PERINATAL

Question 1

GESTATIONAL AGE

Answer 1

Embryonic age + 2 weeks

Question 2

EMBRYONIC AGE

Answer 2

Gestational age - 2 weeks

Question 3

DEFINE THE TRIMESTERS

Answer 3

1st Trimester is 0w1d to 13w,6d
2nd Trimester is 14w0d to 27w6d
3rd Trimester is 280d to end of pregnancy

Question 4

BLASTOCYST

Answer 4

Outer layer&raquo_space; placenta + inner mass of cells&raquo_space; fetus

Question 5

EMBRYONIC STAGE

Answer 5

5w0d GA - 10w0d

Gastrulation (establishment of 3 germ layers (ectoderm, mesoderm, endoderm) + neurulation

Question 6

DATING

Answer 6

U/S in first trimester is most accurate
If spontaneous&raquo_space; comparison of LMP and U/S
Deviations: More than&raquo_space; use U/S, less than&raquo_space; use LMP
If unsure of LMP use U/S
DO NOT alter GA if later U/S has deviations

Question 7

G’s AND P’s

Answer 7

G____(total # of pregnancies; multiples = 1)P____ (total full term which is >37w; multples = 1) _______(total preterm which is 20w to less than 37 w; multiples = 1) _____(total lost at less than 20w; multiples = 1) ______ (total living)

Question 8

ANALYTIC VALIDITY

Answer 8

How accurately the test measures the genotype of interest

Question 9

CLINICAL VALIDITY

Answer 9

How well the test results correlate with what is seen clinically (phenotype)–“how accurate is the test?”

Question 10

CLINICAL UTILITY

Answer 10

How useful is it in determining/changing medical management

Question 11

SENSITIVITY

Answer 11

Proportion of affected individuals with a pos result
AKA detection rate and true-pos rate
“how good is this test at correctly identifying those w/the condition with a pos result
# TRUE POS / # OF POS

Question 12

SPECIFICITY

Answer 12

Proportion of unaffected individuals with a neg result
AKA true-neg rate
Those that do not have the condition who are correctly given a neg result
Opposite of specificity is the false-pos rate 
# TRUE NEG/# NEG

Question 13

POSITIVE PREDICTIVE VALUE

Answer 13

Odds of being affected given a pos result

Question 14

NEGATIVE PREDICTIVE VALUE

Answer 14

Out of neg results, how many truly do not have condition

Question 15

PPV and NPV are affected by prevalence of condition

Answer 15

Rare condition&raquo_space; lower PPV

Question 16

MATERNAL SERUM SCREENING

Answer 16

1st Trimester: PAPP-A and Beta hCG
2nd Trimester: AFP, total hCG, uE3, inhibin-A
a priori risk for ONTD will increase w/ African ancestry, DM, or fam hx ONTD
a priori risk for aneuploidy will increase w/ AMA and previous child with aneuploidy
1st Trimester Screening will NOT screen for ONTD

Question 17

NUCHAL TRANSLUCENCY (NT)

Answer 17

“Increased is defined as >3 mm

>5 mm+ septated&raquo_space; cystic hygroma (1st trimester&raquo_space;DS; 2nd trimester&raquo_space; Turner); also think about Noonan syn

Question 18

SCREEN POS FOR ONTD

Answer 18

Offer U/S + Offer amnio for eval of fetal AFP level&raquo_space; if abnml&raquo_space; acetylcholinesterase

Question 19

SCREEN POS >NT AND CYSTIC HYGROMA

Answer 19

Offer f/u U/S
If pos for >NT or cystic hygroma + NORMAL dx testing for aneuploidy should offer U/S in second trimester, fetal echo, and further counseling regarding other conditions not tested for with aneuploidy testing

Question 20

cfDNA SCREENING

Answer 20

Repeat cfDNA screening is not recommended after “no-call/no read”
Current guidelines do not recommend testing for microdeletions, other autosomal trisomies, or genome-wide testing
Currently not recommended for those carrying multiples
Offer AFP level in 2nd trimester

Question 21

CHORIONIC VILLUS SAMPLING (CVS)

Answer 21

10w0d-13w6d
Risk for fetal loss (1/500 to 1/300), higher in twin pregnancies 1%-4%
not performed before 10 w due to increased risk of limb reduction
Limitations:
Mosaicism (most of the time mosaicism is confined to placenta), but should be f/u with amnio
Trisomy rescue common cause of placental mosaicsm (chr15, 7, 11, 14, 22)
Maternal Cell Contamination (MCC)
Types of tests (ONTD, methylation defects)

Question 22

AMNIOCENTESIS

Answer 22

15w0d - 18w6d
Determination of fusion between amnion and chorion
Risk for fetal loss (1/300 - 1/500)
Not performed before 15 w due to no fusion of amnion and chorion&raquo_space; through two membranes» technically difficult and shown to increase risk for fetal loss, clubfoot (1.5% risk from .1%)

