Prenatal assessment and care
高雄醫學大學醫學系 教授 高雄醫學大學附設醫院 產科主任/遺傳諮詢中心主任
The major goal of prenatal care is to ensure the birth of a healthy baby with minimal risk for the mother. Early, accurate estimation of gestational age Identification of the patient at risk for complications Ongoing evaluation of the health status of both mother and fetus Anticipation of problems and intervention, if possible, to prevent or minimize morbidity. Patient education and communication. Prenatal care is initiated by 10 weeks of gestation.
Ultrasound estimation in the first half of pregnancy is superior to dating based on the LMP or physical examination and also provides information about fetal development. Since gestational age calculations are based upon biometric measurements, the optimal time to obtain an estimate of gestational age is during the first trimester when biologic variation in size from fetus to fetus is minimal. Gestational sac Gestational age (days) = mean sac diameter (MSD) in mm + 30
Crown-rump length CRL at 7 to 10 weeks of gestation is the most accurate biometric parameter for pregnancy dating (Âą3 days). When CRL is <25 mm, gestational age (in days) = CRL (mm) + 42
Adapted from Stevenson, RE and Hall, J. Human Malformations and Related Anomalies, 2nd ed. 2006
Data adapted from Wellesley, D, et al., Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe. Eur J of Hum Gen, 11 January 2012.
二十一世紀產檢 – 倒三角產檢模式
Prenatal Diagnosis Volume 31. Issue1, pages 3-6, 5 Jan 2011
地中海貧血帶因者篩檢 Thalassemia carrier screening 是台灣最常見之 單一基因自體隱性遺傳疾病 目前唯一能夠進行 全國性帶因者篩檢之單一基因疾病
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An mean corpuscular volume (MCV) <80 femtoliters (fL) in the absence of iron deficiency suggests thalassemia; further testing with hemoglobin electrophoresis is indicated. Beta-thalassemia occurs with higher frequency in subcontinental ethnic groups except Northern Europeans. Alpha-thalassemia occurs with higher frequency in Chinese, Taiwanese, South-East Asian (Thai, Laotian, Cambodian, Vietnamese, Burmese, Malaysian, Singaporean, Indonesian, Philippino). The structural hemoglobin variants S and C (sickle cell disease) are most common in Africa including North Africans, African-Caribbeans, AfricanAmericans, Black British and any other African ethnicity (eg, Central and South Americans of partly African ethnicity), Greeks, Southern Italians including Sicilians, Turks, Arabs, Indians. Hemoglobin E is noted among Southeast Asians and may be the most common structural hemoglobin disorder in the world.
Disorder
Genotype
MCV
Anemia
Hemoglobin electrophoresis
Alpha thalassemia Silent carrier
αα/α-
NL
None
Normal <3% Hb Barts at birth
Minor
α α / - - or α-/α-
Low
Mild
Normal 3~8% Hb Barts at birth
Hb H disease (deletional)
α-/--
Low
Moderate
Major (fetal hydrops)
--/--
Low
Fatal
5~30% HbH present in adults 20~40% Hb Barts at birth Hb Barts, Hb Portland, and HbH present HbA, HbF, and HbA2 are absent
Beta thalassemia Minor (trait)
β / βo or β / β+
Low
Mild
Intermedia
β+ / β+ and others*
Low
Moderate
Major
β° / β°
Low
Severe
HbA2 normal or increased (up to 7~8%) HbF increased in approximately half of patients HbA absent Only HbA2 and HbF are present
The major differential diagnosis in patients with microcytic, hypochromic red cells includes iron deficiency and the anemia of (chronic) inflammation, as follows: Iron deficiency â&#x20AC;&#x201C; Patients with iron deficiency will have low levels of serum iron and ferritin and increased levels of transferrin (total iron binding capacity). Those with iron deficiency rarely become microcytic (mean corpuscular volume (MCV) <80 fL) until the hematocrit has dropped below 30 percent. The red cell distribution width (RDW) is usually increased and the total red cell count is decreased in concert with the degree of anemia. A cause for blood loss will be obvious in most patients. Anemia of inflammation â&#x20AC;&#x201C; Patients with the anemia of chronic inflammation will have low levels of serum iron and transferrin. Levels of ferritin will be normal or increased. An inflammatory, infectious, or malignant disease is usually the underlying cause.
Patients with thalassemia will have normal to increased levels of serum iron and ferritin. Levels of transferrin will be normal or decreased. Patients with beta thalassemia trait almost always have a hematocrit >30 percent, and a mean corpuscular volume (MCV) <75 fL. The RDW tends to be normal. The total red cell count is usually normal to increased in those with beta thalassemia trait, reflecting the presence of an increased number of smaller than normal red cells. At least one of the patient's parents will also be affected. A family history of "iron deficiency anemia not responding to treatment with ironâ&#x20AC;? is common.
Normal levels of HEMOGLOBIN A2 (HbA2) are 2.8Âą0.2 percent (range: 2.1 to 3.1) The percent of HbA2 is increased in beta thalassemia trait (5.4Âą0.4 percent, range: 4.5 to 6.2), a finding that is a useful diagnostic aid. HbA2 is also slightly increased in megaloblastic anemia. HbA2 is decreased in alpha thalassemia, iron deficiency, and sideroblastic anemias.
