findings - mo/di twins are the highest risk for TTTS because they are most likely to have unbalanced arterio-venous connections - --dichorionic twins shouldn't have any connecting vessels - --monoamnionic twins have so many vascular connections, they tend to balance out Diagnosis of TTTS: - poly/oligohydramnios - fetal size discordance - usually done w/ US, but fetal MRI and echo may also provide info: - clinically divided into different stages/severities; and the more discordant the growth, the higher the likelihood of perinatal morbidity/mortality - historically: intertwin weight of 15-20% is considered diagnostic of TTTS, but now the cardinal finding is amnionic fluid volume difference - occur via arterio-venous connections and differences in blood flow resistance Implications of TTTS: - untreated, TTTS prior to 24 weeks gestation leads to mortality of one or both twins in 80-90% cases - --after death of 1 twin, other is at increased risk for brain damage in 1/3 cases - severe TTTS prior to 16 weeks has dismal prognosis cause of death of donor twin: - decreased blood volume --> lower urinary output --> oligohydramnios (too little amnionic fluid to move around) - small placental volume --> not enough nutrients to support fetal growth cause of death of recipient twin: -too much blood volume --> strains baby's heart to point of heart failure; also too much urine production --> polyhydramnios (possibly leading to uterine distention and early delivery) and sometimes fetal hydrops (diffuse edema)

Answer 41

reduction amniocentesis: - removal of excess fluid from recipient twin sac using needle through mom's abdomen - --up to 3L may be removed at a time - --repeated every few days to weekly - usually early delivery (29-30 weeks) - survival 18-83% Microseptostomy: - creation of hole between the babies' sacs - --fluid moves into down twin to equalize - if hole gets larger, umbilical cords may become entangled - 80% survival of at least 1 twin and 60% survival of both twins in 1 study Laser ablation: - direct visualization of communicating vessels and ablation with laser - higher complication rate (15-20%) - 70-80% survival of at least 1 twin and 35% survival of both - --if demise to 1 twin, lower rate of mortality for surviving twin (35%--> 7%)

Answer 42

Total Body Water Metabolism: - increase TBW from 6.5L to 8.5L = 2kg - expanded plasma vol, RBC vol, extravascular fluid, intracellular fluid in uterus and breasts - chronic vol overload w/ active Na and H2O retention (changes in osmoregulation and RAAS) - contribue to pregnancy weight gain, hemodilution, physiologic anemia, elevated CO - overall, water retention > Na retention (serum Na decreases by 3-4mEq/L) - plasma osmolarity decreases by 8-10 - polyuria to 8-10 weeks, goes away, returns during 3rd trimester - increase RAAS - increase in ANP and BNP - impaired vol expansion linked to increased risk for preeclampsia, impaired fetal growth/fetal growth restriction - weight gain ~1lb for normal pts; ~0.5lb for overweight/obese pts - early alteration of Arginine vasopressin secretion (initial changes mediated by placental elaboration of NO and Relaxin) - RAAS: marked increases in all components; early pregnancy causes low MAP; triggers activation of RAAS (4-5x higher in pregnancy); 2x increase in Aldo (increases Na retention and prevents Na loss) - ANP/BNP elevated in both physiologic and path states (myocardium releases these neuropeptides to maintain vascular homeostasis); - many physiologic pregnancy complaints mimic heart disease (ex dyspnea); - BNP increases mostly in 3rd trimester

Answer 43

- HR: increases by 20% in 3rd trimester - CO: increases by 40%; (distributed more to breast, skin, uterus; mainly increase in SV) - SVR decreases (NO, progesterone on SM) - CVP decreases - PCWP unchanged - PAP decreases - MAP decreases - BP decreases to 20 weeks (NO, progesterone; vascular resistance decreases); then increases to normal (increased HR) - Preload, EDV, compliance: increase (2/2 increased venous return) - Afterload: decreases (2/2 decreased vascular resistance) - Ventricular wall muscle mass: increases - Advise pt to sleep L lateral decubitus for highest CO (supine compresses IVC--> varicose veins, DVT, hypotension) - decreased birth weight noted in prolonged standing work (decreased CO while standing) Increased venous pressure and P on IVC: -edema, varicose veins, hemorrhoids, and increased risk for DVT - Systolic ejection murmur along L sternal border in up to 96% - --diastolic in 18% but warrants echo) - S3 common; S4 rare - prominent pulmonary vasculature - EKG changes CV changes are most dramatic during labor due to: - contraction of uterus and dumping extra blood into systemic vasculature (uterus forces blood to systemic circulation during contraction; increased venous return--> increased CO) - valsalva maneuver: wide fluctuations in BP and HR - pain induces increased catecholamines (increased sympathetic stimulation) - almost all pts will have some type of arrhythmia during labor - pts w/ heart disease should have precautions (fluid balance, early epidural placement to decrease pain, EPI, and CO) - --cesarean has 2x more blood loss than vaginal delivery (be careful with fluid balance); is not the answer to pt w/ heart disease most of the time For valvular heart lesions: -regurgitation is better tolerated than stenosis Aortic stenosis pts: - pt has fixed SV - changes in HR too extreme either way could cause hypotension - avoid vasodilators Signs/symptoms mimicking heart disease: -dyspnea, exercise intolerance, fatigue, orthopnea, syncope, chest discomfort, peripheral edema, mild tachy, JVD

Answer 44

TV: increases 30-40% (increased min vol; increased O₂ uptake; increases at the expense of ERV) IRV: unchanged ERV: decreases 15-20% VC: unchanged FEV1: unchanged FVC: unchanged FEV1/FVC: unchanged (no change in large airway function) IC: increases 5% RV: decreases 20% (decreased FRC; elevated diaphragm) FRC: decreases 20% (elevated diaphragm) TLC: decreases 5% (elevated diaphragm) Min ventilation (RRxTV): increases 30-40% RR: unchanged (but progesterone does affect sensitivity of resp center to CO₂--> hyperventilation) O₂ consumption: increases PaO2: increases!!! PACO2 and PaCO2: decreases (facilitates gradient for CO₂ fetus-mother transmission) Serum bicarb: decreases (increased excretion to maintain pH) Mechanically: everything is "shoved north" - thoracic changes: increased AP diameter and circumference - diaphragm pushed up, but diaphragmatic excursion actually increases - breathing becomes more diaphragmatic than costal Primary respiratory alkalosis w/ compensatory metabolic acidosis - compensated by increased bicarb secretion - blood gases will naturally be alkalotic w/ metabolic compensation (from kidneys) - asthma may improve from increased serum cortisol - O₂ sat <95% is abnormal- may represent hypoxemia Dyspnea of pregnancy in 60-70%-- reassure pts -probably due to low PaCO2 levels common medical therapies for asthma are safe: -antibiotics for infection (careful in selection) -steroids, etc - PCO2 up to 40 in non-pregnant pt is ok -pregnant pt: indicative of impending respiratory failure

