Prenatal Genetics Flashcards
1
Q
Gestational Age
A
date of pregnancy from LMP; includes first two weeks of ovarian cycle
2
Q
Fertilization Age
A
date of pregnancy from fertilization; GA - 2 weeks
3
Q
1st Trimester
A
1 - 13 weeks
4
Q
2nd Trimester
A
14 - 27 weeks
5
Q
3rd Trimester
A
28- 40 weeks
6
Q
Gravida
A
pregnancies
7
Q
Para/Parity
A
completed pregnancies >20w
8
Q
GTPAL
A
gravida, term (deliveries >37w), preterm (deliveries between 20-37w), abortions (miscarriages and terminations <20w), living
9
Q
Folic Acid Supplementation Recommendations
A
starting prior to conception, 400mcg daily or 4mg daily if prior history of ONTDs
10
Q
% Unplanned Pregnancies
A
45%
11
Q
Carrier Screening
A
genetic testing to identify couples who are at risk of having a child with various genetic conditions (usually AR, some XL)
12
Q
Common Conditions on Carrier Screening
A
- cystic fibrosis
- spinal muscular atrophy
- ethnicity-based conditions (Tay-Sachs, Gaucher, Canavan, familial dysautonomia, hemoglobinopathies)
- fragile X syndrome (not standard)
13
Q
Cystic Fibrosis
A
- carrier frequency: 1/25
- F508del occurs in 70% of cases
- ACOG and ACMG recommend core panel of 23 mutations that identifies 49-98% of carriers
- present on NBS via immunoreactive trypsinogen testing
14
Q
Spinal Muscular Atrophy
A
- carrier frequency: 1/40
- 95% of cases due to homozygous deletions
- 2% de novo cases
- ACOG and ACMG recommend SMA carrier screening for all couples
- some labs test for SNP in intron 7 (g.27134T>G) to determine if copy number 2 in cis or trans; presence of SNP increases chance they’re in cis
15
Q
Ashkenazi Jewish Conditions
A
- ACOG recommends screening for 4 conditions (Canavan, CF, familial dysautonomia, TSD - DNA and enzyme)
- ACMG recommends screening for 11 conditions (Bloom, Canavan, CF, familial dysautonomia, Fanconi anemia C, Gaucher, mucolipidosis type IV, Niemann-Pick A/B, SMA, TSD - DNA and enzyme)
16
Q
Tay Sachs Disease
A
- AJ carrier frequency: 1/30
- Cajun/French Canadian carrier frequency: 1/50
- 3 HEXA mutations account for up to 98% of TSD in AJ
- enzyme testing detects 98% of carriers regardless of ethnicity
- when doing enzyme assay, important to do leukocytes on pregnant women and women on OCP
17
Q
Canavan Disease
A
- carrier frequency: 1/57
18
Q
Familial Dysautonomia
A
- carrier frequency: 1/30
- most individuals homozygous for c.2204+6>C
19
Q
Gaucher Disease (type 1)
A
- carrier frequency: 1/10-1/15
20
Q
Hemoglobinopathies
A
- structural hemoglobinopathies: HbS, HbC, HbE
- thalassemias
- carrier frequency for sickle cell in African Americans: 1/10
- for patient at increased rick for hemoglobinopathy given ethnicity, both CBC and hemoglobin electrophoresis should be performed
- ethnic backgrounds with increased risk: African, Mediterranean, Middle Eastern, Southeast Asian, West Indian
- usually detected on NBS
21
Q
Fragile X Syndrome
A
- 1/260 females are carriers
- normal: <45 repeats
- intermediate/gray zone: 45-54 repeats
- premutation: 55-200 repeats
full mutation: >200 repeats’ - AGG interruptions usually appear every 9-10 CGG repeats and can modify risk
- ACOG and ACMG support offering testing to women with family history of FX-related disorders, women with a personal history of POI or elevated FSH <40y, women who request carrier screening
22
Q
Expanded Carrier Screening
A
- technologies vary between full-exon sequencing and targeted genotyping of predefined pathogenic variants
- as per ACOG, ethnic-specific, pan-ethnic, and expanded carrier screening are acceptable options
23
Q
% Pregnancies with major anatomic malformations
A
2-3% with cardiac and GU anomalies most common
24
Q
Most common genetic cause of miscarriage and birth defects
A
aneuploidy
25
Incidence of chromosomal abnormalities in live births
1/150
26
Risk Factors for Trisomies
- maternal age
- younger women generally have more children than older women, so majority of pregnancies affected occur in younger women
27
Do monosomies have an age-related risk?
