B8.013 Histology/ Immunology of Pregnancy Flashcards
earliest stages of pregnancy
day 0 - fertilization fertilized egg day 1 - first cleavage day 2 - 2 cell stage 4 cell stage day 3-4 - 8 cell uncompacted morula day 4 - 8 cell compacted morula day 5 - early blastocyst day 6-7 - last stage blastocyst (hatching) day 8-9 - implantation of the blastocyst
uterine proliferative phase
days leading up to ovulation (ovarian follicular phase)
estradiol:
-stimulates proliferation of uterine glands
-stimulates proliferation of stroma
-glands lengthen, straight
uterine secretory phase
days following ovulation (ovarian luteal phase)
progesterone and to a lesser extent, estradiol:
-stimulate development of uterine glands (tortuous, curved)
-stimulate endometrium to become thick, vascular, spongey
-glands secrete glycogen, mucin
prepared to support implantation
what happens after the uterine secretory phase if implantation does NOT occur
spiral arteries in the basalis spasm, cutting off the blood supply
hypoxia leads to sloughing off of the wall
what does the uterus do to create the receptive window
expression of several cytokines and growth factors including LIF, integrins, osteopontin
correlates with window of implantation and the development of pinopods
what are pinopods
balloon like protrusions on the endometrium
embryo will sit on them
when and for how long does the receptive window occur
short
begins 6-10 days after the LH surge and is believed to last less than 48 hrs
what happens when the receptive window closes
morphological differentiation of endometrial fibroblasts into secretory epithelioid decidual cells
syncytiotrophoblast
epithelial covering of embryo that interacts with maternal blood (outermost layer)
cytotrophoblast
embryonic cell layer under the syncytiotrophoblast
buds to form villi surrounding the embryo
invade maternal vasculature and form lacunae
embryonic villi
villi initially cover the entire embryo
with further growth, there is partial regression of the villi
remaining villi form the future placenta (smooth portion is the chorion)
where does the embryo implant
endometrium
completely penetrates and becomes surrounded by maternal vessels
function of progesterone during implantation
released from ovary to regulate prostaglandin production and facilitation of immune tolerance in the endometrium
regulates how far the embryo can move into the maternal wall
anchoring villi
cytotrophoblastic cell projections that connect the fetus to the maternal decidua
how does fetal vasculature form?
eventually forms from cytotrophoblastic villi
more complex network grows over time in the intervilous space amongst the lacunar circulation
why is the fetus in such close contact w maternal blood flow
nutrient exchange to developing fetus
what is a hydatidiform mole
benign form of gestational trophoblast disease
nonviable fertilized ovum implants and develops a placenta derived tumor
fills the uterine cavity
what cell types make up a mole
atypical trophoblast proliferation (cytotrophoblast and syncytiotrophoblast)
villi with stromal edema
partial mole
maternal and paternal genetic material
some fetal tissue
focal slight to moderate trophoblast production
variable edematous villi
complete mole
paternal genetic material only
no fetal tissue
diffuse trophoblast proliferation, villous edema
often large uterus for gestational age
elevated bhCG levels
15-20% become deep, develop into choriocarcinoma
symptoms of a mole
vaginal bleeding severe nausea and vomiting pelvic pain anemia hyperthyroidism high blood pressure
risk factors for a mole
age: <20 or 36-40
prior mole
1-2/1000 deliveries
appearance of mole on histo
acellular stroma
abnormal trophoblast proliferation
grape like structure
genetic information about moles
usually results from duplication of the haploid genome of a single sperm or fertilization by 2 sperm occurring in an ovum that has lost its maternal chromosomes
monospermic mole
more common (80%) loss of maternal chromosomes before or immediately after fertilization by 1 sperm followed by duplication of paternal chromosomes 46, XX or 46, YY
dispermic mole
less common (20%) loss of maternal chromosomes before or immediately after fertilization by 2 sperm
placenta previa
potentially serious complication of pregnancy where the placenta implants into the lower segment of the uterus
edge of placenta covers the internal os
normal placenta
edge is 2 cm from internal os
low lying placenta
edge of placenta less than 2 cm from internal os
risk factors for placenta previa
prior endometrial damage
uterine scarring from curettage, surgical insult, prior placenta previa, multiple prior pregnancies
symptoms of placenta previa
painless bleeding most common
premature contractions
baby is breech or in transverse
uterus larger than it should be for gestational age
result of low lying placentas
90% identified ultimately resolve by 3rd trimester
if does not resolve, complications include:
bleeding
preterm birth
risk factors for placenta previa
previous placenta previa previous c section previous suction curettage for abortion age >35 multiparity asian smoking
first immunologic phase of pregnancy
embryo penetrates epithelium -invades decidua -vascular remodeling consists of cellular invasion, tissue remodeling, tissue repair *pro-inflammatory state leads to morning sickness
second immunologic phase of pregnancy
rapid fetal growth and development
general anti-inflammatory state
third immunologic phase of pregnancy
delivery!