Answer 45

kidney size: increases (increase RBF) kidney vasculature: increases (increase RBF) kidney interstitial space: increases urinary dead space: increases bladder capacity: decreases (fetus compresses bladder, but increased urine volume) GFR: increases 50% RPF: increases 60-70% (NO + Relaxin) FF (GFR/RPF): decreases (GFR inc; RPF really increases; NO and Relaxin also implicated in these changes) Serum Cr, BUN: decrease (increase in plasma vol and increase in GFR) Hydronephrosis of pregnancy: - R > L - caused by mechanical compression w/ enlarging uterus and SM relaxation caused by progesterone - will change interpretation of renal/bladder US increased risk of pyelonephritis due to urinary stasis and asymptomatic bacteriuria - treat asymptomatic UTI to prevent pyelonephritis - 90% pyelonephritis is on R - pyelonephritis has increased risk of complications (ARDS, development of preterm labor) increased hematuria due to increased vasculature to urinary tract pt w/ renal pathology: - counsel about risks in pregnancy - baseline and serial 24hr urine CrCl and total protein - tx underlying disease w/ fetus in mind - close observation for pre-eclampsia - serial US to assess fetal growth - fetal monitoring of HR - often permanent worsening of renal pathology w/ each pregnancy - worsening Cr is assoc w/ pregnancy complications

Answer 46

plasma vol: increases 50% (starts week 6-8) RBC mass: increases 20-30% Hct: decreases to 32-36 (dilutional anemia) Plts: decrease (thrombocytopenia <150K in 10-15%; rare to be <100K) Platelet aggregation: increases (from estrogen) WBC: increase 1st trimester; then really increase 2/3rd trimesters; then sky rocket during labor (increased PMNs and granulocytes) Th1: decrease NK: decrease Th2: increase Total clotting factors: increase (to decrease chance of hemorrhage) DVT/PE risk: increases (anatomic factors; L>R; Virchow's triad) Determine risk of hyper/hypocoagulation in Hx Fetus thought of as allograft: must evade the immune system - shifts from Th1 to Th2 thought to contribute to immune acceptance of baby - less cytotoxic potential form fetal antigen w/ this shift - humoral immunity is changed Consider Virchow's triad when advising for DVT risks: - endothelial damage, stasis, coagulation - 90% of DVTs are on L side - marked increase in procoagulants (factors 1,7,8,9,10; minimal increase in 2,5,12; 11 and 13 are the only ones that decrease) - Protein C stays Constant (ATIII also unchanged) - Protein S Sinks - standard of care during pregnancy: LMW Heparin; switch to unfractionated at 36 weeks (shorter half life; can discontinue during labor) - Coumadin is contraindicated- crosses placenta

Answer 47

Daily caloric intake: increase 200 1st; increase 300 in 2/3rd weight: increase 25-35lbs in nl weight pt Saliva production: increases early PUD risk: decreases (increased mucin production; decreased H+; increased tolerance to H pylori) GERD: increases (esophageal dysmotility; gastric compression; decreased LES tone) Gastric tone and motility: decreased (decreased motilin; increased progesterone) SI motility: decreased (progesterone) Gallstones/GB size: increased (GB doubles; empties more slowly) Liver size/blood flow: unchanged Serum Albumin: decreased (Hemodilution) Dental caries: unchanged -"eating for two" --> excessive weight gain LI absorb more H2O and Na --> constipation --> drink more water Displacement of intestines--> changed McBurney's point--> changed eval for appendicitis increased risk of gallstones --> low fat diet or elective cholecystectomy spider angiomas and palmar erythema are nl in pregnancy (normally indicate liver disease) -LFTs can change normally in pregnancy (low Albumin; high Alk phos) N/V is attributed to increased beta-hCG and should subside by end of 1st trimester ---supportive therapy: small meals, avoiding trigger foods, meds Hyperemesis Gravidarum: - 1-3%: refractory N/V assoc w/ weight loss, dehydration, electrolyte imbalance, and ketonemia - may require hospitalization or home IV and bowel rest

Answer 48

most common pregnancy induced liver disorder - itching over palms and soles then generalized itching without rash - assoc w/ Hep C and multiple gestation - elevated serum bile acids - Jaundice in 20% and mild transaminitis (monitor LFTs and PT/PTT) - malabsorption of fat may cause Vit K deficiency and prolonged PTT - --supplement Vit K at 34-36 weeks -increased risk of stillbirth (fetal monitoring)

Answer 49

hyperpigmentation- 90% - areolae, nipples, genital skin, axillae - darkeneing of lines nigra - melasma (Mas of pregnancy) - HCG stimulates melanocyte stimulating hormone (MSH) vascular and CT changes increase blood flow to skin (by 4-16x) - spider angioma - palmar erythema - leg varicosities - gum hyperemia, nose bleeds striae gravidarum (stretch marks) - 90% caucasians - often assoc w/ Pruritis

Answer 50

endocrine: - insulin sensitivity early; resistance later (gestational DM)--> shunt nutrients/glucose to fetus - earlier conversion to fatty acid metabolism if fasting (due to decreased maternal glycogen stores from fetal-placental glucose demands, so mother is left with fatty acids (Fasting ketosis within 10-12 hours; vs 48 hours in a non-pregnant pt)) - hCG-mediated hyperthyroidism --> increased TH levels - increased iodine requirements (goiter, hypothyroid) --> huge demand increase by both mom and baby - changes in autoimmunity (Postpartum thyroiditis: increased Th2 response; decreased Th1 response; rheum conditions improve during pregnancy but postpartum worsening) - estrogen induced pituitary growth (Sheehan's syndrome; estrogen-stimulated PRL production) - absorptive hypercalciuria--> kidney stones - placental vasopressinase --> increase risk of DI CVS: - 30-50% increase in CO (decompensation in CAD, CHF, Marfan's, valvular stenosis) - decreased SVR --> decreased BP - no change in pulm vascular resistance in pts w/ pulm HTN - increase in HR - 30-40% increase in blood vol (anemia of pregnancy) - gestational thrombocytopenia - hypercoagulation state (estrogen increases clotting cascade) Respiratory/ acid base changes: - increase in O₂ consumption - increase in TV, minute ventilation --> resp alkalosis - compensatory metabolic acidosis (decreased serum HCO3) leads to lowering buffering capacity (earlier DKA) - nasal mucosal edema (stuffy nose, sinusitis) Renal: - 40-60% increase in GFR (increase clearance of hormones, iodine, drugs)--> BUN and Cr decrease - increased RBF - altered tubular function (glycosuria) - decreased ureteral peristalsis with mild hydronephrosis --> increased UTI's and pyelonephritis - lowered osmostat for vasopressin release and thirst (nyponatremia) GI: - decrease LES (GERD, aspiration pneumonia) - decrease stomach emptying, peristalsis (gastroparesis, delayed absorption, constipation) - decreased GB emptying (cholestasis)