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Mother-to-child transmission is the predominant mode of transmission in high prevalence areas. Mother-to-child transmission may occur in utero, at the time of birth, or after birth. A study performed in China found that only 3.7 percent of babies who tested positive for HBsAg at birth were infected through intrauterine transmission. The high protective efficacy of neonatal vaccination suggests that most infections occur at birth when maternal secretions and blood in the birth canal come into contact with the infant's mucosal membranes.
The infection rate of infants born to hepatitis B surface antigen (HBsAg)positive mothers is as high as 90 percent among infants who do not receive hepatitis B immune globulin and hepatitis B vaccination at birth. Passive and active immunization of the newborn within 12 hours of delivery has reduced the risk of HBV transmission by more than 95 percent. Despite the proper use of prophylaxis, transmission can still occur. The risk appears to be greatest if the mother is positive for hepatitis B e antigen (HBeAg) and/or has a high HBV viral load >2000 IU/mL, or was <25 years old; transmission was also associated with receiving <3 doses of the hepatitis B vaccine series. Among women with a high viral load, antiviral therapy for the mother can further reduce the risk of transmission.
The risk of HBV transmission has been significantly reduced with the introduction of universal maternal HBV screening, hepatitis B vaccination of all newborns, and the use of prophylactic hepatitis B immune globulin (HBIG) for infants of HBsAg-positive mothers. Testing for HBsAg should be performed on all women at the first prenatal visit. Women who are HBsAg-positive should have further testing to measure baseline HBeAg, hepatitis B e antibody (anti-HBe), HBV DNA, and aminotransferase levels. Women who have a high HBV DNA (ie, >2x105 int. units/mL or >106 copies/mL), elevated aminotransferase levels, and/or a positive HBeAg should be referred to a hepatologist to see if early initiation of antiviral medications is needed.
Syphilis is a systemic infection caused by the spirochete Treponema pallidum, which is of particular concern during pregnancy because of the risk of transplacental infection of the fetus. Congenital infection is associated with several adverse outcomes, including: Perinatal death Premature delivery Low birth weight Intrauterine growth restriction Congenital anomalies Active congenital syphilis in the neonate Long-term sequelae, such as deafness and neurologic impairment
The problems associated with syphilis in pregnancy can be almost completely eliminated by universal early antepartum screening and treatment with appropriate antibiotics. The major harm of screening is the anxiety associated with a false positive result. The US Centers for Disease Control and Prevention (CDC) recommend that all pregnant women be screened for syphilis at the first prenatal visit. For women who are at high risk for syphilis or live in areas of high syphilis morbidity, the CDC also recommends repeating screening during the third trimester (at 28 to 32 weeks) and again at delivery.
T. pallidum cannot be cultured in the laboratory. The diagnosis of syphilis relies upon Direct visualization of the organism Serologic testing is the mainstay of diagnosis of syphilis due to the complexities of direct visualization techniques ▪ There are two types of serologic tests for syphilis ▪ Nontreponemal tests (that are traditionally used for primary screening) ▪ Treponemal tests (usually done to confirm infection) ▪ The use of only one test is insufficient for diagnosis since each test has diagnostic limitations.
Nontreponemal antibody tests They are based upon the reactivity of serum, from patients with syphilis, to a cardiolipin-cholesterol-lecithin antigen. They are used for initial syphilis screening. These screening tests are non-specific and therefore not definitive. The amount of antibody present (both IgM and IgG) generally reflects the activity of the infection, and can be used to follow the response to treatment in many patients.
Nontreponemal tests include: Venereal Disease Research Laboratory (VDRL) Rapid Plasma Reagin (RPR) Toludine Red Unheated Serum Test (TRUST)
It may be identified by a reactive nontreponemal test followed by a non-reactive treponemal test. It is estimated that 1 to 2 percent in United States population False positive tests are particularly common during pregnancy. Some false positive nontreponemal test results are transitory and are related to an acute event, an acute febrile illness (eg, endocarditis, rickettsial disease) or recent immunization. Other include a variety of chronic conditions, autoimmune disorders (particularly systemic lupus erythematosus), intravenous drug use, chronic liver disease, and perhaps underlying HIV disease. These false positive test results tend to be of low titer.
Treponemal antibody tests Treponemal tests have historically been more complex and expensive to perform. As a group, these tests are based upon the detection of antibodies directed against specific treponemal cellular components antigens and thus tend to be more specific than non-treponemal tests. They have traditionally been used as confirmatory tests for syphilis when the nontreponemal tests are reactive. These tests correlate poorly with disease activity, since they remain positive despite treatment.
Specific treponemal tests include: Fluorescent treponemal antibody absorption (FTA-ABS) Microhemagglutination test for antibodies to T. pallidum (MHA-TP) T. pallidum particle agglutination assay (TP-PA) T. pallidum enzyme immunoassay (TP-EIA)
發生率: 男生:1/3600 女生:1/4000~6000 (準突變:1/250)
準突變型 智力正常但有輕微學習障礙、情緒問題 不孕症 X染色體脆折症運動失調症候群
全突變型 智能不足： 男性通常幼年就會有中、重度智能障礙； 女性較為輕微。 行為表現不同 過動、自閉、情緒問題、注意力不足、 言語問題等。
Fragile X syndrome is an Xlinked disorder and the most common inherited cause of intellectual disability. Both males and females can be affected. The fragile X mental retardation 1 gene (FMR1) is located on the X chromosome at Xq27.3 and most commonly has about 30 cytosine-guanineguanine (CGG) trinucleotide repeats; the normal range is about 5 to 44 CGG repeats.