no
28
Does triploidy have an age-related risk?
no
29
Methods of Screening for Aneuploidy
- age
- serum screening
- ultrasound
- cfDNA/NIPS
30
Age
- AMA = 35y at EDD
- 35y is arbitrary cutoff that originates from when amnios were first routinely used
- risk of DS = risk of miscarriage from amnio (1/200)
- 27% detection rate
31
First Trimester Screening
- analyte evaluation: PAPP-A, hCG
- ultrasound evaluation (11-14w): CRL, NT (>2.5-3mm abnormal - f/u with invasive testing, early anatomy scan, fetal echo), nasal bone
32
FTS Patterns
- DS: increased NT, decreased PAPP-A, increased hCG
| - T18/T13: increased NT, decreased PAPP-A and hCG
33
Second Trimester Screening
- triple screen: AFP, hCG, uE3; 69% detection for DS
- quad screen: AFP, hCG (made by placenta), uE3, inhibin A; 80% detection for DS and ONTD; 15w - 22w; may be combined with FTS
- penta screen: AFP, hCG, uE3, inhibin A, hyperglycosylated hCG; 83% detection for DS
34
STS Patterns
- ONTDs: increased AFP
- DS: decreased AFP, decreased uE3, increased hCG, increased inhibin A
- T18/T13: decreased AFP, decreased uE3, decreased hCG, inhibin A N/A
35
Other Problems Affecting STS Analytes
- wrong dates (inhibin A helpful)
- miscarriage
- stillbirth
- IUGR
- infant death/IUFD
- HTN/preeclampsia
- antepartum hemorrhage
- oligohydramnios
- placental abnormalities
- low uE3 may also indicate SLOS, X-linked ichthyosis, steroid sulfatase deficiencies
36
msAFP
- performed during second trimester
- if elevated, increased risk for ONTDs; f/u with AFAFP, ACHE, anatomy scan
- other reasons for elevated AFP include underestimated GA, ventral wall defect, unrecognized twin gestation, fetal demise, abnormality in fetal kidneys, placental insufficiency, maternal malignancy, adverse outcomes
37
T/F: Additional screening for aneuploidy in women who have negative screening is recommended
False
38
T/F: Simultaneous testing with multiple screening methodologies for aneuploidy is recommended
False
39
T/F: Woman with a positive result on serum screening may consider NIPS if they want to avoid invasive testing
True
40
NIPS
- fetal component of cfDNA released into maternal circulation primarily from placental cells undergoing apoptosis and comprises 3-13% of total cfDNA in maternal blood
- reliably performed after 9-10w GA
- MPS based NIPS detects triploidy since extra amounts of chromosome present above what's expected
- SNP based NIPS can be used in twin pregnancies, for surrogates or egg donor pregnancies, to detect triploidy and vanishing twins
- if positive, f/u with invasive testing with amniocentesis > CVS with karyotype or microarray
- T13 and Turner more commonly associated with CPM
- low fetal fraction may associated with aneuploidy
- no call results may be due to sample problem, assay failure, low fetal fraction, obesity, aneuploidy
- false positives may be due to CPM, vanishing twin, rare autosomal trisomies, large segmental aberrations, fetal sex discordance, maternal acquired or consitutional alterations, non-malignant maternal disease, benign maternal del/dups
- false negatives may be due to high BMI, early gestational age, hemolysis in sample, maternal anticoagulation therapy, true fetal mosaicism, normal vanishing twin, maternal deletion and trisomy in fetus
41
Fetal Sex Discordance on NIPS
- u/s and karyotype male, NIPS female: low fetal fraction, placenta sex chromosome mosaicism, demise of female co-twin
- NIPS and karyotype male, u/s female: SLOS, mutations in sex development genes
- NIPS and karyotype female, u/s male: CAH, SRY translocation
- u/s and karyotype female, NIPS male: placental sex chromosome mosaicism, demise of male co-twin, maternal history of transplantation from male donor, recent blood transfusion from male donor
42
% Of first trimester miscarriages due to aneuploidy
50%
43
% Of pregnancies overall that miscarry
10-15%
44
Other uses for NIPS
- microdeletions/duplications
- single gene disorders (especially APA)
- genome wide (not recommended, CMA recommended instead)
45
First Trimester Ultrasound
- establishes viability
- fetal number, chorionicity, vanishing twin
- gestational age
- view uterus
- early detection of congenital anomalies
- early aneuploidy screening
- patient and family bonding (heart rate, pictures)