Answer 51

``` CRH (20 fold increase at term) -likely plays a role in parturition GnRH (stimulates hCG) GHRH TRH ``` hCG - maintains corpus luteum in early pregnancy - similar to LH and has TSH activity at high levels hPL (hCS) - human placental lacgoten or chorionic somatomammotropin - participates in the metabolic adjustments that deliver nutrients to the developing fetus hPGH (hGH-V) - human placental GH - contributes to insulin resistance of pregnancy Relaxin: - role in increased GFR and decreased SVR - softens cervix - decreases uterine contractility PTH-rP: - helps transfer Ca2+ across placenta to help bone formation in growing fetus - increase release of 1-alpha-hydroxylase form placenta--> increased active Vit D

Answer 52

Progesterone Estrogen (up to 100 fold increase) 1,25-OH Vitamin D

Answer 53

hCG: - alpha subunit is the same as LH, FSH, and TSH - TSH activity at high levels (hyperthyroidism of pregnancy --> suppresses TSH = normal) - produced 8 days after ovulation - half life is 24-36 hrs; can use to see if pt is miscarrying - maintains corpus luteum progesterone release/synthesis until placenta takes over at 8-10 weeks - regulates differentiation of cytotrophoblast --> syncytiotrophoblast; controls trophoblastic invasion - induces apoptosis of endometrial T cells to promote immune survival of embryo - stimulates fetal Leydig cells to produce fetal T - decreases myometrial contractility - causes 1st trimester emesis - stimulates Relaxin --> increased GFR/RBF and decreases SVR - monoclonal beta-hCG used in home pregnancy test - peaks 10-12 weeks (peak of hyperemesis) - increased in multiple gestations - increased in Down Syndrome - failure to double in missed abortions - major role is action on thyroid to increase TH Human Placental Lactogen (hPL) or Human Chorionic Somatomamotropin (hCS): - similar to PRL and GH - dectected at 5-10 days; peaks at 32 weeks - made in massive quantities- 1-2g/day - modest metabolic, growth, and lactogenic effects that end up delivering nutrients to baby - stimulates insulin secretion and islet cell number, along w/ lactogens such as PRL - facilitates mobilization and utilization of FFAs for E by increasing lipolysis - both insulin and anti-insulin effects - stimulates insulin secretion!! to maintain euglycemia human placental growth hormone hPGH: - not regulated by GHRH - same affinity for GH receptor - secreted tonically; replaces pituitary GH at 20 weeks - stimulates gluconeogenesis - contributes to insulin resistance in pregnancy - potent somatogen, weak lactogen - stimulates maternal IGF (which regulates transplancental glucose and AA transport) - does not cross placenta but regulates IGF-1 - decreased by glucose, increased by hypoglycemia - hPGH appears to be the major insulin resistance hormone of pregnancy to increase nutrient availability to fetus - maternal insulin resistance necessary to shunt glucose and AAs to fetus to ensure adequate growth - suppresses pituitary GH Estrogen: - steroid hormone - stimulates myometrium - increases hepatic protein synthesis --> SHBG + TBG + CBG binding proteins - induces lactotrophs - peripheral vasodilation - inhibits NE vasoconstriction - inhibits DA --> increases PRL - causes hypercoaguable state - --decreases Protein S - --increases clotting factors and fibrinogen - increases NO synthesis --> decreased SVR and decreased BP - increases CO - increases mucosal edema and uterine blood flow - increases neovascularization - increases blood vol - increases RBF and GFR - increases Triglyceride synthesis - increases pituitary size - increases 100x during pregnancy - hormonal effects due to changes in binding proteins - worsens proliferative retinopathy (increases neovascularization) - increases thrombosis in pregnancy (only protective during labor/hemorrhage; otherwise you get DVT/PE) - PRL macro adenomas will enlarge --> Sheehan's syndrome, visual field defects - increased triglycerides --> pancreatitis

Answer 54

hCG: - greatest early - peaks around 10 weeks in pregnancy - decreases gradually once progesterone takes over estradiol: - rising throughout - greatest amount late (100 fold) progesterone: - starts increasing around 10 weeks gestation - critical to maintain pregnancy - corpus lute produces it prior to 8-11 weeks - rises until partuition Prolactin: -increases with estrogen via inhibition of dopamine

Answer 55

syncytiotrophoblast - is the powerhouse of protein and steroid production - makes all steroid hormones and most peptide hormones - hormones synthesized in placenta - directly bathed in maternal blood within intervillous space - maternal blood >>> fetus cytotrophoblast: - some peptide hormone synthesis - no steroid hormone synthesis ever!

Answer 56

Hemochorioendothelial placentation: - anatomic structure of human placenta that puts syncytiotrophoblasts in direct contact w/ maternal blood supply - location causes net transfer of steroids to maternal blood of ~10x compared to fetal blood - large, lipid soluble molecs cannot cross placenta into fetus Estriol is only synthesized in the placenta -historically used to evaluate placental health in pregnancy

Answer 57

- Insulin sensitivity increases in the first trimester - --Mother is anabolic in first trimester → shuts off lipolysis and stores fat - --Type 1 diabetics can die in their sleep from hypoglycemia if exogenous insulin is not decreased when insulin sensitivity increases. - Insulin resistance develops after first trimester - --Placenta makes factors that increase insulin resistance in mom in order to provide more glucose to the baby. - -----incl hPL, hPGH and probably TNFalpha - --Mother becomes catabolic and fetus is anabolic Mom deals with insulin resistance in two major ways: - Mom pumps up her β cell production of insulin to compensate for ↓ insulin sensitivity. - --If mom can’t do this she is at high risk for DKA - --Women with pre-existing diabetes need to double to triple their insulin requirement during the second and third trimester. - Mom uses fat oxidation for her energy needs → Triglycerides are hydrolyzed producing ↑ fatty acids + ketones If you starve a pregnant woman for more than 12 hours she can easily get starvation ketosis

Answer 58

Gestational diabetes: -manifests during 2/3rd trimester when insulin resistance increases Pre-gestational diabetes: - fasting glucose >125 or random glucose of 200 or an A1c >=6.5 before 2nd trimester of pregnancy - more dangerous than gestational diabetes - if not controlled well, the hyperglycemia can cause neural tube, heart, and kidney defects - glucose is a major teratogen

Answer 59

Overweight and insulin resistant - pre-diabetic, or progressing that way - 2/3 of pregnant women in US are overweight or obese Impaired insulin secretion: - mature onset diabetes of the young (MODY) - autoimmune islet cell antibodies or GAD antibodies

Answer 60

Insulin resistance impaired insulin secretion increased hepatic glucose production

Answer 61

overweight F are more likely to have pre-existing insulin resistance -closer to the GDM threshold Insulin resistance: -body products insulin but does not use it properly Cell conditions that interfere w/ insulin signaling: - inserting new GLUT4 transporters into membrane of skeletal, cardiac, and adipose tissue inhibited by high levels of fatty acids within muscle - contributing to insulin resistance observed in obesity Key cause of insulin resistance: obesity - FAs can disrupt insulin receptor-mediated glucose uptake - loss of effective glucose clearance is compensated by increased insulin release from pancreas - the compensation leads to normoglycemia but w/ increased insulin level - once body is unable to compensate by increasing insulin production, the insulin level in the serum no longer follows the glucose level - uncoupling of the 2 - hyperglycemia (DM2)

Answer 62

increased blood glucose fro mom crosses placenta - leads to increased insulin production in baby - increased growth with fat in cheeks, thighs, and central adiposity - baby will be hypoglycemic at birth because it suddenly sees lower glucose and it takes it a while to reduce its insulin production

Answer 63

Mother: - Short term: - --Cesarean delivery (baby is too big for vaginal delivery; increased risk of infection often related to surgery) - --pre-eclampsia - --polyhydramnios (can result in preterm labor - long term: - --recurrent risk of GDM in future pregnancies - --T2DM 5-10yr risk is 50% - --highest risk of developing T2DM: - -----fasting hyperglycemia during pregnancy, higher doses of insulin, dx prior to 24 weeks (often assoc w/ preexisting glucose intolerance), obesity, demonstrating impaired glucose tolerance at 6 weeks postpartum - pregnancy can be thought of as "stress test" for development of T2DM Fetus and Infant: - Macrosomia (big baby syndrome; abnl fetal growth w/ central adiposity) - Shoulder dystocia (esp concerning w/ body-head disproportion; can lead to Erb's palsy) - preterm labor due to polyhydramnios as a result of fetus hyperfiltrating glucose (neonatal RDS from decreased lung surfactant synthesis) - cardiac septal hypertrophy - increased risk of fetal mortality due to fetal academia and tissue hypoxia - common metabolic abnormalities: hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia

Answer 64

TSH is decreased -due to hCG, which peaks at 10-12 weeks Total T4 and total T3 goes up 50% -because estrogen increases TBG Free T4 and Free T3 stay the same in pregnancy

Answer 65

beta hCG stimulates TSH receptors - increase in T4 and T3 production - decreases TRH and TSH

Answer 66

Mom makes TH for baby + self -requiring additional iodine several fetal hypothyroidism can cause cretinism: - intellectual disability (leading cause of preventable ID) - pot belly - protuberant tongue - protruding umbilicus - pale - puffy face

Answer 67

Hypothyroid F need extra thyroid hormone early in pregnancy Don't give hyperthyroid F methimazole (possible teratogen)

Answer 68

Hyperthyroidism: -usually Graves disease -Antibodies can cross placenta 1st trimester and affect fetus--> fetal or neonatal graves disease -2/3rd trimester antibodies are less of a problem (changes in autoimmunity during pregnancy) -severe thyrotoxicosis can result in poor OB outcomes (5x increased risk for preeclampsia), but controlled hyperthyroidism is generally well tolerated during pregnancy increased T4--> increases risk of low birth weight, prematurity, and placental abruption and fetal loss -thyroid storm can be ppt by: labor, toxemia, placenta previa, infection, trauma -have to be careful about tx of maternal hyperthyroidism leading to fetal hypothyroidism Hypothyroidism: - maternal effects: increased risk of: - --infertility, recurrent losses, preterm labor, pre-eclampsia, stillbirth, placental abruption - fetus effects: - impaired neurodevelopment - deafness - stunted growth - neonatal mortality

Answer 69

Silent Thyroiditis: - likely autoimmune in etiology → lymphocytic thyroiditis - autoantibodies (Anti-TPO) are present in 50-75% of cases - 5-8% of pregnancies are followed by silent thyroiditis, especially if other autoimmune disease like T1DM (18-25%) Clinical Presentation: - Mild hyperthyroidism - --Occurs at 2-4 months - --Non-tender enlargement of the thyroid gland. - --Lasts 1-2 months - --May need to treat if symptoms are profound - Hypothyroidism may follow before a return to euthyroid state is achieved. - Self limiting - Clinical course may be recurrent over a matter of years and there is a predilection for postpartum occurrence of this entity. Lab Tests: ↑ T3/T4, ↓ TSH, ↓ RAIU, ESR is not elevated! lymphocytic pathology

Answer 70

Responsible for insulin resistance of pregnancy: -hPGH and hPL increases lipolysis and insulin secretion in pregnancy: -hPGH and hPL makes proliferative retinopathy worse: -estrogen causes TSH to be suppressed: -beta hCG causes TT4 and TT3 to increase: -estrogen (causing an increase in TBG) causes hyperthyroid symptoms, incl inc HR, CO, heat intolerance, and dec SVR: -estrogen causes 50% of F w/ HG to become hyperthyroid: -hCG Causes GERD, constipation, ↑ risk peel: -progesterone causes Graves disease to improve in 3rd trimester: -progesterone

Answer 71

placenta: - anchors gestation - disposable at birth - produces hormones - functions as kidney, lung, liver, intestine, and endocrine organ to fetus - immunologic organ to fetus and mother - --protects fetal "allograft" from maternal immune system fetal surface: -attachment site of umbilical cord maternal surface: -no umbilical cord - outer chorion - inner amnion Fetal:Placental weight ratio PWR: - increases as gestational age increases - --slower placental growth and faster fetal growth - varies with maternal conditions - surrogate indicator of utero functioning Maternal and fetal blood does not mix - exchange of materials through trophoblasts - maTERnal space= inTERvillous - fetal vessels travel through the villous umbilical cord: - long >75cm (knots and fetal entanglement) - short <30cm (decreased fetal movement and neurodevelopment problems) - 2 arteries (carry de-oxy blood from fetus) - 1 vein (carries oxy blood to fetus) - Wharton's jelly (Stroma) - Remnants (physiologic herniation) - small yellow dots: Candida infection (can be fatal) - barbershop pole: concentric circles: necrotizing funisitis (bacterial) Membranes: - look for completeness and insertion site - fetus papyraceus (vanishing twin) Fetal surface: - indictinct vasculature - amnion nodosum Chorionic plate: - tough fibrous layer - carries vetal vessels parenchyma: - laundry list of diseases - listeria infection- acute infection within the parenchyma - chorangioma: benign hyperplasia of blood vessels basal (maternal) plate: maternal spiral arteriole (wall replaced by trophoblast) -initial anoxic environment due to trophoblast plugging -abundant fibrinoid

Answer 72

Ectopic pregnancy: - hCG level will not increase to the same extent of a normal pregnancy - any implantation other than uterus (90% fallopian tube) - 35-50% assoc w/ PID - Dx: clinical, beta hCG, US Gestational Trophoblastic Disease: - hCG increases along with normal development, but around 5-6 weeks you get a huge surge of hCG (>100K) - group of rare tumors that involve abnormal growth of cells, starting w/ the cells that would normally become placenta - can be benign or malignant - some are abnormal conception/pregnancy - some are true neoplasms: uncontrolled tumor-forming proliferation of malignant trophoblast intrauterine fetal demise: -hCG increases normally for only 2 weeks, then drops off Discriminatory zone: -maternal hCG level above which gestational sac should be visible placental injury: - inflammatory - --acute chorioamnionitis - -----2ndary infection - -----neutrophils in fetal membranes - -----poor correlation w/ clinical chorioamnionitis (fever, leukocytosis, uterine tenderness, tachycardia) - -----Think Group B strep (B for babies) - -----2 routes of infection: - -----Ascending (related to PTL/PROM; maternal neutrophils in membranes); - -----Trans-placental (hematogenous- premature labor, hydrops, IUGR, IUFD; chronic villitis, intervillositis, lymphoblastic deciduitis)- TORCHES infection (Toxoplasma, Rubella, CMV, HIV, HSV, Syphilis) CMV ---chronic villitis or deciduitis - Fetal vascular supply - --maldevelopment (villous maturity, chorangioma) - --obstruction or rupture (myonecrosis, hemorrhage) - --Ma

Answer 73

Abnormal conceptions: - need both maternal and paternal DNA for normal development - mom --> embryonic tissue - dad --> placental tissue too much of dad = molar pregnancy -some degree of overgrowth of placental-type cells complete mole: - diandric diploid (46 XX or XY) - from a single sperm dividing and contributing all of DNA material (85%) - from 2 sperm each contributing half of DNA - "snowstorm" appearance on US - cystically dilated spaces with NO fetus parts - gross: abnormal placental tissue w/ NO fetal development - "grape-like" vesicles - circumferential trophoblast proliferation - central "cisterns" (water-filled) - scallop shaped, hydronic (watery/edematous) villi - present w/ elevated beta hCG, uterine size greater than dates, hyperemesis gravid arum, vaginal bleeding, early pre-eclampsia, hyperthyroidism - 20% complete moles develop persistent GTD - F/U: measure beta hCG levels; MUST use contraception during F/U - if persistently elevated hCG: use methotrexate partial mole: - diandric triploid (69 XXY or XYY) - from 2 sperm and one egg - large cystic spaces +/- fetal tissue - mix of hydronic and fibrotic villi - "lacy" trophoblast hyperplasia - villous inclusions - assoc w/ fetal syndactyly (fusion of digits) - virtually no partial moles recur/progress Risk factors for post-molar GTN: (gestational trophoblastic neoplasm) - >40yo - uterine size - theca lutein cysts - high hCG >100K - medical comp;actions (ARDS), pre-eclampsia, hyperthyroidism

Answer 74

First trimester: -chromosomal 2nd trimester: -structural defects, placenta, infectious 3rd trimester: -placental, structural defects Term gestations: - Trisomy 21 --> Down Syndrome - Trisomy 13--> Patau (P, Patau, Puberty, 13) - Trisomy 18--> Edwards (E, eighteen)

Answer 75

G(number)P(outcome) of pregnancies TPAL: - Term delivery - Preterm delivery - Abortion (<20week delivery- spontaneous or induced) - Living children

Answer 76

Umbilical cord: - insertion pathology - --marginal cord insertion - --velamentous cord insertion - number of vessels: - --should be 2 arteries and 1 vein - length of cord: - --long (>75cm): assoc w/ knots and fetal entanglement (hyper twisted) - --short (<30cm): assoc w/ decreased fetal movement and neurodevelopmental problems (hypo twisted) placenta: - small yellow dots- Candida - inflammation of umbilical cord: necrotizing futisitis - cord edema- can mean polyhydramnios - chorioamnionitis: white-yellow, indistinct vasculature; friable; mom's response to intrauterine infection - acute chorioamnionitis:!!! - --2ndary infection; result of maternal infection - --neutrophils in fetal membranes - --poor correlation w/ clinical chorioamnionitis (fever, leukocytosis, uterine tenderness, tachycardia); only time they correlate well is severe cases - meconium: - --fetal intestine contents (green, brown, slimy) - --can be sign of intestinal maturity, but even if not pathologic, release can cause pathologic lesions in fetus - indistinct vasculature: - --impaired O₂ delivery to fetus - Amnion nodosum: - --severe prolonged oligohydramnios - --fetus rubs up against placenta - chorionic plate: - --baby side of the placenta (lesions= baby lesions) - Parenchyma: - --abscess = listeria infection - --yellow and streaky could be listeria - --chorangioma: extra space of blood vol that baby needs to perfuse can lead to HF in the fetus

