DETECTION AND PREVENTION IN OBSTETRICS
| FIRST-TRIMESTER SCREENING METHODS —Lami Yeo, MD, Associate Professor of Obstetrics and Gynecology, Division
of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, and Director of Perinatal
Ultrasound, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New
Brunswick
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| Assessment of risk for aneuploidy: maternal age and history of, eg, Down syndrome, trisomy 18; fetal nuchal translucency
(NT) measurement; serum biochemical markers (eg, free beta human chorionic gonadotropin [hCG]), pregnancy-associated
plasma protein A (PAPP-A); genetic counseling; invasive testing
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| Nuchal translucency: fluid collection at back of fetal neck in first trimester; thickness normally increases with gestational
age; must take gestational age into account in determining whether NT thickness increased; measurement done between
11 and 13.6 wk gestation; abnormal NT—at 11 wk gestation, 95th percentile 2.1 mm, and 2.7 mm at 13.6 wk
gestation; NT value should increase as crown-rump length (CRL) increases; NT value of 3.5 mm at 99th percentile of
CRL, regardless of gestational age; patient-specific risk calculated by combining maternal age, NT, and biochemistry; abnormal
NT defined as measurement >95th percentile; term used irrespective of whether fluid collection septated, confined
to neck, or envelops fetus entirely; increased NT usually resolves after 14 wk; prevalence of aneuploidy depends on
both NT thickness and maternal age; greater NT thickness, greater chance of aneuploidy; sensitivity for Down syndrome
using NT ≈75%, with false-positive rate of 5%
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| Biochemical serum screening (biochemistry): free hCG should decrease; PAPP-A should increase; higher hCG
and lower PAPP-A, greater chance for Down syndrome; detection rate for Down syndrome using age and first-trimester
biochemistry ≈60%, with 5% false-positive rate; 90% with NT, age, and first-trimester biochemistry; increased NT and
other aneuploidy—for Down syndrome, NT thickness >2.5 mm (greater for Turner’s syndrome); Fetal Medicine Foundation
study—showed free hCG and PAPP-A decreased in trisomy 18 and 13; NT and biochemistry identifies 90% of
other aneuploidy (false-positive rate, 1%); other sonographic markers of aneuploidy—early onset of intrauterine growth
restriction (IUGR) with trisomy 13 and 18, Turner’s syndrome, and triploidy; structural defects, cardiac defects, and genetic
conditions possible with increased NT and normal karyotype; Fetal Medicine Foundation showed the higher NT
measurement, greater the chance of fetal abnormality; 36% chance of fetal abnormality with NT of 6.5 mm; anomalies
associated with increased NT—cardiac defects, omphalocele, and diaphragmatic hernia; multitude of genetic syndromes;
all major abnormalities of heart and great vessels clearly associated with increased NT, regardless of whether
chromosomal problem; prevalence of cardiac defects increases in direct relationship to magnitude of NT increase; strong
association with left-side defects; NT indication for fetal echocardiography; increased NT (despite negative aneuploidy
screen and/or normal karyotype)—perform detailed scan; offer genetic counseling and early anatomy scan (at ≈14-16
wk); fetal echocardiography (debatable); full fetal anatomy survey at 20 to 22 wk (regardless of findings), and fetal
echocardiography at 22 to 24 wk; persistent unexplained increased NT at 14 to 16 wk or evolution to nuchal edema or
hydrops—toxoplasmosis, cytomegalovirus, and parvovirus should be considered genetic syndromes; consider DNA testing
even without family history; monitor edema with serial ultrasonography (US) every 4 wk; who is at risk for adverse
pregnancy outcome—increased NT level; abnormal first-trimester biochemistry; outcomes include fetal loss at <24 wk,
intrauterine fetal demise, low birth weight, and preterm birth; American College of Obstetricians and Gynecologists
(ACOG) states “at present time no data indicating whether or not third-trimester fetal surveillance helpful in care of patients”;
pregnancy outcome when increased NT and normal chromosomes seen—increased risk for miscarriage, perinatal
death, and major fetal abnormalities; 93% chance of live healthy birth if NT in 95th to 99th percentile; greater NT, greater
chance of chromosomal defect and fetal death (NT >3.5 mm associated with 21% chance of chromosomal defect); PAPP-
A—≤0.2 multiples of median (MOM) associated with Cornelia de Lange’s syndrome; lowest 5% of values for gestational
age associated with fetal loss at ≤24 wk, low birth weight, IUGR, preeclampsia or gestational hypertension, preterm birth,
stillbirth, preterm premature rupture of membranes, and abruption (implications of information controversial); no adverse
outcomes associated with high levels; free hCG—low level associated with IUGR and spontaneous loss at ≤24 wk; high
