Obstentrics_Williams

Obstentrics_Williams. In one series of more than 2000 procedures comparing fetal blood sampling near the placental cord insertion site with puncture of a free loop, rates of procedure success, pregnancy loss, visible bleeding from the cord, and fetal bradycardia did not difer. Time to complete the procedure was signiicantly shorter if the cord was sampled at the placental insertion site than in a free 100p-5 versus 7 minutes. However, sampling at the insertion site had a higher rate of maternal blood contamination (T angshewinsirikul, 2011).


Obstentrics_Williams

Obstentrics_Williams. For couples undergoing in vitro fertilization (IVF), genetic testing performed on oocytes or embryos before implantation may provide valuable information regarding the chromosomal complement and single-gene disorders. There are two separate categories of testing-preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)-each with diferent indications. Comprehensive genetic counseling is required before consideration of these procedures. There are three techniques that are used for both categories: 1.


Obstentrics_Williams

Obstentrics_Williams. Polar body anaysis is a technique used to infer whether a developing oocyte is afected by a maternally inherited genetic disorder. The irst and second polar bodies are normally extruded from the developing oocyte following meiosis I and II, and their sampling should not afect fetal development. However, two separate micromanipulation procedures are required, and genetic abnormalities of paternal origin are not detected. his technique has been used to diagnose 146 mendelian disorders, and the reported accuracy exceeds 99 percent (Kuliev, 2011). 2.


Obstentrics_Williams

Obstentrics_Williams. 2. Blastomere biopsy is done at the 6-to 8-cell (cleavage) stage when an embryo is 3 days old. his allows both maternal and paternal genomes to be evaluated. One cell is typically removed through a hole made in the zona pellucida (Fig. 14-8). A limitation of using this technique for aneuploidy assessment is that because of mitotic nondisjunction, mosaicism of the blastomeres may not reflect the chromosomal complement of the developing embryo (American Society for Reproductive Medicine, 2008). In addition, the implantation rate of normal embryos is slightly lower following this technique.


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Obstentrics_Williams. FIGURE 14-8 Blastomere biopsy. After a blastomere is selected, it is then drawn into the pipette. (Reproduced with permission from Doody J: Treatment of the infertile couple. Hoffman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGraw-Hili Education, 2016.) 3. Trophectoderm biopsy involves removal of 5 to 7 cells from a 5-to 6-day blastocyst. An advantage is that because the trophectoderm cells give rise to the trophoblast-the placenta-no cells are removed from the developing embryo. Disadvantageously, because the procedure is performed later in development, if genetic analysis cannot be performed rapidly, then cryopreservation and embryo transfer during a later IVF cycle may be required.


Obstentrics_Williams

Obstentrics_Williams. A genetic abnormality-rather than infertility-may be a reason for a couple to elect IVF. With a known carrier(s) of a speciic genetic disease or a balanced chromosomal rearrangement, PGD may be performed to determine if an oocyte or embryo has the defect. Only embryos without the abnormality would be implanted. This procedure has numerous applications. It is used to diagnose single-gene disorders such as cystic fibrosis, 3-thalassemia, and hemophilia; to determine gender in X-linked diseases; to identiy mutations such as BRA-J that do not cause disease but confer signiicantly greater later cancer risk; and to match human leukocyte antigens for umbilical cord stem cell transplantation for a sibling (de Wert, 2007; Fragouli, 2007; Grewal, 2004; Rund, 2005; Xu, 2004).


Obstentrics_Williams

Obstentrics_Williams. Because typically only one or two cells are available for analysis and because rapid completion time is essential, this procedure is technically challenging. Risks include failure to ampliy the genetic region of interest, selection of a cell that does not contain a nucleus, and maternal cell contamination. Infrequently, afected embryos thought to be normal are implanted, and unaffected embryos are misdiagnosed as abnormal and discarded. Because of this, the American Society for Reproductive Medicine (2008) encourages urther prenatal diagnostic testing-either CVS or amniocentesis-to conirm PGD results. This term is used for aneuploidy screening that is performed on oocytes or embryos before IVF transfer. Such screening is used with couples who are not known to have or carry a genetic abnormality. Although PGS has obvious theoretical advantages, it has faced challenges in practice.