Answer 77

Acute Chorioamnionitis: - Neutrophils in the fetal membranes - Result of maternal infection (2ndary infection) - Ascending infection with cervical vaginal flora - Can also be trans-placental (hematogenous) route of infection (i.e. maternal systemic infection that gets across placenta); less common though - --TORCHES infection (Toxoplasma, Rubella, CMV, HIV, HSV, Syphilis) - Related to preterm labor - white/yellow color; indistinct vasculature Chronic Placentitis or Deciduitis: - CMV placentitis - --Common; Rarely causes problems - --Can cause deafness - --Detected on histology or antibody testing. - --Mom side infection. - --Big cells with big dense pink intranuclear inclusions are hallmark. - -----“Owl Eye” inclusions- intranuclear basophilic inclusion surrounded by clear halo - --CMV suggests that Mom is immunocompromised. Infectious villitis: - Syphilis: must be reported; perivascular fibrous proliferation - Toxoplasmosis: granulomatous w/ cysts - Herpes: multi-nucleated cells with inclusions - Listeria: acute inflammation destroying villi - treatment for mother and child - generally doe not recur - public health/epidemiologic tracking - closure for family in poor outcomes Villitis of unknown etiology (VUE): - inflammation without identifiable infection - --IUGR (intrauterine growth restriction) w/o infectious etiology - Maternal lymphocytes attack villi → T cell attack - Most of the time clinically insignificant - Can recur → more severe Massive chronic intervillositis: - inflammation between the villi - etiology unknown. - Maybe mom autoimmune. - Look for CD68 histiocytes which label macrophages. - One of the more common causes of first trimester miscarriages Meconium: - NEVER normal before 36 weeks GA - --indicates some inrauterine stress. - Meconium is very toxic to vascular SM - Meconium laden macrophages= golden brown pigment. - How long baby has been living in meconium is important. - --complications incl aspiration pneumonia and myonecrosis - --myonecrosis=meconium laden macrophages leads myonecrosis. - -----look for necrotic myocytes - -----associated with low APGAR scores and neurodevelomental delay Intervillus thrombus: - feto-maternal hemorrhage FMH - -----baby side problem. - Babies capillaries are leaky. - Indication of fetal anemia - laminated appearance - --"lines of Zahn"-like - FMH represents massive fetal blood in maternal circulation (small amounts are nl) - do a Kleihauer-Betke Test - --tests for fetal hemoglobin Placental Infarction - mom side problem - --acute cessation of maternal flow w/ live fetus - evolves from red/firm to white/hard - --peripheral= edges of placental disk - --central= involves lots of placental parenchyma; more significant; indicative of hypertensive injury Placenta Accreta - abnormal attachment of placenta to uterus (too adherent) - --chorionic villi adhere to myometrium - Failure of decidual formation → placenta leave myometia (“its stuff") behind during delivery → scar tissue w/o normal decidual left behind - This can pose serious danger to mom during delivery or postpartum hemorrhage - sometimes requires a hysterectomy during delivery in order to remove the placenta without highly dangerous damage to uterus - Predisposing factors include prior c-section, endometrial ablation, or multiple D&Cs - Chorionic villi touching myometrial fibers. - --accreta= abnormal adherence - --increta= villi invade into myometrium - --percreta= villi penetrate through serosa Placenta previa: - placenta covers internal os - increased risk for abruption, postpartum hemorrhage, C section Pre-eclampsia - HTN, proteinuria, and edema TRIAD after 20 weeks GA - Symptoms: Headache, RUQ/epigastric pain, Visual Changes, Hemolysis, Elevated LFTs, Low platelets, Oligouria, Pulmonary edema, Seizure - Defective implantation → placental problem - --Inappropriate remodeling of the spiral arterioles → never convert to low resistance vessels - --Impaired oxygenation of fetus - --Fetal growth restriction and fetal demise - --Placenta releases protein factors to increase oxygen supply from mother to baby and this exacerbates the problem. - Decidual vasculopathy: - --atherosis (foamy macrophages; bad prognostic), deposition of dense pink fibrinoid around vessels (high resistance) - --widely spaced villi - --small terminal villi - --big syncytial knots - --last 3 --> chronic severe hypoxia - placenta is trying to make more small terminal villi to ↑ O₂ intake - both fetal and maternal sequelae - Only treatment for severe pre-eclampsia is to deliver the placenta Pre-eclampsia and eclampsia -if mom seizes it’s eclampsia Abruptio placentae - detachment of placenta from decidual seat - variable symptoms: vaginal bleeding, abdominal/back pain, rapid uterine contractions - if rapid and close to delivery, may find no histo evidence - --clot forms, then suppresses underlying villous tissue - --Hemosiderin appears after 4-5 days - Clot can form and cause intravillus hemorrhage - "acute abruption" - --intravillous hemorrhage 2/2 sudden placental ischemia with disruption of capillaries. - "Chronic abruption" - --pathologic lesion due to the clinical condition of abruption (mostly marginal) - --fibrin clot w/ rim of villous infarction - --may se evidence of bleeding during pregnancy (Hemosiderin in decidua) - Fetal sequelae: deprivation of O₂/nutrients, premature birth, stillbirth - maternal sequelae: shock (2/2 blood loss) - clotting problems (DIC)- blood transfusions - organ failure Post-Partum Hemorrhage: - DIC - --massive activation of clotting cascade --> widespread thrombosis - --2ndary depletion of plts and coagulation factors --> bleeding, ischemia, and shock Fetal Thrombotic Vasculopathy. - Baby side problem. - Avascular villi, vessel thrombi, hemorrhagic endovasculitis - Maternal or fetal thrombophilias. - Indication that fetus was under some degree of stress - IUGR, IUFD, seizures Ectopic pregnancy - Implantation outside of the uterus - PID= major predisposing factor - beta hCG and ultrasound used for diagnosis

Answer 78

Intrauterine Growth Restriction (IUGR) - Symmetric - --genetic etiology - Asymmetric - --Relative macrocephaly - --Placental or maternal etiology - --often oligohydramnios Monosomy X - AKA Turner Syndrome - 45 XO - 1st trimester SAB Trisomy 21 - AKA Down Syndrome - external: small for GA, round/flat face w/ slanting palpebral fissures, transverse palmar crease - internal: heart and GI abnormalities; pancreatic, bone fibrosis Trisomy 13 - AKA Patau's syndrome - external: small for GA; polydactyly and facial defects; cutis aplasia - Internal: heart and brain defects; pancreato-splenic fusion Trisomy 18 - AKA Edward's Syndrome - External: small for GA; Hand deformities, micrognathia, "ROCKER BOTTOM FEET" - Internal: heart anomalies, renal fusion, omphalocele Triploidy: - 69 XXX/Y - 85% diandric--> partial hydatidiform mole - 15% digynic --> Non-molar triploidy - Incompatible w/ life - Severe IUGR - Syndactyly - --3-4 hands - --2-3 feet Fetal Hydrops: - abnormal edema within abdomen or chest cavity - Presents: - --polyhydramnios - --size >> dates - --fetal tachycardia - --decreased fetal movement - prognosis dependent on underlying cause - --immune 10-20% - -----maternal Ab's against fetal RBCs cross placenta; hemolyzed in fetal spleen--> severe anemia; high output CHF; portal HTN - -----usually Rh antigens; diagnostic via indirect Coombs test - --Non-immune 80-90% - -----many causes (infections, cardiac/congenital anomalies, neoplasm, metabolic, etc.) Neural tube defects: - failure in neurulation- wide range of severity - determined in 1st month of pregnancy - --Folic acid intake helps prevent - --elevated maternal serum AFP - Anencephaly - Encephalocele - Myelomeningocele Acardiac twin: - "parasitic" twin fails to develop head, arms, and heart; gets blood from host twin - CHF in normal twin from working hard to perfuse both (ascites, pleural effusion) Teratomas: - can be sacrococcygeal (most common neoplasm of newborn) - --yolk sac most frequent - can be cervical - --due to airway obstruction

Answer 79

Myometrial inhibitor is progesterone, a smooth muscle relaxant, pro-gestation hormone. Blocks MLCK and thus the action of prostaglandins, promoting quiescence. - Progestin uses NO → cGMP to inhibit myosin, actin, and calcium interaction. - CRH interacts through cAMP and PKA to inhibit these interactions, and stimulates NO as well.

Answer 80