46
Second Trimester Ultrasound
- examine fetal anatomy
- fetal size
- aneuploidy screening
- placental location
- cervical length measurement
- patient and family bonding (fetal sex, 3D u/s pictures)
47
Additional Ultrasounds
- 3D/4D imaging
- biophysical profile
- color doppler flow
- fetal echo
- transvaginal ultrasound
- guidance for diagnostic procedures
48
Soft Markers
anatomic findings on u/s that are not congenital anomalies and may be normal variants that resolve on their own
49
Increased Nuchal Fold
- soft marker
- thickening of fetal neck area
- strongest second-trimester marker
- increased risk of DS, Noonan
- fetal echo recommended
50
Intracardiac Echogenic Focus
- soft marker
- echogenic area in region of papillary muscles of fetal heart
- common in Asians
- increased risk for DS
- no association with structural cardiac abnormalities or dysfunction
51
Renal Pyelectasis
- soft marker
- dilation of renal pelvis that may be uni/bilateral, stable, progressive, or resolves
- more common in male fetuses
- increased risk for DS, urinary tract abnormalities
52
Echogenic Bowel
- soft marker
- fetal bowel as bright as bone but may be a subjective finding
- may be normal variant
- increased risk for aneuploidy, CMV infection, CF, intra-amniotic bleeding, GI tract abnormality
53
Shortened Long Bones
- soft marker
- some ethnic variation present (Caucasian femoral length > African American, Asian)
- short humerus marker for DS
- short long bones may be marker for skeletal dysplasia
54
Choroid Plexus Cyst
- soft marker
- cysts within fetal choroid plexus that result from entrapment of CSF in tangled villi
- 95% resolve by end of 2nd trimester
- increased risk for T18
- in absence of aneuploidy, not associated with increased risk for brain problems/delays
55
Ventriculomegaly
- soft marker
- dilation of fetal cerebral ventricles
- may be mild (normal neurodevelopment), moderate (most likely normal neurodevelopment), severe (need shunt)
- male fetuses more commonly affected
- marker for DS
- fetal MRI recommended
56
Single Umbilical Artery/2-Vessel Cord
- soft marker
- most common anomaly of umbilical cord
- increased risk for GU anomalies, cardiac anomalies, IUGR, aneuploidy (if not isolated)
57
Hypoplastic/Absent Nasal Bone
- soft marker
- little to no ossification of nasal bone observed
- may be normal variant
- significantly increases risk for T212
58
T/F: If >1 marker detected, risk for aneuploidy increases
True
59
T/F: Detection of a soft marker after negative NIPS significantly increases risk for aneuploidy
False
60
Structural Abnormalities
- significantly increase risk for fetal morbidity and mortality
- present in 2-3% of all pregnancies
- majority detected in second trimester
61
Structural Abnormalities Detected in First Trimester
acrania, anencephaly, cystic hygroma, severe heart defects
62
Congenital Heart Defects
- structural abnormality
- most common birth defect; 1-2% of all live births
- may be due to syndromic pathogenic CNVs, aneuploidy, single gene disorders, environmental, mutifactorial causes
- may be suspected in first trimester by increased NT
- fetal echo, fetal u/s, prenatal diagnosis, cardiology consultation recommended
- recurrence risk: 1-4% if isolated
63
AV Canal
DS
64
Coarctation of Aorta
Turner
65
Tetralogy of Fallot
22q11.2 (other conotruncal heart defects common too)
66
Ebstein's anomaly
Lithium exposure
67
Pulmonary Valve Stenosis
Noonan
68
Supravalvular Aortic Stenosis
Williams
69
Anencephaly
- structural abnormality (ONTD)
- failure of closure of anterior neural tube
- multifactorial etiology
- associated with T18
- likely to lead to IUFD
- recurrence risk: 3-4%
70
Encephalocele
- structural abnormality (CNTD)
- skin-covered defect affecting cranium in occipital, frontal, or parietal regions
- prognosis and severity dependent on how much neural tissue involved
- associated with T13
- fetal MRI recommended
71
Myelomeningocele
- structural abnormality (most common ONTD)
- failure of vertebral arches to close prior to 6th week of pregnancy leading to protrusion of neural elements and meninges
- often located in lumbosacral region (bowel/bladder functions affected, ambulation affected)
- associated with T18
- may be observed in u/s by cranial changes and clubfoot