Question 23

DIAGNOSTIC TESTING

Answer 23

Karyotype: Cultured cells
FISH: interphase FISH on uncultured cells; metaphase FISH on cultured cells (del and dups)
FISH should not be stand alone test
Microarray: Can detect small del/dups, UPD, regions of homozygosity, VUSs; Cannot detect balanced chr rearrangements
Fragile X recommended for amnio and not CVS as methylaton pattern has not been set in chorionic villi
All pregnant women should be offered prenatal assessment for aneuploidy by screening or diagnostic testing regardless of maternal age or other risk factors (ACOG)
CMA should be made available to all patients undergoing invasive diagnostic testing (ACOG)
CMA should be offered first for abml U/S findings (before karyotype) (ACOG)

Question 24

MATERNAL AGE

Answer 24

Aneuploidy caused by nondisjunction of the chr during maternal meiosis I
Chr 21&raquo_space; usually meiosis I event
T18 and sex chr&raquo_space; usuallly meiosis II error
Initiation of MI in females during fetal development, then oocytes enter state of meotic arrest

Question 25

PATERNAL AGE

Answer 25

APA = >40 years of age Increased risk for de novo mutations: Skeletal dysplasias (achondroplasia, Pfeiffer, Crouzon, Apert, thatophoric dysplasia) Autism, bipolar, schizophrenia APA >50 associated with T21

Question 26

ONTD (OPEN NEURAL TUBE DEFECTS)

Answer 26

1st trimester U/S detects about 90% anencephaly 2nd trimester U/S 90-98% cases of spina bifida 2-5% ONTDs are syndromic >> aneuploidy Nongenetic risk factors: folate, maternal anticonvulsant meds, maternal DM, obesity Recurrence for woman who had previous child with ONTD is 2-5% Recurrence for woman w/ x2 affected previous children with ONTD is 10% Spina bifida occulta NOT same as ONTD--does not have same recurrence risks

Question 27

TERATOGENS

Answer 27

Dose (and route): Oral vs. applied Duration: one time exposure vs repeated Timing: All or none period, embryonic period (organogenesis), fetal period (cognitive development and organ maturity and growth) Motherrisk approach: Weighing risk for maternal illness vs. fetal exposure Thalidomide: Critical time 21-40 day post conception >> Limb reduction Maternal DM: Critical time 1st trimester if poorly controlled >> ONTD, cardiac defects Maternal PKU: Critical time 1st trimester if poorly controlled >> ID, cardiac defects, microcephaly Alcohol: Critical Time is throughout pregnancy--No amount has been found to be safe

Question 28

RPL (Recurrent Pregnancy Loss)

Answer 28

Two or more failed pregnancies Miscarriage: <20 wks GA Pregnancy loss does not have to be consecutive Up to 70% 1st trimester losses due to sporadic chromosome abnormalities Testing POC >> microarray, as limitations of karyotype include cell culture failure, formalin-fixed and paraffin embeded tissue, selective overgrowth of maternal cells Any couple with 2 or more losses >> offer parental karyotype Male Infertility: Klinefelter syn; Offer Karyotype and Y chromosome microdeletion analysis; Cystic fibrosis >> male with CBAVD should be offered renal sonogram > if no malformations > offer CF testing Female Infertility: think POI >> premutation carriers of fragile X, Turner syndrome, triple X syn; Offer karyotype and fragile X testing

Question 29

CARRIER SCREENING

Answer 29

Cystic Fibrosis: Offered to all regardless of ethnicity, or if prenatal U/S shows echogenic or dilated bowel, or peritoneal calcifications; ACOG recommendation for 23-mutation panel; R117H mutation: ACOG recommends reflex testing to determine 5T SMA: 95% will have homozygous del of exon 7 or 7-8 in SMN1 gene; "silent carrier" (two SMN1 copies on one chromosome) and the 2% with point mut only detectable by sequencing will have "nml" dosage analysis FMR1-related disorders: CGG repeat in 5' untranslated region; >200 repeats considered full mutation (hypermethylation leads to silencing of gene); Premutation carriers have increased risk for FXTAS and POI (menses ceases <40 years of age; ACOG recommends Fragile X premutation carrier screening to those with unexplained fam hx ID, DD, or autism, unexplained POI or elevated FSH level condition <40; Testing: PCR w/ reflex to Southern blot; limitation of CVS for methylation Hemoglobinopathies: Testing should be CBC first (+hemoglobin electrophoresis if from high risk ethnicity) >> if low MCV, evaluate/rule out iron deficiency anemia. If low MCV, nml electrophoresis and nml iron >> genetic testing for alpha-thal ACOG: ethnic, pan-ethnic and expanded carrier testing are all acceptable strategies Expanded carrier screening does not replace CBC or hemoglobin electrophoresis for hemoglobinopathies, and does not replace Hex A analysis for Tay Sachs

Question 30

PGD (PREIMPLANTATION GENETIC DIAGNOSIS)

Answer 30

Ability to analyze the genetic composition of an embryo produced by IVF prior to implanting the embryo into the uterus