inflammatory
influx of immune cells into the myometrium
proinflammatory setting promotes decidual activation, cervical changes, uterine contraction, rejection of the placenta
immune cells present at the placental uterine interface
uNK macrophages t cells dendritic cells mast cells b cells
uterine natural killer cells
recognize virally infected or malignant cells without being previously sensitized
CD56 and CD 16+
function of uNK cells during pregnancy
poor cytotoxic function in healthy pregnancy
low levels during proliferative phase, peaks during secretory phase of menstrual cycle (reflects a role in implantation)
levels remain high until the 2nd trimester, then begin to drop
70% of decidual leukocytes are uNK cells during the 1st trimester
interaction between uNK and trophoblast cells
provides for trophoblast invasion, while also limiting it
secrete both pro and anti inflammatory cytokines
HLA G on trophoblast
increased expression associated with suppressed implantation
TLR 3 on uNK cell
increased expression associated with increased miscarriage
number of uNK cells
increased number associated with miscarriage, implantation failure
NKG2A on uNK cells
recognizes self, inhibitory to cytotoxicity
low levels of NKG2A associated with recurrent pregnancy loss
CD161 on uNK cells
increased expression associated with increased miscarriage
relationship between uNK cells and angiogenesis
high uNK density or activity associated with excessive angiogenesis and increased blood flow increases oxidative stress
can lead to pregnancy loss
how do uNK cells influence angiogenesis
secrete VEGF, PIGF, and angiopoietin
deficient remodeling of spiral arteries
associated with poor trophoblast invasion, reduced number of invasive trophoblasts
preeclampsia
high BP in women who havent had it before high protein in urine swelling in feet, legs, hands rapid weight gain severe headaches vomiting, nausea appears late in pregnancy
“cure” for preeclampsia
delivery
pathophys of preeclampsia
deficient remodeling of the spiral arteries, reduced placental blood flow
action of prednisolone in pregnancy
reduced numbers of uNK cells and suppresses uNK cell cytotoxicity
given preconception can improve pregnancy rates\not effective if anti phospholipid Abs present
IVIg therapy in pregnancy
immunosuppressive
reduces uNK cell cytotoxicity
macrophages at the maternal placental interface
primary APC in decidua
20% of decidual leukocytes
numbers constant throughout pregnancy
role of macrophages in pregnancy
generally M2 phenotype -tissue repair -inhibition of inflammation role in trophoblast invasion, placental growth, fetal development, parturition removal of dying trophoblasts
why is removal of dead trophoblasts by macrophages important
prevent release of paternal antigens, thus limit maternal immune response
function of T reg cells in pregnancy
maintenance of immunologic self tolerance
significant expansion in the decidua and systemically during pregnancy
specific to paternal antigens
persist after delivery, rapidly accumulate with subsequent pregnancy
FOXP3
regulates Treg cells
reduced expression in endometrium associated with infertility
spontaneous abortion associated with lower systemic Treg levels
Th17 cells in pregnancy
IL-17 producing CD4+ numbers expand in uterus during pregnancy inflammatory thought to protect from microbes thought to be regulsted by Tregs
altered Th17:Treg ratio
associated with spontaneous abortion, preeclampsia, preterm birth
function of dendritic cells in pregnancy
initiate and coordinate innate and adaptive immune responses
accumulate before implantation, remain throughout gestation
play a role in decidualization, exhibit low levels of antigen presentation