- fetal MRI recommended
- prenatal repair may be an option
72
Lemon Sign
head bilaterally flattened in frontal region; myelomeningocele
73
Banana Sign
cerebellum rounded and width decreased; myelomeningocele
74
Spina Bifida
- structural abnormality (CNTD)
- usually sporadic/mutifactorial but can be associated with other anomalies
- fetal MRI recommended
- recurrence risk: 3%
75
Other Factors Causing ONTDs
- pregestational diabetes
- valproic acid (anti-epileptic)
- exposure to high temps
- amniotic bands
- VACTERL
- T18/T13
- single gene disorders (Meckel-Gruber, Walker-Warburg, Joubert)
76
Agenesis of Corpus Callosum
- structural abnormality (congenital brain anomaly)
- failure of axons to cross midline between right and left hemispheres
- ID/DD ranges from mild to severe
- if not isolated, may be associated with Dandy-Walker malformation, T13, T18, T8, Aicardi syndrome, Mowat-Wilson syndrome
- prenatal diagnosis with CMA, TORCH titers
- recurrence risk: 2-3% if isolated
77
Dandy-Walker Malformation
- structural abnormality (congenital brain anomaly)
- enlarged posterior fossa, defect in cerebellar vermis, dilation of 4th ventricle
- associated with T13, T18, T21, Walker-Warburg, Meckel-Gruber, Aicardi, teratogens
- prenatal diagnosis with CMA, TORCH titers
- recurrence risk: 1-5% if isolated
78
Holoprosencephaly
- structural abnormality (congenital brain anomaly)
- failed/incomplete separation of prosencephalon, craniofacial anomalies (cyclopia, anopthalmia, proboscis, CL/P; single central incisor, anosmia)
- associated with sporadic causes, teratogens, T13, T18, triploidy, SLOS, Meckel, Kallman, SHH gene mutation
79
Duodenal Atresia
- structural abnormality (GI)
- congenital absence of closure of portion of duodenal lumen leading to blockage of duodenum
- most common neonatal intestinal obstruction
- "double bubble", polyhydramnios, preterm labor
- associated with DS and other causes
80
Gastroschisis
- structural abnormality (GI)
- evisceration of small and/or large bowel through abdominal wall adjacent to umbilical cord
- typically isolated, sporadic/multifactorial, and seen when mother <20y
81
Omphalocele
- structural abnormality (GI)
- abdominal wall defect with sac of amnion containing herniated abnominal viscera and/or liver into umbilical cord
- 2/3 have other anomalies like cardiac defects and may lead to lung hypoplasia
- associated with BWS, T13, T18
82
Clubfoot (Talipes Equinovarus)
- structural abnormality (skeletal)
- abnormal relation of foot/ankle to tibia and fibula such that foot bends inward
- male fetuses more commonly affected; bilateral more common
- may be related to positional factors (oligohydramnios, multiple gestations, uterine abnormalities)
- could be sign of neurological, muscular, or connective tissue, chromosomal (T18) issues
83
Polydactyly
- structural abnormality (skeletal)
- postaxial: extra pinky/pinky toe
- preaxial: extra thumb/big toe
- more common in African Americans
- when associated with genetic/chromosomal cause, not usually isolated
84
Skeletal Dysplasia
- structural abnormality (skeletal)
- genetically heterogeneous group of >450 disorders
- if detected in 1st or 2nd trimester, likely lethal
- some features seen include poor mineralization, fractures, bent/bowed bones, clubfoot, absent scapula, small chest circumference
85
Renal Abnormalities
- structural abnormality (GU)
- unilateral agenesis: can be associated with aneuploidy, VACTERL
- bilateral agenesis: associated with ectopic pregnancy, Potter sequence
- hyperechoic and isolated: associated with ARPKD, ADPKD, multicystic kidney disease
- hyperechoic and not isolated: chromosomal, 22q11.2, infection, Meckel-Gruber, Bardet-Biedl
86
Bladder/Ureter/Urethral Abnormalities
- structural abnormality (GU)
- lower urinary tract obstruction (LUTO): fetal bladder outlet obstructions including posterior urethral valves (common in males), urethral atresia (common in females)
- uretero-pelvic junction obstruction (UPJ): most common cause of hydronephrosis, more common in males
87
Gonadal Anomalies
- structural abnormalities (GU)
- includes DSDs
- need to determine fetal chromosomes, especially if ambiguous genitalia