level associated with IUGR, preterm delivery, and pregnancy loss; chromosomally and anatomically normal fetuses with
increased NT—studies show developmental delays or adverse outcomes (2%-4% prevalence reported)
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| Ultrasonographic markers: ductus venosus—abnormal ductus flow associated with chromosomal defects, cardiac
anomalies, and adverse pregnancy outcome; can be combined with NT to improve effectiveness in screening for Down
syndrome; data show increased NT and abnormal ductus venosus in 91% of aneuploid fetuses and 3% of chromosomally
normal fetuses; 50% had major cardiac defect at second scan; tricuspid flow—tricuspid regurgitation more common in
fetus with increased NT; seen in 74% of Down syndrome fetuses and 7% of normal fetuses; tricuspid regurgitation, NT,
and biochemistry shown to identify 90% of fetuses with Down syndrome; prevalence of tricuspid regurgitation increases
with NT thickness; nasal bone—should appear brighter than nasal skin; first appears at CRL of 10.9 wk gestation or 42
mm; increases throughout gestation; incidence of absent nasal bone decreases as pregnancy progresses; higher NT thickness,
greater chance of absent nasal bone; false-positive absent nasal bone more likely in normal black fetuses and Asian
fetuses than in white fetuses; ≈70% sensitivity; 60% to 70% of Down syndrome fetuses have absent nasal bone; false-
positive rate, 2%; trisomy 18 and 13 also associated with absent nasal bone; First and Second Trimester Evaluation of
Risk (FASTER) trial showed 0% of 10 Down syndrome fetuses had absent nasal bone; 97% sensitivity with 5% false-
positive rate when combined with NT and biochemistry; sonographic markers time-consuming and require highly skilled
operators; use in routine first-trimester screening unlikely; should be used in specialized centers to reevaluate intermediate-risk
patients; screen for only one of 3 markers
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| Screening: 2-tier screening—all patients should undergo screening by age, NT, and biochemistry; offer high-risk patient
chorionic villus sampling (CVS); no further testing if low risk; in intermediate-risk population, perform assessment of nasal
bone, ductus venosus, or tricuspid regurgitation; patient low risk if results normal; offer CVS if abnormal; maxillary
length—underdevelopment of maxillary bone in >50% of fetuses with Down syndrome; maxillary length increases linearly
with gestation in chromosomally normal fetuses; implication for screening for Down syndrome unknown; advantages
of first-trimester screening—patient has information sooner; option of CVS with increased risk; first-trimester
termination of pregnancy preferable to second-trimester termination; incidence of abnormal accumulation of nuchal fluid
in aneuploid fetus lower at 14 to 18 wk than at <14 wk; CVS and earlier selective reduction option for women with multiple
gestations; first- and second-trimester screening tests should not be performed independently; high Down syndrome
detection rate (94%-98%) when performed and interpreted independently; false-positive rates additive and lead to more
unnecessary invasive procedures (11%-17%); women who have first-trimester screening should not undergo independent
second-trimester serum screening; women who want higher detection rate can have integrated or sequential screening
(combines first- and second-trimester results); Nicholaides’ statement—since first-trimester screening identifies 90% of
Down syndrome, second-trimester biochemical screening will identify, at best, 6% of affected pregnancies, but will increase
invasive testing by ≈10%; increased risk for aneuploidy after first-trimester screen—offer genetic counseling and
invasive testing; when only first-trimester screen performed or normal CVS results seen—offer screening for neural tube
defect (alpha-fetoprotein screening or US)
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| Integrated screening: uses first- and second-trimester markers to adjust; results reported only after completion of first-
and second-trimester tests; can be performed using only first- and second-trimester serum markers when NT not available
or when reliable measurement cannot be obtained; advantages—higher sensitivity (≈95%), with lower false-positive rate,
results in fewer invasive tests; disadvantages—patient anxiety; lost opportunity to consider CVS; possibility of failure to
complete second-trimester portion of screening test leaves patient without screening results; patient has US without receiving
results; second-trimester diagnosis and termination of pregnancy vs first-trimester termination
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| Sequential screening: patient informed of first-trimester screening result; high-risk patient offered early diagnostic procedure;
low-risk patient has first- and second-semester screening to determine final risk; stepwise sequential—sensitivity