Xq27.3
Fragile X syndrome is primarily caused by expansion in the number of CGG repeats within the FMR1 gene; deletions or point mutations within FMR1 account for only 1 percent of cases. Expansion of CGG repeats allows hypermethylation of FMR1, resulting in impaired transcription and reduced production of the fragile X mental retardation protein (FMRP), which adversely impacts prenatal and postnatal brain development.
As repeat size increases, stability decreases, and further increases in the number of repeats in the FMR1 region become likely. Intermediate expansion has been variably defined as ranging from about 45 to about 54 CGG repeats, a premutation is above this level but â&#x2030;¤200 CGG repeats, and full mutation is >200 CGG repeats. Expansion in the number of CGG repeats within the FMR1 gene occurs during oocyte meiosis, and may be as few as one repeat or over 100 repeats.
Matern al repeats
Percent of offspring with expansion to full mutation (>200 repeats)
55 to 59
4
60 to 69 5 70 to 79
31
80 to 89 58 90 to 99 80 100 to 200
Approximately 100
Criteria for offering fragile X screening or referral for diagnostic testing: Individuals seeking reproductive counseling who have a family history of fragile X syndrome (confirmed premutation or full mutation of FMR1 gene) or undiagnosed intellectual disability. Individuals of either sex with intellectual disability, developmental delay, or autism. Young women with elevated levels of follicle-stimulating hormone, especially with a family history of premature ovarian insufficiency (menopause before age 40), fragile X syndrome, or a relative of either sex with undiagnosed intellectual disability. Individuals with late-onset intention tremor or ataxia (usually after age 50), especially with a history of infertility, family history of movement disorders, fragile X, or undiagnosed intellectual disability.
Some authors suggest routinely offering fragile X carrier laboratory screening to all women, given the high test sensitivity (99 percent), the potential impact of the full mutation in offspring, and the relatively high premutation carrier rate (in one study, 1 in 154 for women with a negative family history of intellectual disability, developmental problems, or autism, and 1 in 128 women with a positive family history). This is not common practice due, in part, to the difficulty in predicting phenotype in offspring of lowrisk women (women with a negative personal and family history) with a premutation.
We suggest offering preconception or prenatal screening for fragile X syndrome to individuals at increased risk of carrying a premutation or full mutation, rather than universal screening ( Grade 2C ). Sample: Matenal Blood；CVS；Amniotic fluid；Umbilical cord blood Test: (1) Fluorescent polymerase chain reaction (PCR): identifies normal alleles and the small differences that distinguish intermediate expansions from premutations. (2) Southern Blot: analysis distinguishes large premutations from full mutations and, importantly, measures the degree of methylation.
Neuromuscular disorders that present in the newborn period with hypotonia and weakness are caused by a variety of conditions. SMA disorders are characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. These diseases are classified as types 1 through 4 depending upon the age of onset and clinical course. The different forms of 5q-SMA are caused by biallelic deletions or mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q13.2.
The most common mutation of the SMN1 gene is a deletion of exon 7. Approximately 94 percent of patients with clinically typical SMA carry homozygous deletions of exon 7. The level of SMN protein correlates with severity of disease. The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease-causing SMN1 mutations ranges from 1/90 to 1/50. The inheritance pattern of 5q-related SMAs is autosomal recessive.
Early detection of pregnancies at high risk for trisomy 21 (Down syndrome) is the primary target of prenatal aneuploidy screening since this syndrome is the most common autosomal trisomy among live births. RATIONALE FOR SCREENING The prevalence of the syndrome in live births is relatively high in the absence of screening (about 1/600 for Down syndrome and 1/4000 for trisomy 18). The burden of disease for the affected individual and his/her family can be significant. Diagnostic tests are readily available. Prenatal diagnosis gives parents options: an opportunity to plan for the birth of an affected child or pregnancy termination.
1994 Second Trimester Screening, Double Test 1996 NT scan st 1998 1 NT training course nd NT training course 2 2002 rd NT training course 3 2006
20062007
First Trimester Combined Test
2008 Second Trimester Quadruple Test
Maternal serum marker pattern in selected fetal syndromes Second trimester markers
First trimester markers
Genetic disorder
AFP
uE3
hCG
Down syndrome
↓
↓
↑
↑
↓
↑
↑↑
Trisomy 18
↓
↓↓
↓↓
↔
↓↓
↓↓
↑↑
Trisomy 13
↔
↔
↔
↔
↓↓
↓
↑
Turner syndrome with hydrops
↓
↓
↑
↑
↓↑
↓↑
↑
Turner syndrome without hydrops
↓
↓
↓
↓
↓↑
↓↑
↑
Triploidy (paternal)
↔
↓
↑
↑
↓↑
↑↑
↑
Triploidy (maternal)
↔
↓
↓
↓
↓↑
↓↓
↑
Smith-Lemli-Opitz syndrome
↓
↓↓
↓
NR
NR
NR
NR
Inh A PAPP-A beta hCG Nuchal translucency
Glossary of Down syndrome screening terms Nuchal translucency (NT) measurement The width of the translucent space at the back of the fetal neck determined by ultrasound. Combined test First trimester test based on sonographic and maternal serum measurements: NT, β-human chorionic gonadotropin (β-hCG: free or total), and pregnancy-associated plasma protein-A (PAPP-A), together with maternal age. Triple test Second trimester test based on measurement of maternal serum alphafetoprotein (AFP), unconjugated estriol (uE3), and β-hCG (free or total), together with maternal age.