- ambiguous genitalia: consider maternal history (virilization, teratogens, androgens), family history, prenatal diagnosis (SRY, CAH)
88
Congenital Diaphragmatic Hernia
- structural abnormality (lung/chest)
- incomplete formation of diaphragm leading to abdominal viscera herniating into chest, pulmonary hypoplasia, pulmonary HTN
- usually isolated but may be associated with T18, T21, Pallister-Killian, BWS
- fetal MRI recommended
- may need ECMO
89
Cystic Adenomatoid Malformation of Lung (CCAM/CPAM)
- structural abnormality (lung/chest)
- benign hamartomatous or dysplastic lung tumor
- sporadic, not chromosomal
- may lead to polyhydramnios, hydrops
90
Tracheoesophagela Fistula
- structural abnormality (lung/chest)
- 1+ abnormal connections between trachea and esophagus +/- esophageal atresia
- polyhydramnios and absent stomach bubble
- associated with VACTERL, maternal DM, T21, T18, 22q11.2, single gene disorders
91
Cleft Lip/Palate
- structural abnormality (face/neck)
- most common fetal craniofacial malformation
- CL more common in males
- CP more common, and more common in females
- midline cleft associated with holoprosencephaly and T13
- best visualized with 3D/4D u/s
92
Cystic Hygroma
- structural abnormality (face/neck)
- multiseptated cysts of lymphatic system due to vascular malformation
- most commonly nuchal and may resolve in 25% of cases
- associated with aneuploidy, cardiac anomalies, Noonan, multiple pterygium
93
Pierre-Robin Anomaly
- structural abnormality (face/neck)
- sequence; mandibular hypoplasia leads to posterior displacement of tongue and u-shaped cleft palate
- airway obstruction, repeated ear infections, natal teeth
- keep baby in prone position, tongue-lip adhesion, mandibular bone expansion
- associated with Stickler
94
Fetal Hydrops
- condition in fetus characterized by accumulation of fluid in at least two fetal compartments (skin, abdomen, scrotum/hydrocele, lungs)
- two etiologies: immune and non-immune
95
Immune Hydrops
- due to Rh isoimmunization
- Rh negative mother makes antibodies against Rh positive fetus, causing hemolytic disease of the fetus/newborn
- usually involves D antigen but others involved as well (Lewis lives, Kell kills)
- administration of Rhogam before procedures, before delivery at 28w GA, postpartum
- MCA dopplers used to look at how fast blood traveling through middle cerebral artery to monitor immune reaction
- monitored through titers
96
Non-Immune Hydrops
- aneuploidy (Turner, T21, T13, T18)
- syndromes (Noonan, myotonic dystrophy, skeletal dysplasia)
- metabolic conditions (MPS IVA, GM1 gangliosidosis)
- infection (CMV, toxo, parvo, syphilis, herpes, rubella, coxsackie, lepto, trypanosoma cruzi)
- alpha-thalassemia
97
% Live births with birth defect or developmental disability
3-5%
98
% birth defects due to teratogens
5-10%
99
Teratogen
any medication, chemical, infectious disease, or environmental agent that might interfere with normal developmental of fetus and result in pregnancy loss, birth defect, or adverse outcome
100
5 Factors Influencing Teratology
- timing of fetal development
- dosage
- tissue access
- pattern of malformation
- genetic susceptibility
101
"All or Nothing" Period
teratogenic exposure at 2-4 weeks GA leads to miscarriage, fetal death, or continuation of pregnancy
102
Teratogen Exposure 4-10w GA
fetal death, major malformations (organogenesis and neural tube closure happening), growth retardation, impaired IQ
103
Teratogen Exposure 10-13w GA
fetal death, vascular disruption, hemorrhage, tissue loss
104
Teratogen Exposure in 2nd or 3rd Trimester
stillbirth, growth restriction, impaired IQ
105
Thalidomide
- used for morning sickness, leprosy treatment
- phocomelia
- critical exposure 34-50 days post LMP (4-10w GA); 20% exposed have affected infants
106
Isotretinoin (Accutane)
- vitamin A derivative; retinoid
- CNS anomalies, ear anomalies, cardiovascular defects, thymus anomalies, ID
- critical period 15th day following conception - end of first trimester
- half-life of 16-20 hours and out of body in <1w
107
Other Vitamin A Products
- etretinate: orally active retinoid that produces similar effects as isotretinoin
- tretinoin: topical retinoid poorly absorbed through skin
- dietary vitamin A: metabolized to retinoids that can be teratogenic at high concentrations, not including beta-carotene