Obstentrics_Williams

Obstentrics_Williams. Mosaicism is common in cleavage-stage embryo blastomeres. However, it may not be clinically signiicant because it often does not relect the actual embryonic chromosomal complement. In addition, among women 35 years or older, pregnancy rates following PGS with FISH are significantly lower than rates observed following IVF without PGS (Mastenbroek, 2007,2011). Because the number of chromosome pairs per cell nucleus that can be evaluated with FISH is limited, more recent eforts have focused on the use of chromosomal comprehensive screening with CMA (Dahdouh, 2015). Agathokleous M, Chaveeva P, Poon LC, et al: Meta-analysis of second-trimester markers for trisomy 2l. Ultrasound Obstet GynecoIo41(3):247, 2013 Akolekar R, Beta J, Picciarelli G, et al: Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet GynecoIo45(1):16, 2015


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Obstentrics_Williams. American College of Medical Genetics: Technical standards and guidelines for CFTR mutation testing, 2006. Available at: https:!lwww.acmg.net/Pagesl ACMG_Activitieslstds-2002/cf.htm. Accessed December 30, 20o16 American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 2015 American College of Obstetricians and Gynecologists: Neural tube defects. Practice Bulletin No. 44, July 2003, Reairmed 2016a American College of Obstetricians and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b American College of Obstetricians and Gynecologists: Screening for fetal aneuploidy. Practice Bulletin No. 163, May 2016c American College of Obstetricians and Gynecologists: Carrier screening in the age of genomic medicine. Committee Opinion No. 690, March 2017a


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Obstentrics_Williams. American College of Obstetricians and Gynecologists: Carrier screening in the age of genomic medicine. Committee Opinion No. 690, March 2017a American College of Obstetricians and Gynecologists: Carrier screening for genetic conditions. Committee Opinion No. 691, March American College of Obstetricians and Gynecologists: Cell-free DNA screening for fetal aneuploidy. Committee Opinion No. 640, September 2015, Reairmed 20o17 c American Society for Reproductive Medicine: Preimplantation genetic testing: a Practice Committee Opinion. Fertil Steril 90: S 136, 2008


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Obstentrics_Williams. Ashoor G, Syngelaki A, Poon LC, et al: Fetal fraction in maternal plasma cellfree fetal DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 41 (1) :26, 2013 Baer RJ, Fiesselle, Jellife-Pawlowski LL, et al: Detection rates for aneuploidy by irst-trimester and sequential screening. Obstet GynecoIo126(4):753, 2015 Bafero GM, Somigliana E, Crovetto F, et al: Confined placental mosaicism at chorionic villus sampling: risk factors and pregnancy outcome. Prenat Diagn 32(1o1):1o102,o2012 Benacerraf BR, Barss VA, Laboda A: A sonographic sign for the detection in the second trimester of the fetus with Down syndrome. Am J Obstet GynecoIo151(8):1078,o1985 BenacerrafBR, Gelman R, Frigoletto FD: Sonographic identification of secondtrimester fetuses with Down's syndrome. N EnglJ Med 317(22):1371,o1987 Benn PA, Leo MV, Rodis JF, et al: Maternal serum screening for fetal trisomy 18: a comparison of fixed cutof and patient-specific risk protocols.


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Obstentrics_Williams. with Down's syndrome. N EnglJ Med 317(22):1371,o1987 Benn PA, Leo MV, Rodis JF, et al: Maternal serum screening for fetal trisomy 18: a comparison of fixed cutof and patient-specific risk protocols. Obstet Gynecolo93 (5 Pt 1):707, 1999


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Obstentrics_Williams. Best E, Tennant PW, Addor Me, et al: Epidemiology of small intestinal atresia in Europe: a register-based study. Arch Dis Child Fetal Neonatal Ed 97(5):F353, 2012 Bianchi DW, Chudova 0, Sehnert AJ, et al: Noninvasive prenatal testing and incidental detection of occult malignancies. JAMA 314(2): 162, 2015 Bombard AT, Powers JF, Carter S, et al: Procedure-related fetal losses in transplacental versus nontransplacental genetic amniocentesis. Am J Obstet Gynecol 172(3):868, 1995 Borgida AF, Mills A, Feldman OM, et al: Outcome of pregnancies complicated by ruptured membranes after genetic amniocentesis. Am J Obstet GynecoIo183(4):937,o2000 Boupaijit K, Wanapirak C, Piyamongkol W, et al: Efect of placental penetration during cordocentesis at mid-pregnancy on fetal outcomes. Prenat Diagn 32(1):83, 2012