Glossary of Down syndrome screening terms Quadruple test Second trimester test based on measurement of maternal serum AFP, uE3, β-hCG, and inhibin-A, together with maternal age. Integrated test (full) The integration of measurements performed during the first and second trimesters into a single test result. Typically, the integrated test refers to the integration of NT and PAPP-A measurements in the first trimester with the quadruple test markers in the second trimester, together with maternal age. Serum Integrated test A variation of the integrated test using maternal serum markers only: PAPP-A in the first trimester and the quadruple markers in the second trimester, together with maternal age.
Nuchal translucency is the hypoechoic region located between the skin and soft tissues behind the cervical spine. This hypoechoic space is presumed to represent mesenchymal edema and is often associated with distended jugular lymphatics. A small, but measurable, amount of nuchal fluid can be identified in virtually all fetuses between the 10th and 14th week of gestation. Increased nuchal translucency can be associated with a wide range of abnormalities or a normal fetus. The pathogenesis of nuchal edema is unknown, but probably multifactorial. It may involve fluid retention with hemodynamic disturbance, delayed or disturbed lymphangiogenesis, cardiac and vascular structural and functional abnormalities, and abnormal extracellular matrix components.
時間 一孕期母血唐氏 症篩檢 新二孕期血清四 指標唐氏症篩檢
檢測項目
篩檢率
8~13+6
• • •
PAPP-A Free beta-hCG NT
82~87%
15~20
• • • •
Free beta-hCG AFP uE3 Inhibin A
83%
56
Women who screen positive on a biochemical markerbased test may undergo secondary screening or a diagnostic procedure. Definitive diagnosis is provided by invasive testing (chorionic villus sampling [CVS], or amniocentesis). Biochemical marker screening tests should not be repeated. Repeat testing of the entire population would result in a small increase in detection rates but is not justified because of the expense and risk of false reassurance. Repeat biochemical marker testing limited to only screen-positive women can reduce the false positive rate, but a small percentage of affected pregnancies will incorrectly reclassified as screen-negative.
A screen-negative result means the fetus is at low risk of Down syndrome and trisomy 18 as defined by the specific laboratory cut-off (eg, <1 in 250). It does not exclude the possibility of Down syndrome or trisomy 18 or the possibility of a fetus with a chromosomal abnormality not targeted by the screening test but detectable with diagnostic testing. It is not appropriate to tell women with a screen-negative result that their test was "normal" or "negative" , as they may interpret these terms to mean the fetus definitely has a normal karyotype. The patientâ&#x20AC;&#x2122;s pre- and post-test risks of Down syndrome and trisomy 18 are provided in the report (eg, pre-test risk of Down syndrome: 1 in 290, post-test risk of Down syndrome: 1 in 1900).
1 in 20 women will receive a “positive” result: Vast majority will be “false positives” Referral to specialist, multiple office visits Prolonged uncertainty, worry Safety concerns with diagnostic testing
19 in 20 women will receive a â&#x20AC;&#x153;negativeâ&#x20AC;? result: But some of these women still have risk for trisomy (due to 80-95% detection rate)
非侵入性產前染色體篩檢 Non-Invasive Prenatal Screening (NIPS)
只要10 c.c.孕婦血液，分析 母血中胎兒游離DNA，檢測 胎兒唐氏症(T21)、愛德華氏 症(T18)、巴陶氏症(T13)等染 色體數目疾病。
敏感度專一性
95%
步驟簡單
時間
年
價格低廉
高解析度
縮短
提升
50%
高通量
時
MiSeq
Ion Torrent NextSeq500 HiSeq
Ion Proton
Dennis Yuk-ming Lo 盧煜明
Placenta. 2014 Feb;35 Suppl:S64-8. doi: 10.1016/j.placenta.2013.11.014. Epub 2013 Dec 1.
2014年，美國首份大規模臨床驗證（美 國21個醫學中心，1914個低風險族群孕 NIPT 非侵入性，不僅適合高風險族群使用，對低風險族群的檢 婦）所做的NIPS和傳統母血篩檢的比較 測效益，也證實明顯優於傳統篩檢。準媽媽有更好的選擇囉！
傳統唐氏症血清生化篩檢係指一孕期二 指標 (PAPP-A和 free β-hCG) 搭配頸部 透明帶 (NT) 檢測 懷孕週數10～14週的單胞胎孕婦，孕婦 年齡為18至48歲（平均30歲）
Aneuploidy Screening Using Noninvasive Prenatal Testing in Twin Pregnancies. Fosler L1, Winters P1, Jones KW 1, Curnow KJ1, Sehnert AJ1, Bhatt S1, Platt LD2,3. 1. Illumina, Redwood City, CA, USA. 2. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 3. Center for Fetal Medicine and Women's Ultrasound, Los Angeles, CA, USA. Ultrasound Obstet Gynecol. 2016 May
“…NIPT performed well for trisomy 21 in twin gestations with a combined trisomy 13, trisomy 18, and trisomy 21 false-positive frequency of 0% for clinical study A and 0.2% for clinical study B.”