108
Maternal Depression/Anxiety
- untreated associated with increased risk of miscarriage, preterm delivery, low birth weight, increased fetal distress, disruptive social behavior, changes in period of sensitivity for language
- mother at risk for postpartum depression
109
Antidepressants
- neonatal adaptation syndrome
110
Anticonvulsants
- include phenytoin, trimethadione, carbamazepine, valproate, barbiturates
- "anticonvulsant embryopathy": cupid's bow lip, hypertelorism, short nose with anteverted nares, fingernail hypoplasia, meningomyelocele (ONTD); looks like FAS
111
Lithium
- Ebstein's anomaly
| - critical period of exposure in 1st trimester when heart valves forming
112
SSRIs
- increased risk of CHD (2% vs 1%)
113
Benzodiazepines
- possible risk for orofacial clefts
114
ACE inhibitors
- reduce uterine blood flow leading to decreased placental perfusion and severe fetal hypotension
- renal tubular dysplasia leads to oligohydramnios, Potter's sequence, and pulmonary hypoplasia; hypocalvaria
- critical period of exposure in 2nd and 3rd trimesters
115
Tetracycline
- binds to calcium and leads to discoloration of teeth
| - critical period 4m of pregnancy
116
Warfarin
- "warfarin embryopathy": nasal hypoplasia, stippled epiphyses, limb hypoplasia
- critical period 8-11w GA
117
Fluconazole
- antifungal agent used to treat mycotic infections
- craniofacial, limb, and cardiac anomalies
- large doses may create phenocopy of Antley-Bixler
118
Methylmercury
- congenital Minamata disease
| - stems from eating fish high in mercury
119
Radiation
- threshold >5 rads imposes risk to fetus
- may lead to miscarriage, failure to implant, IUGR, ID, microcephaly, seizures
- critical period for ID 8-15w
120
Toluene
- microcephaly, ID, growth deficiency, craniofacial anomalies similar to FAS
121
Varicella
- varicella embryopathy: hydrops, echogenic bowel, cardiac anomalies, scarring of skin, eye abnormalities, limb underdevelopment, ID
- 25% infection rate if mom infected and 1-3% chance of birth defects if fetus infected
- greatest risk period 7-20w
122
Zika Virus
- severe microcephaly, decreased brain tissue, lissencephaly, retinal damage, hypotonia
- infection can occur in any trimester and transmission of virus may stem from semen
- women with potential exposure should wait 8 weeks before trying to conceive, men should wait 3 months
123
CMV
- petechiae ("blueberry muffin"), hearing loss, CNS problems
| - primary maternal infection results in fetal infection rate of 30-40%
124
Vaccines
- many can have adverse effects on CNS and hematopoietic development
125
Maternal Pregestational Diabetes
- caudal dysgenesis, congenital heart disease, kidney problems, ONTDs
126
Gestational Diabetes
- macrosomia and HCM due to increased insulin output from fetus, premature birth, hypoglycemia, ONTDs
- need to sample amniotic fluid to determine lung function
127
Alcohol
- no known safe level of alcohol
- FAD: ptosis, short palpebral fissures, smooth philtrum, thin upper vermilion, cardiac defects, DD, neurobehavioral issues
128
Cigarette Smoke
- IUGR, preterm delivery, SIDS, orofiacial clefts, low birth weight
- 10+ cigarettes a day leads to 7oz decrease
129
Heroin
- strabismus, low birth weight, respiratory distress, jaundice, SIDS, neonatal withdrawal
- IQ not affected
130
Cocaine
- prematurity, IUGR, neurobehavioral problems, intracranial hemorrhage, intestinal atresia, limb reduction, urinary tract anomalies
131
FDA Drug Category Update
- previously A, B, C, D, X but oversimplified and didn't take into account timing, dose, indication/maternal condition
- letter categories removed and replaced with extensive narratives including info about pregnancy, lactation, fertility, and untreated maternal condition
132
Prenatal Testing Options
- initial first trimester labs: antibody screen, blood type/Rh, CBC with differential, Rubella/RPR/Varicella
- carrier screening: CF, SMA, hemoglobin electrophoresis
- aneuploidy screening: serum, NIPS
- second/third timester labs: GBS, glucola
133
IgM antibody
induced production with current infection
134
IgG antibody
produced after IgM response
135
IgG avidity
- measures maturity of IgG antibody
| - increases months after initial infections
136