95%; patient told of first-trimester screen results; if patient at high risk, offer genetic counseling and invasive testing; offer
second-trimester screening if not high risk; results combined for final number in second trimester; detection rates
sensitivity—integrated, ≈95%; stepwise sequential, ≈95%; serum integrated, ≈95%
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| ACOG practice bulletin: all women, regardless of age, presenting at <20 wk gestation should be offered diagnostic
and invasive testing and screening; if patient desires invasive testing—CVS or amniocentesis; detection rate 100%; if patient
desires screening—quadruple screening only option if first prenatal visit at 14 wk; detection rate ≈80%; if first visit
at <14 wk, offer serum integrated screening if NT not available; detection rate 85%; NT available, CVS not available—
first- and second-trimester combined screening; ideally, patients seen early in pregnancy should be offered first- and second-trimester
combined screening (integrated or sequential)
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| DRUGS TO AVOID IN PREGNANCY —Michael J. Barsoom, MD, Assistant Professor and Co-Director of Perinatal Ultrasound,
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Creighton University Medical Center,
Omaha, NE
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| General considerations: medications account for 1% to 3% of birth defects; teratogenicity of drugs—depends on
when in gestation drug administered; 31 to 71 days from last menstrual period classic teratogenic period; before this window,
effect all or none; effect depends on time of organ system development; pregnancy categories—inadequate for determining
safety; placenta—allows transfer of drugs and dietary substances; lipid-soluble compounds readily cross
placenta; water-soluble compounds less able to cross placenta as molecular weight increases; drug binding to plasma protein
influences amount of drug free to cross placenta; virtually all drugs cross placenta to some degree, with exception of
large organic ions
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| Antihypertensive agents and anticoagulants: angiotensin-converting enzyme (ACE) inhibitors and angiotensin II
receptor antagonists—pregnancy category D; teratogenic in second and third trimesters; bony malformations, limb contractures,
persistent patent ductus arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged hypotension,
neonatal death, and renal anomalies; oligohydramnios, IUGR, premature labor, and fetal and neonatal renal failure;
β-blockers—methyldopa not recommended; increased uterine activity theoretic concern, but not seen in clinical usage;
no evidence of teratogenicity; US monitoring of fetal growth recommended for patient on β-blocker; neonatal bradycardia
(especially with propranolol or atenolol); inform pediatrician postpartum if mother on β-blocker during pregnancy; warfarin
(Coumadin)—class X; fetal warfarin syndrome; central nervous system defects, nasal hypoplasia, skull defects,
abnormal ears, malformed eyes, microcephaly, skeletal deformities, and mental retardation; increased risk for spontaneous
abortion, stillbirth, and prematurity; ophthalmic abnormalities and mental retardation in second and third trimesters
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| Antibiotics, sulfonamides, and aminoglycosides: tetracycline—readily crosses placenta; brown discoloration of
deciduous teeth and hypoplasia of tooth enamel; not teratogenic in first trimester; ehrlichiosis exception to use in pregnancy;
penicillins—no increased teratogenic effect; penicillins and ampicillin readily cross placenta; ampicillin plus sulbactam
(Unasyn) associated with necrotizing enterocolitis in preterm infants; selects for specific pathogens, which leads
to abnormal microbial colonization of gastrointestinal tract; sulfonamides—no teratogenic effects; avoid in patients with
personal or family history of glucose-6-phosphate dehydrogenase deficiency (dose-related hemolysis); kernicterus does
not occur in newborn after in utero exposure; trimethoprim–sulfamethoxazole (eg, Bactrim)—risk for cardiac defects
when used in first trimester; aminoglycosides—ototoxicity reported after maternal exposure; gentamicin ototoxic to
adults and fetuses; hearing defects, vestibular problems, and inner ear damage; cranial nerve XIII damage in 10% of patients;
18 wk gestation most sensitive period; difficult to obtain therapeutic level; other broad spectrum agents recommended;
fluconazole (Diflucan)—congenital anomalies reported in infants similar to those observed in animals;
craniofacial, skeletal, and cardiac defects; fetal anomalies often observed with high-dose parenteral therapy for yeast
meningitis (safe to use single-dose fluconazole)
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| Psychotropics and anticonvulsants: selective serotonin reuptake inhibitors (SSRIs)—no increased risk for congenital
heart defects or most other categories or subcategories of birth defects; maternal SSRI use associated with anencephaly