An important event in labor is the expression of a group of proteins termed ‘contraction-associated proteins’. There are three primary types: Proteins that promote contractility of actin and myosin -Calmodulin and increased calcium → activate myosin light chain kinase (MLCK) → MLCK activates myosin via phosphorylation. Following myocyte depolarization there is an influx of [Ca2+]E through voltage-regulated calcium channels and the release of calcium from intracellular stores results in an increased [Ca2+]I, thereby promoting myosin-actin interactions and, consequently, contractions Proteins that increase myocyte excitability: - ↓ Na+/K+ exchange pumps → At the time of labor, the function and distribution of these channels are altered so that a lower intensity stimulus is required to depolarize myocytes and produce the associated influx of calcium that generates contraction - ↓ β2 and β3 - sympathomimetic receptors. These normally ↑ the opening of potassium channels, which reduces the excitability of the cell Proteins that promote intracellular connectivity: connexin 43 - As parturition progresses → ↑synchronization of the electrical activity of the uterus - This is achieved via connecting myofibrils and through the production of prostaglandins, which act in a paracrine fashion to depolarize neighboring myocytes → increased recruitment into contraction - Multimers of connexin 43 connect myocytes, permitting function in concert

Answer 81

- Put simply, prostaglandins (PGE) and oxytocin (OT) binding stimulate ligand-gated calcium receptors. - PGE and OT also promote Ca2+ release from SR - All of this intracellular Ca2+ triggers the opening of voltage gated Ca2+ channels and depolarization of the cell. then: -Calcium enters the depolarizing cell and combines with calmodulin to form calmodulin–calcium complexes that activate myosin light-chain kinase, which in turn phosphorylates the myosin light chain. The phosphorylation of the myosin light chain causes the generation of ATPase activity, which promotes the sliding of myosin over the actin filaments and the movement that constitutes contraction.

Answer 82

CRH - maintains quiescence, mid-trimester - Stimulates labor late pregnancy - Induces fetal cortisol secretion which → fetal pulmonary maturity, - ↑ rapidly before delivery and peaks at delivery Fetal cortisol induces fetal pulmonary maturity progesterone: - important quiescence factor mid-trimester; MAY contribute to labor last trimester w/ reduced activity - switch in progesterone receptors which changes the way the myometrium sees the progesterone and inactivates that signaling at the end of pregnancy Estrogens - Induce contraction. - Increases in inflammatory factors such as COX-2 and IL-8 which are early events in the progression to active labor. - These increases precede changes in progesterone receptors, which cause changes in estrogen receptors and, as a consequence, expression of connexin 43 and the oxytocin receptor Oxytocin - Stimulates phasic uterine and myometrial contractions - differenterial distribution on uterus, highest at fundus - Activates MLCK, - ↑ intracellular Ca2+ - Activates prostaglandins Prostaglandins - Stimulate myometrial contractions - ↑ intracellular Ca2+

Answer 83

As term approaches, there is an ↑corticotropin by the fetal pituitary and ↑steriodogenesis in the fetal adrenal glands. ↑ fetal cortisol → maturation of fetal lungs → maturing fetal lungs ↑ surfactant production. Amniotic fluid surfactant proteins stimulate the inflammation that is observed in the adjacent fetal membranes, cervix and underlying myometrium at the time of labor. This inflammatory process is one element that leads to the onset of labor. Hypothalamus releases CRH goes to pituitary, makes ACTH

Answer 84

Labor: -effective uterine contractions leading to BOTH dilation and effacement of the cervix and delivery of the fetus Labor: 1- Onset of effective contractions to complete dilation of the cervix ---Latent phase → Cervix closed --Active phase → Cervix thinned out 2- Complete dilation of the cervix to delivery of the fetus; maternal expulsive efforts 3- Delivery of the fetus to delivery of the placenta 4- First 6 hours after delivery. After this, mom is usually by this time in the clear, ↓ risk of complication Myometrial activation: 0 - Quiescence (uterus is not contracting) 1 - Activation → it is unclear what signals the switch from quiescence to activation (uterus is getting ready to contract) 2 - Stimulation → encompasses LABOR PHASES 1 - 3 3 - Involution → corresponds to phase 4 of labor; the six hours post delivery

Answer 85

synchronicity theory: - AP propagation in regions - cells connected by gap junctions - mechano-transduction across the uterus: - --one region contracts, and pressure rises - --triggers stretch-initiated contractions elsewhere

Answer 86

stroma: - collagen 1 and 3 - collagen has linked strands - proteases degrade collagen - edema in later pregnancy - dilates passively w/ contractions weight increases 50 to 1000g - growth primarily cellular hypertrophy - increased connectivity - increased oxytocin receptors - receptors most highly conc at the fundus

Answer 87

preterm labor: - delivery before 37 weeks - 11-12% in US - >70% of neonatal morbidity ``` maternal diabetes intrauterine infection premature cervical dilation, placental abruption fetal growth restriction cervical insufficiency placenta previa maternal HTN environmental factors prematurely ruptured membranes multifetal pregnancy idiopathic reproductive tract anomalies ```

Answer 88

preterm labor "treatments": tocolytics ``` Ca antagonists (decrease intracellular Ca) ``` oxytocin-receptor antagonists (decrease IP3) inhibitors of prostaglandin synthesis NO donors betamimetics magnesium (block Ca channels; decrease Ca entry)

Answer 89

PGE2 - Gq- myometrial contraction - Gs- cervix ripening/dilation PGF2alpha -Gq- myometrial contraction Oxytocin Gq- myometrial contraction EPI- Gs- myometrial relaxation

Answer 90

prostaglandins -stage 1 PGs and oxytocin via Ca movement through LTCC's -stage 2 beta2 adrenergic receptors that mediate relaxation -stage 2 hemostasis via contraction of uterine SM -stage 3

Answer 91

oxytocic agents: Prostaglandins: PGE2 analog: poorly tolerated when admin systemically - ADRs: intestinal cramping, diarrhea, nausea - Dinoprostone: stimulates cervical effacement (ripening) when applied vaginally PGE1 analog: fewer systemic side effects - Misoprostol: given orally is effective at inducing uterine contractions - vaginal prep's being tested for cervical ripening Oxytocin: - posterior pit hormone: breast stim --> oxytocin --> uterine-mammary ductal contractions (let down) - effect to augment uterine contractions at end of pregnancy - used most commonly for labor induction after cervical ripening (no effect on cervical dilatation) - alos effective for postpartum hemorrhage - ADRs: - --higher doses- water intoxication (~ADH)- coma, convulsions, and even death - --uterine rupture and impaired fetal oxygenation Oxytocic agents for postpartum hemorrhage: Ergonovine and methylergonovine -Ergot alkaloids: ---act via alpha1 and 5HT2 receptors: direct contraction of vascular and uterine SM ---only used for control of late uterine bleeding (never before delivery) -oxytocin is preferred for postpartum hemorrhage (if ineffective, methylergonovine can be given at time of delivery or immediately after if bleeding is sig)

Answer 92

Tocolytic agents: - delay delivery for 48hrs will benefit newborn - delay long enough to reduce prematurity-related problems: not recommended >34 weeks - allows time for: - --admin of antenatal corticosteroids (pulm maturity) - --transportation to facility for management of high risk deliveries - single course will not delay weeks/months NSAIDs: Prostaglandin synthesis inhibitors Indomethacin: most potent and widely used (IV ibuprofen also available) - COX inhibitor - use is increasing; delays labor - fetal circulation through ductus arteriosus dependent on local (cervial) production of PGs - closure of ductus arteriosus in utero can lead to pulm HTN postnatally - closure of the DA unlikely following use of acetaminophen (safest peripheral analgesic for use during pregnancy) CCBs: Nifedipine: - most commonly used 32-34 weeks - choice at 24-32 if maternal contraindications to NSAIDs - --plt disorders, renal dysfunc, GI ulcer, asthma - fewer maternal side effects than MgSO4 or beta agonists - probably better at prolonging labor - potential concern that fall in maternal BP may have neg effect on blood flow between uterus and placenta - greater ratio of vascular:cardiac effects - --Diltiazem and Verapamil have SA/AV conduction effects so not interested in using over Nifedipine Beta 2 agonists: Terbutaline: - effective at suppressing contractions; treating premature labor- not recommended beyond 48-72 hrs - less effective if cervix has dilated and membranes have ruptured - higher relative incidence of maternal side effects - --tachy, palp's, unpleasant jitteriness, hypokalemia, hyperglycemia, hypotension - if delivery occurs despite use, infants may be born w/ decreased ability to adapt to extrauterine life (hypoglycemia from increased insulin exposure) Magnesium sulfate: - generally sedating, depresses SM contractions by antagonizing Ca actions - anti-convulsant; thought to effectively inhibit uterine contractions - no benefit in preventing pre-term birth, but increases total pediatric mortality - --narrow therapeutic window - --no longer used as tocolytic at UCH - --still indicated for pre-eclampsia and eclampsia Ethanol: - theoretical action as tocolytic - inhibits pituitary release of oxytocin - not effective in prolonging pregnancy - no longer used due to potential for adverse side effects in both mother and fetus/infant 17-alpha-hydroxyprogesterone caproate: - natural progesterone metabolite - --Given IM 1/week for F at high risk for preterm delivery (Hx of preterm birth) - tx begins 16-20 weeks; continues to 36 weeks