TORCH
```
T = toxoplasmosis gondii
O = other (parvovirus, syphilis, varicella, Zika)
R = rubella
C = CMV
H = herpes
```
137
Rubella
- congenital rubella syndrome: hearing loss, vision loss, cataracts, ID, CHDs, microcephaly, IUGR, postnatal growth retardation
138
Testing for Hemoglobinopathies/Prenatal anemia
- CBC
- iron binding studies
- hemoglobin electrophoresis
- ACOG recommends screening all pregnant women for thalassemias and hemoglobinopathies with CBC and f/u heme elec based on ancestry or low MCV/MCH
139
Carrier Frequencies for Hemoglobinopathies
- 1/10 African Americans for sickle cell
- 1/7 Mediterraneans for beta thal
- 1/20 Southeast Asians for alpha thal
- least common in Northern European, Japanese, Native American, Inuit, and Korean ancestries
140
CBC Indices
- MCV: average volume of RBCs; normal MCV >80
- MCH: average amount of Hb in RBC/sample
- Hemoglobin level
- RDW: variability in size of RBC; may indicate if microcytic cells present
141
Hemoglobin electrophoresis
- HbA: >96%
- HbA2: 1.8-3.5%
- HbF: <2%
- may detect other variants like HbS (African Americans), HbC (West Africans), HbE (Southeast Asians)
142
Diagnostic Prenatal Testing
- goal is to determine whether specific genetic disorder present in fetus and to provide information for decision-making/pregnancy management
- benefits: identifying conditions where prenatal treatment may be available, allowing opportunity for termination, improving neonatal outcomes
- limitations: invasive, risk for infection, risk for miscarriage, risk for premature birth, cramping/bleeding/spotting
143
CVS
- performed 10-13w GA
- placental villi obtained through transcervical or transabdominal access to placenta under u/s guidance
- procedure-related loss: 1/200 - 1/455
- used in conjunction with karyotype, FISH, CMA
144
Amniocentesis
- performed 15-20w GA or until chorion and aminon have fused
- if completed after 22w, may not get results in time for legal termination
- if performed after 20w risk for premature birth
- amniotic fluid sample obtained using needle and u/s guidance
- procedure-related loss: 1/300 - 1/500
- used in conjunction with karyotype, FISH, CMA, CPM, AFAFP/ACHE, biochemical studies, fetal lung maturity
145
Percutaneous Umbilical Blood Sampling (PUBS)
- needle inserted into umbilical vein for access to fetal blood for sample collection or transfusions
- may be used to diagnose and treat severe anemia
- 1% loss rate
146
Medication Abortion
- <10w GA
- mifepristone causes separation of trophoblast from decidua
- misoprostol causes softening of cervix and uterine contractions
147
Surgical Abortion (1st Trimester)
- cervical dilation followed by procedure to empty uterus
- manual vacuum aspiration
- dilation and aspiration (D&C; dilation with electric vacuum)
148
Surgical Abortion (2nd Trimester)
- dilation and evacuation: cervical dilation, electric vacuum aspiration, forceps with disarticulation, u/s guidance
- labor induction: administration of misoprostol/mifepristone, delivery in hospital
149
Diamniotic Dichorionic
each twin has own placenta and amniotic sac; lambda sign on u/s
150
Diamniotic Monochorionic
each twin has own amniotic sac but share placenta
151
Monoamniotic Monochorionia
twins share amniotic sac and placenta
152
Risks of Multiple Gestations
- gestational diabetes
- preeclamspia
- preterm birth
153
Selective Termination/Multifetal Pregnancy Reduction
- performed 10-13w GA to reduce risk of pregnancy-related complications or to selectively terminate fetus with problems
- reduction technique depends on chorionicity
- injection of KCl if placentas separate, cord occlusion with ablation if not
154
Infertility
- 1+ years of unprotected intercourse without achieving pregnancy
- affects 1/8 couples
155
Causes of Infertility
- male factor (35%)
- ovulation (15%)
- tubal pathology (35%)
- other (5%)
- unknown (10%)
156
Male Factor Infertility
- anatomic: hypospadias, obstruction of vas deferens (CBAVD), vericocele
- endocrine: testosterone
- genetics: chromosomal anomalies, deletions in Yq
- other: testicular injury, surgery, heat, exposure, marijuana usage, drug usage (including chemo)
157
Treatment for Male Factor Infertility
IUI, therapeutic donor insemination, IVF with ICSI
158
Infertility d/t Ovulation