and omphalocele; late-pregnancy exposure associated with transient neonatal complications (mild respiratory distress,
transient tachypnea, weak cry, poor tone, and admission to neonatal intensive care unit); 6-fold increased risk for pulmonary
hypertension; withdrawal syndrome in ≈30% of neonates exposed >20 wk; paroxetine (eg, Paxil)—increased risk
for cardiac defects; abrupt discontinuation associated with withdrawal symptoms (taper down); lithium—reported cardiac
malformations, with Ebstein’s abnormality unconfirmed; fetal echocardiography recommended; perinatal effects include
hypotonia, lethargy, poor feeding, goiter, and hypothyroidism; diabetes insipidus in infant resulting in
polyhydramnios; anticonvulsants—risk for malformations ≈5%; combination therapy increases risk, especially for cleft
lip (with or without cleft palate) and congenital heart disease; risk for neural tube defects with valproic acid and carbamazepine;
fetal hydantoin syndrome associated with phenytoin; clinical characteristics similar to those of fetal alcohol syndrome;
developmental delays, mental retardation; patients with seizure disorder at increased risk for fetus with congenital
anomalies (may not be due to drug, but to conditions that predispose patient to seizure disorder); 5 mg/day of folate recommended;
speaker uses Diatx Fe (multivitamin with iron) for patients with methyltetrahydrofolate reductase deficiency;
risk for seizures outweighs risk of drugs in most cases
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| Analgesics and other drugs: nonsteroidal anti-inflammatory drugs (NSAIDs)—no increased risk for congenital
anomalies; use in second and third trimesters associated with oligohydramnios, ductus arteriosus constriction, and pulmonary
hypertension; with close monitoring, safe to continue drug for preterm labor; narcotics—no increased risk for congenital
anomalies; can cause withdrawal symptoms in neonate (inform pediatric team if mother taking narcotics close to
delivery); radioactive iodine—no increased risk for anomalies when used in first trimester; can be concentrated in fetal
thyroid after 12 wk; no adverse outcome if identified and treated early; isotretinoin (Accutane)—class X drug; hydrocephaly,
ear malformations, cardiovascular defects, and decreased IQ scores
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Suggested Reading
ACOG Practice Bulletin: Screening for fetal chromosomal abnormalities. Obstet Gynecol 109:217, 2007; Chambers
CD et al: Drug safety in pregnant women and their babies: ignorance not bliss. Clin Pharmacol Ther 83:181, 2007;
Dane B et al: Pregnancy outcome in fetuses with increased nuchal translucency. J Perinatol [Epub ahead of print], 2008;
Mattison D, Zajicek A: Gaps in knowledge in treating pregnant women. Gend Med 3:169, 2006; Nicolaides KH:
First-trimester screening for chromosomal abnormalities. Semin Perinatol 29:190, 2005; Nicholaides KH et al: Multicenter
study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact
of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 25:221, 2005; Saller DN et
al: Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol 51:24,
2008; Souka AP et al: Increased nuchal translucency with normal karyotype. Am J Obstet Gynecol 192:1005, 2005;
Umans JG: Medications during pregnancy: antihypertensives and immunosuppressives. Adv Chronic Kidney Dis 14:191,
2007; Yeo L et al: Prenatal detection of fetal trisomy 18 through abnormal sonographic features. J Ultrasound Med
22:581, 2003.
Educational Objectives
| The goal of this program is to improve decision-making related to appropriate obstetric screening and to improve obstetric
outcomes. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Evaluate evidence for the use of nuchal translucency and biochemical serum markers for aneuploidy screening in
pregnancy.
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| 2. Define abnormal nuchal translucency.
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| 3. Discuss the role of ductus venosus, tricuspid flow, and nasal bone in detecting fetal abnormalities.
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| 4. Determine the appropriate strategy for first-trimester screening for fetal abnormalities.
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| 5. Safely prescribe medications during pregnancy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported
nothing to disclose.
Acknowledgments
Dr. Yeo was recorded at the 22nd Annual Issues and Controveries in Ob/Gyn, sponsored by the Robert Wood Johnson Medical
School, University of Medicine and Dentistry of New Jersey, and held on November 8-10, 2007, in Lake Buena Vista,
FL. Dr. Barsoom was recorded at A Day with the Perinatologists: Perspectives in Practice, sponsored by Creighton University
Medical Center, and held on September 14, 2007, in Omaha, NE. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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