Answer 93

medical abortion: -interruption of est pregnancy w/ delivery of products of conception Mifepristone: - progesterone derivative- competitive receptor antagonist - blocks receptor; decidual breakdown; detachment of blastocyst; decreases PROG secretion from corpus luteum; decidual breakdown - anti-progesterone actions also lead to increased uterine prostaglandin levels and a PG-sensitized myometrium - use: oral abortifacient: terminates pregnancies <=9 weeks - --single dose; followed by prostaglandin (misoprostol, gemeprost, sulprostone) - ADRs: - --prolonged bleeding vs surgical abortion - --incomplete abortion - --continued pregnancy Misoprostol: - PGE1 analog w/ utertonic properties - constrict SM - use in combo w/ mifepristone (or methotrexate) - ADRs: - --abdominal pain and uterine cramps, N, diarrhea oxytocin: - NOT involved in initiation of labor, but in maintenance of labor - uterus is insensitive to oxytocin until 20-36 weeks gestation - uterus is sensitive to PGs throughout pregnancy (Misoprostol)

Answer 94

oral phosphodiesterase inhibitors: - Sildenafil, Vardenafil, Tadalafil - considered 1st line therapy for ED - oral route of admin - relatively low incidence of serious effects - Mech: - --sexual stimulation- NO released from ACh-stimulated endothelial cells (muscarinic!) and from NANC neurons - --NO activates guanylyl cyclase- increases cGMP formation- increased vasodilation in penile vascular tissue - --cGMP is metabolized by phosphodiesterase-5 - --PDE inhibitors block cGMP breakdown- increases cGMP- enhance vasodilation, increase blood flow - ADRs: - --most common is via extra genital inhibition of PDE-5 (HA, facial flushing, dyspepsia, nasal congestion, dizziness) - --Sildenafil and Vardenafil decrease BP - --careful in symptomatic CVS disease

Answer 95

Avoid the use of nitroglycerin if it is suspected or known that the patient has taken sildenafil or vardenafil within the previous 24 hours or tadalafil within 48 hours. Nitrates may cause severe hypotension refractory to vasopressor agents. Do not take Viagra if also taking Nitrates for chest pain as it may cause an unsafe drop in blood pressure

Answer 96

transplacental exposure to drugs: - dose dependent - passive vs protein transport - receptors in placenta - biconversion of molecs (protective vs harmful); ex. caffeine shift from descriptive and comparative approach to describing birth defects to a more experimental and systems approach -technology: advanced imagining, cell migration can classify based on: - syndrome: constellation of symptoms/signs w/ one underlying defect (trisomy 21) - sequences: an initial event with other findings 2/2 cascade of occurrences (renal agenesis --> amnion nodosum, pulm hypoplasia, etc)

Answer 97

liability threshold model: - all genetic and environmental factors that influence the development of a multifactorial disorder (ex. NTD) - there's a threshold that you reach that will lead to expression of that disorder Liability: - genetic predisposition - sporadic genetic causes - decreased maternal folate - mechanical disruption Relative of an affected pt has a higher liability at the same threshold (liability is shifted to the R and family incidence is larger, so the threshold is easier to reach) ---able to shift the threshold to the R w/ folic acid supplementation

Answer 98

Malformations: - morphologic or structural abnormality due to an intrinsically abnormal developmental process - --ex. polydactyly and syndactyly Deformations: - morphologic or structural abnormalities due to a mechanical force, extrinsic or intrinsic - --ex. arthrogryposis and club feet 2/2 oligohydramnios Disruptions: - morphologic or structural abnormality due to destruction of normally developing tissue - --ex. amniotic band syndrome

Answer 99

Developmental field: - groups of embryonic structures that respond as a single developmental unit - --tissues 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) Ex. VACTERL association - Vertebral anomalies - Anal atresia - Cardiac anomalies - Tracheal / Esophageal anomalies - Renal anomalies - Limb anomalies - --likely a developmental field defect; defect of blastogenesis?; common timing for critical development Timing of exposures: - exposure of same teratogen at different times during gestation can cause different effects - earlier exposures are always more critical - different organs have different "critical times" but are generally early on - Ex. Rubella: - --1st trimester: congenital heart defects, deafness, neuro defects, retinopathy, cataracts, then inflamm and destructive lesions

Answer 100

Phenocopy: similar birth defect phenotype resulting from different genetic and environmental factors - Ex. DiGeorge Syndrome- 22q11.2 - --multiple genes, affecting neural crest cell migration and pharyngeal arch development - --CATCH-22 - -----Cardiac anomalies, Abnl facies, Thymic hypoplasia/aplasia, Cleft palate, Hypocalcemia - phenocopy w/ Isotretinoin exposure (Acutane)

Answer 101

Hierarchies of gene expression: | -cell migration, mitotic rate, interaction between tissue types, controlled cell death

Answer 102

Hierarchies of gene expression: - different genes being turned on/off at certain times to ensure proper: - --cell migration, mitotic rate, interaction between tissue types, controlled cell death

Answer 103

Screening the general population for common disorders: - Down Syndrome - Congenital birth defects Other screening to risk groups for clustered disorders: - Cystic Fibrosis - Tay Sachs Offer screening to families w/ known disorders Screening components: - clinical hx - FHx, pedigree - diganostic tests in parents: - --Hgb electrophoresis (SC) - --DNA analysis for singe gene disorders (CF) - --Karyotypes (prior infant w/ aneuploidy) - Screening tests for fetus - --maternal serum biochemical screening - --US - --maternal serum cell free fetal DNA + microarray - options counseling ``` Screening: -assess risk quick noninvasive less expensive? widely accessible high NPV low false positives first step only pre and post test counseling ``` ``` Diagnostic: as close to truth as possible may be longer may be invasive maybe special training gives a dx if completed last or first step risks and pre/post test counseling ``` Diagnostic tests: - amniocentesis (15 weeks) - chorionic villus sampling (samples placenta, detects genetic and metabolic abnormalities; does not detect NTD's; 10-13 weeks) - percutaneous blood sampling

Answer 104

Targeted: - Screen with history, exam, routine labs, or other data - Examine highest risk subgroups, especially for rare diseases - Could be screen-in or screen-out (example, GDM testing) - Counseling issues are the same Population: - Everyone screened to identify disease or disease risk - Can be opt-out - Example: neonatal metabolic screening - We offer screening or diagnosis to all for fetal evaluation

Answer 105

due date is important lab values are based off of baby's age -a baby could have a low value and have disease, or baby could be younger than you though

Answer 106

Fetal anatomy survey placental locational maternal uterine/pelvic anatomy cervical length assessment ---longer cervical length is correlated w/ lower risk of pre-term birth ---TYVU shapes are progressive in cervical shortening First Trimester: -Crown-rump length Second and third trimester - Biparietal Diameter (BPD) - Abdominal Circumference (AC) - Femur Length (FL) Earlier the US, the more accurate the dating: - Up to 9 weeks: +/- 5 days - 9 weeks to 16 weeks: 7 days - 16 to 22 weeks: 10 days - 22 to 28 weeks: 14 days - 28 weeks on: 21 days

Answer 107

First trimester analysis: - Nasal bone - Nuchal translucency Second trimester markers: - Nuchal thickening - Nasal bone hypoplasia/absence - Brachycephaly - Short ear length - Echogenic intracardiac focus - Echogenic bowel - Renal pelvis dilation - Widened iliac angle - Clinodactyly - Short femur or short humerus Second trimester aneuploidy and open NTD screening: - trisomy 13, 18, 21, open NTDs - maternal serum analytes - --AFP (NTD) - --unconjugated estriol - --hCG - --dimeric inhibin-A - ultrasound - --nuchal translucency, anatomy

Answer 108