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Obstentrics_Williams. Brock OJ, Bolton E,Monaghan JM: Prenatal diagnosis of anencephaly through maternal serum-alpha-fetoprotein measurement. Lancet 2(7835):923, 1973 Brock OJ, Sutclife RG: Alpha-fetoprotein in the antenatal diagnosis of anencephaly and spina bifida. Lancet 2(7770):197, 1972 Bromley B, Lieberman E, Shipp TO, et al: he genetic sonogram, a method for risk assessment for Down syndrome in the mid trimester. J Ultrasound Med 21(10):1087,o2002 Bush MC, Malone FD: Down syndrome screening in twins. Clin Perinatol 32(2):373, 2005 Cahill AG, Macones GA, Stamilio OM, et al: Pregnancy loss rate after mid-trimester amniocentesis in twin pregnancies. Am J Obstet Gynecol 200(3):257.e1,o2009 Callaway JL, Shafer LG, Chitty LS, et al: he clinical utility of micro array technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn 33(12): 1119,o2013 Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT) Group:


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Obstentrics_Williams. Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT) Group: Randomised trial to assess safety and fetal outcome of early and mid trimester amniocentesis. Lancet 351(9098):242, 1998 Canfield MA, Honein MA, Yuskiv N, et al: National estimates and racelethnicspecific variation of selected birth defects in the United States, 1999-200l. Birth Defects Res A Clin Mol Teratol 76(1o1):747, 2006 Caughey AB, Hopkins LM, Norton ME: Chorionic villus sampling compared with amniocentesis and the diference in the rate of pregnancy loss. Obstet Gynecolo108(3):612,o2006 Centers for Disease Control and Prevention: Natality trends in the United States, 1909-2013. 2015. Available at: https:llblogs.cdc.gov/nchs-datavisualization/us-natality-trends.l Accessed December 15,o2016


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Obstentrics_Williams. Cignini P, Maggio Savasta L, Gulino FA, et al: Predictive value of pregnancyassociated plasma protein-A (PAPP-A) and free beta-hCG on fetal growth restriction: results of a prospective study. Arch Gynecol Obstet 293(6): 122 , 20o16 Cleary-Goldman J, D'Alton ME, Berkowitz RL: Prenatal diagnosis and multiple pregnancy. Semin Perinatol 29(5):312, 2005 Colvin J, Bower C, Dickinson JE, et l: Outcomes of congenital diaphragmatic hernia: a population-based study in (lestern Australia. Pediatrics 116(3):e356,o2005 Comstock CH, Malone FD, Robert H, et al: Is there a nuchal translucency millimeter measurement above which there is no added beneit from irst trimester screening? Am J Obstet Gynecol 195(3):843, 2006 Cowett MR, Hakanson DO, Kocon RW, et al: Untoward neonatal efect of intraamniotic administration of methylene blue. Obstet Gynecol 48(1 Suppl):74S, 1976


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Obstentrics_Williams. Cowett MR, Hakanson DO, Kocon RW, et al: Untoward neonatal efect of intraamniotic administration of methylene blue. Obstet Gynecol 48(1 Suppl):74S, 1976 Cragan JD, Gilboa SM: Including prenatal diagnoses in birth defects monitoring: experience of the Metropolitan Atlanta Congenital Defects Program. Birth Defects Res A Clin Mol Teratol 85(1):20, 2009 Cuckle H: Biochemical screening for Down syndrome. Eur J Obstet Gynecol Reprod Bioi 92(1):97, 2000 Cuckle H, Wald N, Stevenson JD, et al: Maternal serum alpha-fetoprotein screening for open neural tube defects in twin pregnancies. Prenat Diagn 10(2):71, 1990 Cuckle HS, Malone FD, Wright 0, et al: Contingent screening for Down syndrome-results from the FaSTER trial. Prenat Diagn 28(2):89, 2008 Curnow KJ, Wilkins-Haug L, Ryan A, et al: Detection of triploid, molar, and vanishing twin pregnancies by single-nucleotide polymorphism-based noninvasive prenatal test. Am J Obstet GynecoIo212(1):79.e1, 2015


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Obstentrics_Williams. Dashe JS, Twickler OM, Santos-Ramos R, et al: Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound. Am J Obstet GynecoIo195(6):1623,o2006 Davies SC, Cronin E, Gill M, et al: Screening for sickle cell disease and thalassemia: a systematic review with supplementary research. Heath Technol Assess 4(3):1,o2000 Davis e, Cuckle H, Yaron Y: Screening for Down syndrome-incidental diagnosis of other aneuploidies. Prenat Diagn 34(1o1): 1044, 2014 de Wert G, Liebaers I, Van De Velde H: The future (r)evolution of preimplantation genetic diagnosis/human leukocyte antigen testing: ethical reflections. Stem Cells 25(9):2167,o2007 de Wit Me, Srebniak MI, Govaerts LC, et al: Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyorype: a systematic review of the literature. Ultrasound Obstet GynecoIo43(2):139, 2014