mast cells in pregnancy
numbers expand in the uterus with pregnancy
promote anti-inflammatory state; function unknown
B cells in pregnancy
IL-10 producing B cells expand peripherally
present in decidua
importance unknown
immune role of decidual cells in pregnancy
recent evidence suggests decidual cells play a role in regulating differentiation, migration, and function of uterine immune cells
express chemoattractant, inhibit recruitment of T cells into uterus
complications of bacterial infection in pregnancy
cause of 40% of preterm labor
cause of 80% of preterm birth before 30 weeks
preeclampsia
complications of viral infection in pregnancy
fetal developmental complications preterm birth spontaneous abortion stillbirth preeclampsia
routes of infectivity of decidua, placenta, fetal membranes
ascend into uterus from lower tract
descend into uterus from peritoneal cavity
maternal circulation
preterm birth
when a baby is born too early, before 37 weeks
affects 1 in 10 infants
risk factors for premature birth
previous premature birth
pregnancy with multiples
problems with the uterus, cervix, or placenta
smoking cigs or doing drugs
infections of amniotic fluid and lower genital tract
difference between trophoblast response to infection in 1st and 2nd trimesters vs the 3rd
1st and 2nd: milder response to gram (-) compared to gram (+) TLR8 active TLR6 active 3rd: gram (+) and gram(-) responses similar TLR2 active in decidual cells
NOD receptor activation
pathogen enters intracellular space
infection/response via NOD1/2 has been associated with preterm birth
what inflamm cytokines are released in response to infection at placenta
TNFa
IFNg
IL-12
IL-8
result of placental infection
may result in a fetal inflammatory response, and may lead to morphological and developmental abnormalities
fetus has a mature immune system!!!
what is RPL
recurrent pregnancy loss
3 or more consecutive, spontaneous pregnancy losses under 20 wks
affects 5% of repro aged women
risk factors for miscarriage
advanced maternal age smoking alcohol consumption use of illicit drugs like cocaine use of NSAIDs high caffeine consumption extremes of maternal weight
common causes of RPR
50% unexplained autoimmune (15-20%) endocrine (15-20%) anatomic (10-15%) genetic (2-5%) infection (0.5-5%)
what is antiphospholipid Ab syndrome
most common hypercoagulable disorder
heterogenous autoantibody binds to phospholipid protein complex
includes: lupus anticoagulant syndrome and anticardiolipin antibody syndrome
symptoms of antiphospholipid Ab syndrome
venous and arterial thrombosis
recurrent spontaneous abortion
stroke
TIA
treatment for antiphospholipid Ab syndrome
anticoagulation
lovinox
low dose aspirin
invasive placenta
placenta attaches too strongly or invades too deeply into the wall of the uterus
placenta accreta
placenta attaches too strongly to myometrium, but does not invade into it
placenta increta
placenta invades into the myometrium
placenta percreta
placenta invades through the full thickness of the uterine wall
can attach to adjacent organs in the abdomen, usually the bladder
risk factors for invasive placenta
previous c-section is biggest
previous gynsurgeries
intra-uterine surgery
embolization treatment for a fibroid
complications of placenta accreta
heavy bleeding, can lead to DIC during delivery as well as lung failure and kidney failure
premature birth
management of invasive placenta
antenatal evaluation using US and MRI
planned c-section in a specialized unit
planned hysterectomy in severe cases
symptoms of placenta accreta
no signs of symptoms during pregnancy
vaginal bleeding during 3rd trimester might occur