``` NT alone ultrasound Pros: -use for multiples -early assessment -early dating Cons: -poor screen alone -certification needed ``` ``` First Tri NT + hCG + PAPP-A Pros: -early test -single test -other outcomes Cons: -Lower detection than combo tests -NT required ``` ``` Quad Screen hCG, AFP, uE3, DIA Pros: -single test -no soon required -also screens ONTD -other outcomes Cons: -lower detection than combo tests -later in gestation ``` ``` Sequential stepwise first Tri then Quad Pros: -first try results early -improved overall detection -also screens ONTD -other outcomes Cons: -2 visitis and 2 blood draws ``` ``` Cell-free DNA fetal free DNA Pros: -highest detection for screen -any time after 10 w -low false positive for DR Cons: -just approved in low risk F -NPV and PPV not clear -other findings (maternal) ```

Answer 109

Cell free fetal DNA testing - non invasive test w/ no miscarriage risk - high sensitivity and specificity - available early in gestation - pts at increased risk of aneuploidy - --AMA, FHx, abnl serum testing, abnl US Massively parallel sequencing - sequencing tells you which chromosome the ccd fragment comes from - does not differentiate fetal vs maternal DNA

Answer 110

NTD: increased MS-AFP normal uE3 normal HCG ``` Trisomy 21: low AFP low uE3 high HCG high Inhibin A low PAPP-A ``` ``` Trisomy 18: low AFP low uE3 low HCG (Inhibin A not used) low PAPP-A ``` Trisomy 13: low PAPP-A