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Obstentrics_Williams. DiMaio MS, Baumgarten A, Greenstein RM, et al: Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N Engl J Med 317(6):342,o1987 Dolk H, Loane M, Garne E: The prevalence of congenital anomalies in Europe. Adv Exp Med Bioi 686:349, 2010 Doody KJ: Treatment of the infertile couple. Hofman BL, Schorge JO, Bradshaw KD, et al (eds): Williams Gynecology, 3rd ed. New York, McGrawHill Education, 20o16 Drumm ML, Konstan MW, Schluchter MD, et al: Genetic modiiers of lung disease in cystic ibrosis. N Engl J Med 353(14):1443, 2005 Dugof L, Hobbins JC, Malone FD, et al: First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropic concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (The FaSTER Trial). Am J Obstet Gynecol 191(6):1446, 2004


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Obstentrics_Williams. DugofL, Hobbins JC, Malone FD, et al: Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 106(2):260, 2005 Dugof L, Sociery for Maternal-Fetal Medicine: First-and second-trimester maternal serum markers for aneuploidy and adverse pregnancy outcomes. Obstet GynecoIo115(5):1052, 2010 Ecker JL, Shipp TD, Bromley B, et al: The sonographic diagnosis of DandyWalker and Dandy-Walker variant: associated indings and outcomes. Prenat Diagn 20(3):328, 2000 Evans MI, Wapner RJ: Invasive prenatal diagnostic procedures. Semin PerinatoIo29(4):215,o2005 Filly A, Callen PW, Goldstein RB: Alpha-fetoprotein screening programs: what every obstetric sonologist should know. Radiology 188(1):1, 1993 Firth HV, Boyd PA, Chamberlain PF, et al: Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet 343(8905): 1069, 1994


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Obstentrics_Williams. Firth HV, Boyd PA, Chamberlain PF, et al: Analysis of limb reduction defects in babies exposed to chorionic villus sampling. Lancet 343(8905): 1069, 1994 Firth HV, Boyd PA, Chamberlain P, et al: Severe limb abnormalities after chorion villus sampling at 56-66 days' gestation. Lancet 337(8744):762, 1991 Flessel MC, Lorey FW: The California Prenatal Screening Program: "options and choices" not "coercion and eugenics." Genet Med 13(8): 11,o201o1 Fragouli E: Preimplantation genetic diagnosis: present and future. J Assist Reprod Genet 24(6):201,o200 Gallot 0, Boda C, Ughetto S, et al: Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol 29(3):276, 2007 Ghidini A, Sepulveda W, Lockwood CJ, et l: Complications of fetal blood sampling. Am J Obstet GynecoIo168(5):1339, 1993


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Obstentrics_Williams. Ghidini A, Sepulveda W, Lockwood CJ, et l: Complications of fetal blood sampling. Am J Obstet GynecoIo168(5):1339, 1993 Gil MM, Quezada MS, Revello R, et al: Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet GynecoIo45(3):249, 2015 Goetzl L, Krantz 0, Simpson JL, et al: Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss. Obstet Gynecol 104(1):30,o2004 Grati FR, Malvestiti F, Ferreira JC, et al: Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 16(8):620,o2014 Greene MF, Haddow JE, Palomaki GE, et al: Maternal serum alpha-fetoprotein levels in diabetic pregnancies. Lancet 2(8606):345, 1988


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Obstentrics_Williams. Reddy UM, Abuhamad Z, Levine D, et al: Fetal imaging: Executive summary of a joint Eunice Kennedy Shriver National Institute for Child Health and Human Development, Society for laternal-FetaloIedicine, American Institute for Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. Obstet GynecoIo123(5):1070, 2014