Aneuploidy Screening Using Noninvasive Prenatal Testing in Twin Pregnancies. Fosler L1, Winters P1, Jones KW 1, Curnow KJ1, Sehnert AJ1, Bhatt S1, Platt LD2,3. 1. Illumina, Redwood City, CA, USA. 2. David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. 3. Center for Fetal Medicine and Women's Ultrasound, Los Angeles, CA, USA. Ultrasound Obstet Gynecol. 2016 May
年輕孕婦
雙胞胎孕婦
35歲以下孕婦 (n=11,994) 檢測率 偽陽性
100% (19 of 19)
0.05% (6 of 11,975)
*僅檢測13 18 21號染色體
1. Gil et al. Fetal Diagn Ther. 2014;35:204-11. 2. Bevilacqua et al. Ultrasound Obstet Gynecol. 2015 Jan;45(1):61-6. 3. Norton M, et al, N Engl J Med. 2015 Apr 23;372(17):1589-97.
人的身體中，只要任何一對染色體有問題， 都會有很大的影響，輕則發育遲緩、智能障 礙，重則在剛出生就夭折或流產。因此只看 染色體數目是不夠的… 染色體微片段缺失也是很常見的。染色體小 片段的缺失，造成寶寶有智能、生長發育的 問題；而且檢查時間較晚，都要等到16週後 才能用羊水穿刺檢查，對父母都是一個煎熬。
2013年，超過60個美國醫學中心篩選近 3000名孕婦，對期中高危險孕婦進行相 關分析，並透過羊水晶片進行後續分析。
The American Journal of Human Genetics 92, 167–176, February 7, 2013
非侵入性產前染色體篩檢可做之微片段缺失 疾病名稱 狄喬治氏症候群 DiGeorge Syndrome 1p36 缺失症候群 1p36 Deletion Syndrome 威廉氏症候群 Williams Syndrome 小胖威利症候群 Prader-Willi Syndrome 天使症候群 Angelman Syndrome 史密斯-馬吉利氏症候群 Smith-Magenis Syndrome Koolen-de Vries 症候群 Koolen-de Vries Syndrome 貓哭症 Cri-du-chat Syndrome 18q 缺失症候群 18q Deletion Syndrome 沃夫-賀許宏氏症候群 Wolf-Hirschhorn Syndrome 阿拉吉歐症候群 Alagille Syndrome
染色體異常
發生率
病徵
22q11
1/4,000
1p36.3
1/5,000~1/10,000
7q11.23
1/7,500~1/20,000
15q11-q13
1/10,000~1/30,000
15q11-q13
1/12,000~1/20,000
17p11.2
1/15,000
心智發育遲緩、行為異常等
17q21.31
1/16,000
心智發育遲緩、癲癇等
5p15
1/20,000~1/50,000
18q
1/40,000
心智發育遲緩、多重器官異常等
4p16.3
1/50,000
心智發育遲緩、先天性心臟病、癲 癇、多重器官異常等
20p11.23
1/70,000
先天性心臟病、多重器官異常等
心智發育遲緩、學習障礙、先天性 心臟病等 心智發育遲緩、先天性心臟病、癲 癇、多重器官異常等 心智發育遲緩、先天性心臟病、多 重器官異常等 心智發育遲緩、情緒問題、飲食問 題等 心智發育遲緩、情緒問題、語言障 礙、過動等
心智發育遲緩、語言障礙等
非侵入性產前染色體篩檢可做之微片段缺失 疾病名稱
染色體異常
發生率
病徵
Jacobsen 症候群 Jacobsen Syndrome
11q
1/100,000
心智發育遲緩、多重器官異常、 行動遲緩等
17p11.2-12
2~5/100,000
遺傳性壓力易感性神經病變 HNPP Rubinstein-Taybi 症候群 Rubinstein-Taybi Syndrome
16p13.3
運動神經失調
1/100,000~1/125,000 心智發育遲緩、情緒問題等。
WAGR 症候群 WAGR Syndrome
11p13
1/500,000~1/1,000,000
心智發育遲緩、多重器官異常 等
Potocki-Shaffer 症候群 Potocki-Shaffer Syndrome
11p11.2
罕發
心智發育遲緩等
Miller Dieker 症候群 Miller-Dieker Syndrome
17p13.3
罕發
心智發育遲緩、癲癇等
1q21.1 缺失症候群 1q21.1 Deletion Syndrome
1q21.1
罕發
先天性心臟病、凝血問題、骨 骼發育問題
Kleefstra 症候群 Kleefstra Syndrome
9q34.3
罕發
先天性心臟病、情緒問題、運 動失調等
Phelan-Mcdermid 症候群 Phelan-Mcdermid Syndrome
22q13
罕發
心智發育遲緩、情緒失調、癲 癇、語言障礙等
NIPS vs 傳統檢測 檢測項目 侵 入 性 檢 測
非 侵 入 性 檢 測
絨毛採樣
檢測時間 滿10週以 上
檢測率
優點
缺點
>99.5%
準確度高 檢查週數早
侵入式檢查，約 1/100-1/500流產率 採檢難度高
準確度高 雙胞胎可各別檢查
侵入式檢查，約 1/1000流產率 檢查週數較晚
羊膜穿刺檢查
16週以上
>99.5%
一孕期唐氏症 篩檢
11～13+6週
82-87%
二孕期唐氏症 篩檢
15～20週
81%
無超音波檢查 減少人為誤差
篩檢時間晚
>99%
檢查週數最早 安全性最高 雙胞胎可檢測 13、18、21號染色體皆可以 檢測 全染色體數目檢測、微片段 缺失可以檢測 (依廠商提供有 所差異)
價格較高
NIPS
10週以上
檢查週數早
操作技術門檻高
The primary source of fetal cfDNA in the maternal circulation is thought to be apoptosis of placental cells (syncytiotrophoblast), while maternal hematopoietic cells are the source of most maternal cfDNA. Apoptosis of fetal erythroblasts also generates cfDNA, which can cross the placenta and enter the maternal circulation. Since the fetus and the placenta originate from a single fertilized egg, they are usually genetically identical.