- natural hormonal stimulus in hypothalamic-pituitary-ovarian axis not happening correctly
- assessed via ovarian reserve testing
- stress, anorexia, marathon running can shut down pathway
- genetic etiologies include fragile X premutation, X chromosome abnormalities, PCOS, autoimmune disease
159
Ovulation Treatment
ovulation induction (Clomid), human gonadotropins, donor egg
160
Infertility d/t Tubal Pathology
- pelvic inflammatory disease, septic abortion, endometriosis, ruptured appendix, tubal surgery/ectopic pregnancy
- diagnosed via hysterosalpingogram, sonohystogram, hysteroscopy, laparoscopy
161
Other Causes of Female Infertility
Mullerian anomalies
162
Recurrent Pregnancy Loss
2+ failed documented clinical pregnancies or 3 consecutive pregnancy losses
163
% Women experiencing miscarriage
15-25%
164
% Women experiencing 2 consecutive losses
>5%
165
% Women experiencing 3 consecutive losses
1%
166
Causes of RPL
- uterine/cervical factors (12-13%): congenital uterine anomalies, uterine fibroids, cervical incompetence
- hormonal/metabolic: diabetes, thyroid disease, PCOS, luteal phase defect
- immunologic factors (5-20%): antiphospholipid antibody syndrome, blood group alloimmunization, inherited thrombophilias
- cytogenetic factors (2-5%): chromosomal rearrangement (4% of couples with RPL)
- environment
167
% Patients with RPL that experience future successful pregnancy
50-60%
168
Assisted Reproductive Technologies
- ovulation induction
- IUI
- IVF
- ovarian tissue cryopreservation
- PGT
169
Ovulation Induction
- used for anovulatory infertility or unexplained infertility
- stimulates development of follicle(s) and hCG trigger used to induce ovulation followed by timed intercourse/IUI
170
IUI
- used for unexplained infertility, male subfertility, failure to conceive after ovulation induction, retrograde ejaculation
- washed sperm deposited in uterus before ovulation
171
IVF
- ovarian hyperstimulation, u/s-guided oocyte retrieval, insemination, fertilization, embryo culture, embryo transfer, cryopreservation of supernumerary embryos
- fertilization may happen by allowing multiple sperm to interact with egg or through ICSI
- 3-5 day embryos transferred may be fresh or frozen
- risks of IVF include ovarian hyperstimulation syndrome, ovarian torsion, infection, bleeding, injury, multiple gestations, ectopic pregnancy, cost, potential risk of congenital anomalies/imprinting defects
172
Ovarian Tissue Cryopreservation
- used for women with cancer or at high risk of developing cancer
- surgical tissue retrieval, cryopreservation of ovarian tissue, tissue thawed (or transplanted) and follicles allowed to grow, mature egg fertilized and embryo implanted in patient
173
PGT-M
- single gene/monogenic disorders
- variant/mutation must be known so probe can be developed
- probe development is a linkage-based test, so patient's parents often needed to provide DNA samples
- problem is allele drop out
- non-disclosure PGT possible when patient does not want to know own risk status; direct method involves determining genetic status but not disclosing it and indirect method does not test genetic status of patient but uses linkage to select based on inheritance of maternal/paternal allele
- PGT-M not feasible when unable to establish linkage, de novo mutations, genes with pseudogenes, mtDNA mutations, repeat expansions
- PGT-M reduces but does not eliminate risk of unaffected pregnancy
174
PGT-HLA
- HLA matching for bone marrow transplant (like in Fanconi anemia)
- only full sibs have potential to be exact matches
175
PGT-SR
- structural rearrangements like translocations, inversions
- most commonly done to identify balanced embryos for transfer
- testing techniques same as for PGT-A
176
PGT-A
- aneuploidy
| - largely run on NGS platform and enables single embryo transfer, high live birth rates, low multiple gestation rates
177
Benefits of PGT
- for couples at high risk of sex-linked disorders, aneuploidy, and single gene defects
- avoid decision regarding termination
- possibly improve success rates of IVF by not transferring abnormal embryos
178
Limitations of PGT
- technical expertise required
- cost
- doesn't obviate need for invasive prenatal testing
- what conditions are acceptable?