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Obstentrics_Williams. Reddy UM, Mennuti MT: Incorporating irst-trimester Down syndrome studies into prenatal screening: executive summary of the National Institute of Child Health and Human Development workshop. Obstet Gynecol 107(1):167,o2006 Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185, 20o12 Reichler A, Hume F Jr, Drugan A, et al: Risk of anomalies as a function of level of elevated maternal serum a-fetoprotein. Am J Obstet Gynecol 1 1(4):1052, 1994 Rund D, Rachmilewitz E: Beta-thalassemia. N Engl J Med 353(11): 1135, 2005 Sharma R, Stone S, Alzouebi A, et al: Perinatal outcome of prenatally diagnosed congenital talipes equinovarus. Prenat Diagn 31(2):142, 2011 Shulman LP, Elias S, Phillips OP, et al: Amniocentesis performed at 14 weeks' gestation or earlier: comparison with irst-trimester transabdominal chorionic villus sampling. Obstet Gynecol 83(4):543, 1994


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Obstentrics_Williams. Silver RK, MacGregor SN, Sholl JS, et al: An evaluation of the chorionic villus sampling learning curve. Am J Obstet Gynecol 163(3):917, 1990 Simpson LL, Malone FD, Bianchi DW, et al: Nuchal translucency and the risk of congenital heart disease. Obstet Gynecol 109(2 Pt 1):376,o2007 Smith-Bindman R, Hosmer W, Feldstein VA, et al: Second-trimester ultrasound to detect fetuses with Down syndrome. A meta-analysis. JAMA 285(8):1044,o2001 Society for Maternal-Fetal Medicine: Prenatal aneuploidy screening using cell-free DNA. SMFM Consult No. 36. Am J Obstet GynecoI212(6):711, 2015 Society for Maternal-Fetal Medicine, Berry SM, Stone J, et al: Fetal blood sampling. Am J Obstet GynecoI209(3):170, 2013 Solomon BD, Rosenbaum KN, Meck JM, et al: Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet 154C(1):146,o2010


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Obstentrics_Williams. Solomon BD, Rosenbaum KN, Meck JM, et al: Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet 154C(1):146,o2010 Stevenson DA, Carey JC: Contribution of malformations and genetic disorders to mortality in a children's hospital. Am J Med Genet (Part A) 126(4):393, 2004 Sundberg K, Bang J, Smidt-Jensen S, et al: Randomised study of risk offetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 350(9079):697, 1997 Tangshewinsirikul C, Wanapirak C, Piyamongkol W, et al: Efect of cord puncture site on cordocentesis at mid-pregnancy on pregnancy outcome. Prenat Diagn 31(9):861, 2011


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Obstentrics_Williams. Tangshewinsirikul C, Wanapirak C, Piyamongkol W, et al: Efect of cord puncture site on cordocentesis at mid-pregnancy on pregnancy outcome. Prenat Diagn 31(9):861, 2011 Tongsong T, Wanapirak C, Kunavikatikul C, et al: Fetal loss rate associated with cordocentesis at midgestation. Am J Obstet Gynecol 184(4):719, 2001 van der Pol JG, Wolf H, Boer K, et al: Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins. BJOG 99(2): 141, 1992 Vink J, Wapner R, D'Alton ME: Prenatal diagnosis in twin gestations. Semin PerinatoIo36(3):169,o2012 Vintzileos AJ, Egan JF: Adjusting the risk for trisomy 21 on the basis of secondtrimester ultrasonography. Am J Obstet Gynecol 172(3):837, 1995 Wald NJ, Cuckle H, Brock JH, et al: Maternal serum-alpha-fetopro.tein measurement in antenatal screening for anencephaly and spina biida in early pregnancy. Report of UK Collaborative Study on alpha-fetoprotein in relation to neural-tube defects. Lancet 1 (8026): 1323, 1977


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Obstentrics_Williams. Wald NJ, Densem JW, George L, et al: Prenatal screening for Down's syndrome using inhibin-A as a serum marker. Prenat Diagn 16(2): 143, 1996 Wald NJ, Rodeck C, Hackshaw AK, et al: First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Technol Assess 7(11):1, 2003 Walker SJ, Ball RH, Babcook q, et al: Prevalence of aneuploidy and additional anatomic abnormalities in fetuses and neonates with cleft lip with or without cleft palate. A population-based study in Utah. J Ultrasound Med 20(1o1):1o175,o2001 Wang Y, Chen Y, Tian F, et al: Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with non-invasive prenatal testing. Clin Chen 60(1):251, 2014 Wapner R, Thon E, Simpson JL, et al: First-trimester screening for trisomies 21 and 18. N Engl J Med 349(15):1471,o2003