Fetal cfDNA can be isolated from maternal blood as early as five weeks of gestation and almost always by nine weeks of gestation. The relative concentration of fetal cfDNA increases modestly (0.1% per week) with gestational age until approximately 20 weeks, and then increases rapidly (1 % per week) until term.
An adequate amount of fetal cfDNA must be present to obtain a reliable test result. Four factors can systematically reduce the average fetal fraction, which can lead to an assay failure. A low fetal fraction may be due to: Early gestational age Suboptimal sample collection Obesity Fetal karyotype
The fetal fraction is substantially lower prior to 10 weeks, so most laboratories require that patients undergo screening at â&#x2030;Ľ10 weeks of gestation to ensure an adequate fetal fraction (ie, at least 4% of the total maternal cfDNA) for testing. Fetal cfDNA comprises approximately 13% of the total cfDNA in the maternal circulation in the late first and early second trimesters, when prenatal screening is typically performed. It may comprise as much as 50% of the total cfDNA in the maternal circulation near term.
Appropriate sample collection and DNA stabilization are important to preserve the fetal fraction, as a small number of degraded white blood cells from the mother's blood will greatly dilute the sample. To solve this problem, the sample should be collected in a standard purple top (EDTA) tube and centrifuged within six hours; the resulting plasma is stable with -80°C freezer storage. Alternatively, a special DNA collection tube (eg, Cell-Free DNA BCT) can be used that stabilizes the sample for up to five days at room temperature; these tubes should not be refrigerated or frozen until processed.
This inverse relationship has been attributed to the dilution of a relatively constant amount of fetal cfDNA in the larger maternal plasma volume of obese women and also to an increase in the concentration of maternallyderived cfDNA as maternal weight increases. Women weighing over 180 pounds (81 kg) can be informed that their chance of having a test failure or an inaccurate result is at least three or four times higher than in women of lower weight. If it is late in the pregnancy and the woman is high-risk, we suggest offering diagnostic testing rather than screening.
The average fetal fraction at 10 to 20 weeks of gestation is lower in pregnancies with a trisomy 18 fetus (average fetal fraction 9%) than pregnancies with a euploid fetus (average fetal fraction 13%) or pregnancies with a Down syndrome fetus (average fetal fraction 15%). This may partially explain why detection rates for Down syndrome are higher than for trisomy 18, especially when test failures are considered. There are less data for other abnormalities, but it appears that the fetal fraction in both trisomy 13 and Turner syndrome is also lower than in euploid fetuses. Triploid fetuses have extremely low fetal fractions
The most common method of cfDNA screening counts cfDNA fragments for which the chromosome of origin has been identified (aligned). Shotgun sequencing: cfDNA fragments are sequenced randomly. Targeted sequencing: use a preliminary step to enrich for fragments of interest (eg, chromosome 21, 18, 13, X, and Y)
Another method uses over 10,000 highly polymorphic single nucleotide polymorphisms (SNPs) on chromosomes of interest. Maternal white cell SNP genotypes are compared with the corresponding genotypes of the mixture of cfDNA from the mother and fetus in the plasma sample. An extra (or missing) chromosome in the plasma results in a shift in the pattern of informative SNPs.
Screening Performance
Disorder
Detection rate (%)
False-positive rate (%)
False-negative rate (%)
Down syndrome
98.6 %
1.01 %
1.4 %
Trisomy 18
94.9 %
0.14 %
5.1 %
Trisomy 13
91.3 %
0.14 %
8.7 %
Screening Performance DRs are lower and the failure rates are higher for sex chromosome abnormalities than for the autosomal aneuploidies. DR and FPR for the four commonly reported sex chromosome aneuploidies are: 45X (DR 90.3 %, FPR 0.23 %) and 47XXY, 47XYY, and 47XXX (DR 93.0 %, FPR 0.14 %) Test failure rates (ie, no result) for trisomy 21, 18, and 13 are at least 1 % and may be as high as 5 %. The failure rate for sex chromosome testing is higher: 4 to 7 %. Low fetal fraction appears to be the reason for most test failures.
Screening Performance False-positive tests may be due to: confined placental mosaicism demised twin maternal mosaicism maternal cancer maternal copy number variants technical issues chance
False-negative tests may be due to: confined placental mosaicism, borderline low fetal fraction, maternal copy number variants, technical issues.
Some laboratories offer cfDNA screening in twin pregnancies and may use methods that are "blind" to the number of fetuses. Based on preliminary data, test performance will be very good but probably not at the level reported for singleton pregnancies. One methodology using single nucleotide polymorphisms can identify dizygotic twins but cannot provide an interpretation. This may be seen as a disadvantage, but such a test can also identify a vanished twin in the same way, which may have clinical advantages.