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Obstentrics_Williams. Wapner R, Thon E, Simpson JL, et al: First-trimester screening for trisomies 21 and 18. N Engl J Med 349(15):1471,o2003 Warsof SL, Larion S, Abuhamad Z: Overview of the impact of noninvasive prenatal testing on diagnostic procedures. Prenat Diagn 35(10):972, 2015


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Obstentrics_Williams. Warsof SL, Larion S, Abuhamad Z: Overview of the impact of noninvasive prenatal testing on diagnostic procedures. Prenat Diagn 35(10):972, 2015 Wellesley D, Dolk H, Boyd PA, et al: Rare chromosome abnormalities, prevaWou K, Hyun Y, Chitayat D, et al: Analysis of tissue from products of conception lence and prenatal diagnosis rates from population-based congenital anomand perinatal losses using F-PCR and microarray: a three-year retrospective aly registers in Europe. Eur J Hum Genet 20(5):521,o2012 study resulting in an eicient protocol. Eur J Med Genet 59(8):417,o2016 Wenstrom KD, Weiner CP, Williamson A, et al: Prenatal diagnosis of fetal Xu K, Rosenwaks Z, Beaverson K, et al: Preimplantation genetic diagnosis for hyperthyroidism using funipuncture. Obstet Gynecol 76(3 Pt 2):513, retinoblastoma: the irst reported liveborn. Am J OphthalmoIo137(1): 18,o2004 1990 Zhang H, Gao Y, Jiang F, et al: Non-invasive prenatal testing for trisomies


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Obstentrics_Williams. Wijnberger LD, van der Schouw T, Christiaens GC: Learning in medicine: 21, 18, and 13: clinical experience from 146,958 pregnancies. Ultrasound chorionic villus sampling. Prenat Diagn 20(3):241, 2003 Obstet Gynecol 45(5):530, 2015 CHAPTER 15 . FETAL ANEMIA .........e...e..e...e.. .....e....e.... 300 RED CEll AllOIMMUNIZATION ..e.............e.... 301 FETOMATERNAl HEMORRHAGE . . . . . . . . . . . . . . . . . . 306 FETAL THROMBOCYTOPENIA ...e..e..e...e...e.....e. 307 HYDROPS FETAlIS. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 309 MIRROR SYNDROMEe. . . . . . . . . . . . . . . . . . . . . . . . . . . . 312


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Obstentrics_Williams. HYDROPS FETAlIS. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . 309 MIRROR SYNDROMEe. . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 General dropsy of the oetus is a rare condition in which the oetus and placenta are markedy oedematous. As the result of iniltration with serum the ormer may attain immense proportions and the latter may be increased to three or our times its normal size. Although a good deal has been written on the subject, no satiactory explanation of the anomay has as yet been arrived at. -J. Whitridge Williams (1903)


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Obstentrics_Williams. -J. Whitridge Williams (1903) Little was written of fetal disorders in the first edition of this textbook. General dropsy described above is today known as hydrops etalis (p. 309). Hydrops is perhaps the quintessential fetal disorder, as it can be a manifestation of severe illness from a wide variety of etiologies. Fetal disorders may be acquired-such as alloimmunization, they may be genetic-congenital adrenal hyperplasia or aA-thalassemia, or they may be sporadic developmental abnormalities-like many structural malformations. In this chapter, fetal anemia and thrombocytopenia as well as immune and nonimmune fetal hydrops are reviewed. Fetal structural malformations are reviewed in Chapter 10, genetic abnormalities in Chapters 13 and 14, and conditions amenable to medical and surgical fetal therapies in Chapter 16. Because congenital infections arise as a result of maternal infection or colonization, they are considered in Chapters 64 and 65.


Obstentrics_Williams

Obstentrics_Williams. Of the many causes of fetal anemia, one of the most frequent is red cell alloimmunization, which results from transplacental passage of maternal antibodies that destroy fetal red cells. Alloimmunization leads to overproduction of immature fetal and neonatal red cells-erythroblastosis etalis-a condition now referred to as hemoytic disease of the etus and newborn (HDFN).


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Obstentrics_Williams. In addition, several congenital infections are also associated with fetal anemia, particularly parvovirus B19, discussed in Chapter 64 (p. 1216). In Southeast Asian populations, x4-thalassemia is a common cause of severe anemia and nonimmune hydrops. Fetomaternal hemorrhage occasionally creates severe fetal anemia and is discussed on page 306. Rare causes of anemia include red cell production disorders-such as Blackfan-Diamond anemia and Fanconi anemia; red cell enzymopathies-glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; red cell structural abnormalities-hereditary spherocytosis and elliptocytosis; and myeloproliferative disorders-leukemias. Anemia may be identified through fetal blood sampling, described in Chapter 14 (p. 294), or by Doppler evaluation of the fetal middle cerebral artery (MCA) peak systolic velocity, described on page 303.


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Obstentrics_Williams. Progressive fetal anemia from any cause leads to heart failure, hydrops fetalis, and ultimately death. Fortunately, the prevalence and the course of this otherwise devastating disorder have been dramatically changed by prevention and treatment. Prevention ofD alloimmunization is with anti-D immune globulin. Identiication and treatment of fetal anemia is with MCA Doppler studies and intrauterine transfusions, respectively. Severely anemic fetuses transfused in utero have survival rates exceeding 90 percent, and even in cases of hydrops fetalis, survival rates approach 80 percent (Lindenberg, 2013; Zwiers, 2017).


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Obstentrics_Williams. Currently, 33 diferent blood group systems and 339 red cell antigens are recognized by the International Society of Blood Transfusion (Storry, 2014). Although some of these are immunologically and genetically important, many are so rare as to be of little clinical signiicance. Any individual who lacks a specific red cell antigen may produce an antibody when exposed to that antigen. Such antibodies can prove harmful to that individual if she receives an incompatible blood transfusion. Accordingly, blood banks routinely screen for erythrocyte antigens. hese antibodies may also be harmful to a mother's fetus during pregnancy. As noted, maternal antibodies formed against fetal erythrocyte antigens may cross the placenta to cause fetal red cell lysis and anemia.


Obstentrics_Williams

Obstentrics_Williams. Typically, a fetus inherits at least one red cell antigen from the father that is lacking in the mother. hus, the mother may become sensitized if enough fetal erythrocytes reach her circulation to elicit an immune response. Even so, alloimmunization is uncommon for the following reasons: (1) low prevalence of incompatible red cell antigens; (2) insuicient transplacental passage of fetal antigens or maternal antibodies; (3) maternalfetal ABO incompatibility, which leads to rapid clearance of fetal erythrocytes before they elicit an immune response; (4) variable antigenicity; and (5) variable maternal immune response to the antigen. In population-based screening studies, the prevalence of red cell alloimmunization in pregnancy approximates 1 percent (Bollason, 2017; Koelewijn, 2008). Most cases of severe fetal anemia requiring antenatal transfusion are attributable to anti-D, anti-Kell, anti-c, or anti-E alloimmunization (de Haas, 2015).


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Obstentrics_Williams. At the first prenatal visit, a blood type and antibody screen are routinely assessed, and unbound antibodies in maternal serum are detected by the indirect Coombs test (Chap. 9, p. 160). When the result is positive, the specific antibodies are identified, their immunoglobulin subtype is determined as either immunoglobulin G (IgG) or M (IgM) , and the titer is quantiied. Only IgG antibodies are a concern because IgM antibodies do not cross the placenta. Selected antibodies and their potential to cause fetal hemolytic anemia are listed in Table he critical titer is the level at which significant fetal anemia could potentially develop. This may be diferent for each antibody, is determined individually by each laboratory, and usually ranges between 1:8 and 1 :32. If the critical titer for anti-D antibodies is 1: 16, a titer : 1: 16 indicates the possibility of severe hemolytic disease. An important exception is Kell sensitization, which is discussed on page 302.


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Obstentrics_Williams. he CDE system includes ive red cell proteins or antigens: C, c, D, E, and e. here is no "d" antigen, and D-negativity is deined as the absence of the D antigen. Although most people are D positive or negative, more than 200 D antigen variants exist (Daniels, 2013). h was formerly termed rhesus because of TABLE 15-1. Selected Red Cell Antigens and Their Relationship to Fetal Hemolytic Disease CDE (Rh) 0,E, Bea, Ce, Cw, Cx, ce, c Ow, Evans, e, G, Goal, Hr, Hro, JAL, HOFM, LOCR, Riv. Rh29, Rh32, Rh42, Rh46, STEM, Tar k, Kp3, Kpb, K1s1, K22 Ku, Jsa, Jsb, Ula Jkb, Jk3 MNS M, N, S, s, U, Mtd, Ena, Far, Hil, Hut, Mia, Mit, Mut, Mur, Mv, sO, Vw Colton Cd, C03 Severe disease risk Severe disease infrequent, mild disease risk Severe disease infrequent, mild disease risk Severe disease infrequent, mild disease risk Not associated with fetal hemolytic disease Severe disease infrequent, mild disease risk Mild disease possible Severe disease infrequent, mild disease risk