Screen-positive Even with the high performance of cfDNA screening, invasive diagnostic testing should be offered to confirm screen-positive test results. There is some controversy about whether an early gestation cfDNA positive screen should be confirmed by chorionic villus sampling or postponed until â&#x2030;Ľ15 weeks when amniocentesis can be performed, as analysis of amniocytes is more definitive and representative of the fetal genotype than analysis of placental cells. For disorders where definitive diagnosis will not affect continuation of pregnancy or pregnancy management, the parental choice to delay diagnostic testing until after delivery, or even later, is also reasonable.
Screen-negative A screen-negative result means the fetus is at a reduced risk of having one of the aneuploidies in the test panel, but does not eliminate the possibility of an affected fetus or the possibility of a fetus with a chromosomal abnormality not targeted by the screening test but detectable with diagnostic testing. Screen-negative women are not offered invasive diagnostic testing.
No result As discussed above, 1 to 5 percent of tests do not yield a result, and obese women are at increased risk. The patient has three options in this setting: Repeat the cfDNA test. Repeat testing is successful in 50 to 80 percent of cases. Standard serum marker/ultrasound screening. Invasive diagnostic procedure (amniocentesis, CVS)
Testing for cell-free DNA in maternal blood is another method for screening for Down syndrome. Maternal plasma cell-free DNA screening programs can detect more than 99 percent of pregnancies affected by Down syndrome with a screen-positive rate of <0.2 percent. One to 5 percent (or more) of samples fail to produce an interpretation, even after repeat testing. If cost is not an issue, we recommend cell-free DNA screening rather than biochemical marker-based screening for Down syndrome (Grade 1B). Cell-free DNA screening has higher sensitivity for detection of Down syndrome and a lower false positive rate, which leads to more cases detected with far fewer invasive procedures.
Cell-free DNA screening can be used as a primary screening test in the following high risk groups: Maternal plasma cell-free DNA testing is a screening test not a diagnostic test. Maternal age 35 years or older at delivery Fetal ultrasound finding of a soft marker associated with an increased risk of aneuploidy for trisomies 13, 18, or 21. (Diagnostic testing is recommended if a structural abnormality is identified) History of prior pregnancy with a trisomy detectable by cell-free DNA screening (trisomies 13, 18, or 21) Parental balanced Robertsonian translocation with increased risk of fetal trisomy 13 or 21 Cell-free DNA screening can be used as a secondary screening test in women who are at high risk because of: Screen-positive biochemicalbased test for Down syndrome
In the first trimester, a conventional karyotype is obtained by chorionic villus sampling (CVS). Preliminary results can be obtained within two days if a direct preparation is performed; final results from cultured cells take 7 to 10 days.
In the second trimester, amniocentesis is performed to obtain fetal cells for chromosomal analysis. A rapid targeted screening result may be available within two days, but complete karyotype results from cultured cells take about 8 to 14 days.
Chromosomal microarray (CMA) CMA is an array-based molecular cytogenic technique that can overcome some limitations of a karyotype, and is particularly useful for its ability to detect submicroscopic gains and losses on every chromosome
Prenatal CMA provides most of the information derived from conventional G-banded chromosome analysis (ie, presence/absence of aneuploidy, unbalanced structural changes), and also detects submicroscopic deletions and duplications (ie, copy number variants). Prenatal CMA is performed on DNA from uncultured amniocytes (amniotic fluid), chorionic villus cells, or cord blood. CMA is not able to be performed on cell-free DNA in maternal blood during noninvasive prenatal testing because there is no amplification step so the signal from the fetus would be "drowned out" by the maternal DNA.
Benefits • Higher diagnostic yield −CMA over conventional Gbanding in the prenatal setting include higher diagnostic yield • No requirement for cell culture • Faster turnaround time
Limitations/disadvantages • Inability to detect balanced structural rearrangements −However, these represent a smaller number of cases as compared to those with genomic imbalance. • Inability to detect all cases of uniparental disomy • Detection of variants of uncertain significance (1-2%) −Counseling patients with these findings can be difficult • Expense (relatively expensive)
The benefit of such prenatal sonographic screening on neonatal outcomes remains unproven. In the second trimester, fetal anomaly detection rates range from 16 to 44 percent, with detection rates up to 84 percent for lethal anomalies. Ultrasound examination also improves the detection of fetal growth disturbances and abnormalities in amniotic fluid volume; however, a beneficial impact on pregnancy outcome has not been proven. Factors affecting detection rates â&#x2013;Ş Gestational age at examination, type of malformation, number of ultrasounds performed, operator experience, quality of equipment, population characteristics
Better estimate of gestational age/delivery date Determination of the expected date of delivery (EDD) is essential in obstetrics so that misdiagnosis (and inappropriate intervention) of previable, preterm, and postterm pregnancy can be avoided. Ample evidence has accumulated that routine ultrasound examination results in more accurate assessment of the EDD than last menstrual period (LMP) dating or physical examination
Reduction in intervention for postterm pregnancy Before the 24th week of pregnancy, routine use of early ultrasound and the subsequent adjustment of the EDD led to a significant reduction in induction of labor for postterm pregnancy (RR 0.59, 95% CI 0.42-0.83). First trimester ultrasound examination in a low-risk population was more effective than second trimester ultrasound examination in decreasing postterm pregnancy.
Better detection of aneuploidy Routine ultrasound estimation of gestational age may reduce the number of women who have anxiety caused by false positive results in serum screening.
Better identification of multiple gestation Women who did not have a routine second trimester ultrasound examination had 38 percent of twin pregnancies unrecognized until after 26 weeks of gestation and 13 percent of twins were not diagnosed until delivery. There were no twin pregnancies missed on ultrasound examination. Improved neonatal outcomes with early diagnosis of twin pregnancy
Better detection of congenital anomalies Routine ultrasound before the 24th week of pregnancy described above, performance of routine/revealed early pregnancy ultrasound significantly increased detection of fetal abnormalities before 24 weeks of gestation (RR 3.46, 95% CI 1.67-7.14; 2 trials, 387 patients)
Prevention of preterm birth No sufficient evidence to recommend routine cervical length screening of all pregnant women Better diagnosis of deficient growth and improvement in perinatal outcome Assessment of placental position, fetal presentation, amniotic fluid volume, macrosomia The American College of Obstetricians and Gynecologists Aneuploidy screening examinations can be performed in the first and/or second trimester. A fetal structure screening examination is typically performed in the second trimester. If a single screening examination is performed, the optimal time is at 18 to 20 weeks of gestation.
In women with a singleton gestation and no prior preterm birth, the sensitivity of short cervix for subsequent preterm birth is approximately 35 to 45 percent, and the positive predictive value is approximately 20 to 30 percent, which means that the majority of women with a short cervical length will deliver at â&#x2030;Ľ35 weeks. In women with a prior preterm birth, sensitivity increases to 70 percent and is highest in women with early and/or repeated preterm births. Women carrying twins are approximately twice as likely to have a short cervix at 24 to 28 weeks of gestation as women carrying singletons; 40 to 50 percent of twin pregnancies with cervical length â&#x2030;¤25 mm at 24 to 28 weeks deliver at <35 weeks of gestation.
Gestational diabetes mellitus (GDM) is a condition in women who have carbohydrate intolerance with onset or recognition during pregnancy. It has been estimated that up to 6â&#x20AC;&#x201C;7% of pregnancies are complicated by diabetes mellitus (DM). Women with GDM are at higher risk of gestational hypertension, preeclampsia, and cesarean delivery and its associated potential morbidities. Women with GDM have an increased risk of developing diabetes later in life (50 %, 22â&#x20AC;&#x201C;28 years ). The offspring of women with GDM are at increased risk of macrosomia, neonatal hypoglycemia, hyperbilirubinemia, operative delivery, shoulder dystocia, and birth trauma. A continuous relationship between maternal glucose levels and cesarean delivery, birth weight greater than the 90th percentile, clinical neonatal hypoglycemia, and fetal hyperinsulinemia.
Universal screening is better than risk factor based ,improving early diagnosis and pregnancy outcome All pregnant patients should be screened for GDM. Screening is generally performed at 24â&#x20AC;&#x201C;28 weeks of gestation. First screening with the administration of 50 g of an oral glucose solution followed by a 1-hour venous glucose determination. Screening thresholds for the 1-hour glucose challenge have varied from 130 mg/dL to 140 mg/dL, with varying sensitivities and specificities reported. There are no randomized trials to support a clear benefit to one cutoff compared with others.
100g 3 hrs OGTT
The criteria from Carpenter and Coustan is lower than the NDDG criteria. It resulted in a higher prevalence of GDM 4 % 7 %. Women diagnosed with GDM by the C&C only (not by NDDG) have higher risk of operative delivery, macrosomia and shoulder dystocia. So Carpenter and Coustan criteria were recommended for interpretation of the 100g OGTT.
A one-step approach to establishing the diagnosis of GDM using a 75-g , 2-hour OGTT. An odds ratio of 1.75 (compared with the population mean) for various adverse outcomes was used to define blood glucose thresholds for diagnosis of GDM. Single threshold value on the 75-g, 2-hour OGTT was met or exceeded (fasting value, 92 mg/dL; 1-hour value, 180 mg/dL ; and 2-hour value , 153 mg/dL). Approximately 18% of the U.S. population as having GDM.
Group B Streptococcus (GBS or Streptococcus agalactiae) is an encapsulated gram-positive coccus that colonizes the gastrointestinal and genital tracts of 15 to 40 percent of pregnant women. Although GBS colonization usually remains asymptomatic in these women, maternal colonization is the critical determinant of infection in neonates and young infants (less than 90 days of age), in whom GBS is the most common cause of bacterial infection. Vertical (mother-to-child) transmission primarily occurs when GBS ascends from the vagina to the amniotic fluid after onset of labor or rupture of membranes, but can occur with intact membranes. In the mid-1980s, randomized and controlled clinical trials demonstrated that intrapartum administration of intravenous penicillin or ampicillin to GBS carriers protected their newborns from developing early-onset disease (ie, GBS infection at 0 to 6 days of age).
The CDC recommends GBS rectovaginal screening cultures for all pregnant women at 35 to 37 weeks of gestation, with the following two exceptions: (1) women with GBS bacteriuria (â&#x2030;Ľ104 colonies in pure culture or mixed with a second microorganism) during the current pregnancy and (2) women who previously gave birth to an infant with invasive GBS disease. Cultures are performed near term because many women have transient or intermittent disease, thus GBS colonization status in early pregnancy may not be predictive of status late in pregnancy. Cultures are performed at 35 to 37 weeks of gestation because the results will be available before most women go into labor and are reasonably predictive of GBS status for about five weeks. The negative predictive value of GBS cultures performed â&#x2030;¤5 weeks before delivery is 95 to 98 percent, but declines after five weeks.