Obstentrics_Williams

Obstentrics_Williams. Severe disease infrequent, mild disease risk Severe disease infrequent, mild disease risk Severe disease infrequent, mild disease risk Dd, Gy3, Hy, Joa Mild disease possible , Ge3, Ge4 , Lsa Mild disease possible I I, i Not associated with fetal hemolytic disease Lewis Lea, Leb Not associated with fetal hemolytic disease From de Haas, 2015; Moise, 2008; Weinstein, 1982. a misconception that red cells from rhesus monkeys expressed human blood group antigen. In transfusion medicine, "rhesus" is no longer used (Sandler, 2017).


Obstentrics_Williams

Obstentrics_Williams. a misconception that red cells from rhesus monkeys expressed human blood group antigen. In transfusion medicine, "rhesus" is no longer used (Sandler, 2017). CDE antigens are clinically important. D-negative individuals may become sensitized after a single exposure to as little as 0.1 mL of fetal erythrocytes (Bowman, 1988). The two responsible genes-RHD and RHCE-are located on the short arm of chromosome 1 and are inherited together, independent of other blood group genes. The incidence of antigen positivity varies according to racial and ethnic origin. Nearly 85 percent of non-Hispanic white Americans are D-positive. The incidence approximates 90 percent for Native Americans, 93 percent for frican Americans and Hispanic Americans, and at least 99 percent for Asian individuals (Garratty, 2004).


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Obstentrics_Williams. The prevalence of D alloimmunization complicating pregnancy ranges from 0.5 to 0.9 percent (Koelewijn, 2008; \1artin, 2005). Without anti-D immune globulin prophylaxis, a D-negative woman delivered of a D-positive, ABO-compatible newborn has a 16-percent likelihood of developing alloimmunization. Two percent will become sensitized by the time of delivery, 7 percent by 6 months postpartum, and the remaining 7 percent will be "sensibilized"-producing detectable antibodies only in a subsequent pregnancy (Bowman, 1985). If there is ABO incompatibility, the D alloimmunization risk approximates 2 percent without prophylaxis (Bowman, 2006). The reason for the difering rates relative to ABO blood type results from erythrocyte destruction of ABO-incompatible cells, which thereby limits sensitizing opportunities. D sensitization also may occur following irst-trimester pregnancy complications, prenatal diagnostic procedures, and maternal trauma (Table 15-2).


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Obstentrics_Williams. The C, c, E, and e antigens have lower immunogenicity than the D antigen but can cause hemolytic disease. Sensitization to E, c, and C antigens complicates approximately 0.3 percent of pregnancies in screening studies and accounts for about 30 percent of red cell alloimmunization cases (Howard, 1998; Koelewijn, 2008). Anti-E alloimmunization is the most common, but the need for fetal or neonatal transfusions is greater with anti-c alloimmunization than with anti-E or anti-C (de Haas, 2015; Hackney, 2004; Koelewijn, 2008).


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Obstentrics_Williams. The Grandmother Efect. In virtually all pregnancies, small amounts of maternal blood enter the fetal circulation. Realtime polymerase chain reaction (PCR) has been used to identiy maternal D-positive DNA in peripheral blood from pre term and full-term D-negative newborns (Lazar, 2006). hus, it is possible for a D-negative female fetus exposed to maternal D-positive red cells to develop sensitization. When such an individual reaches adulthood, she may produce anti-D antibodies even before or early in her irst pregnancy. This mechanism is called the grandmother eect or theory because the fetus in the current pregnancy is jeopardized by maternal antibodies that were initially provoked by his or her grandmothers erythrocytes. Alloimmunization to Minor Antigens Because routine administration of anti-D immunoglobulin prevents anti-D alloimmunization, proportionately more cases of hemolytic disease are caused by red cell antigens


Obstentrics_Williams

Obstentrics_Williams. Because routine administration of anti-D immunoglobulin prevents anti-D alloimmunization, proportionately more cases of hemolytic disease are caused by red cell antigens TABLE 15-2. Causes of Fetomaternal Hemorrhage Associated with Red Cell Antigen Alloimmunizationa Procedures Chorionic villus sampling Amniocentesis Fetal blood sampling Evacuation of molar pregnancy aFor each of the above, anti-D immune globulin is recom mended. Expanded from American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2017; American College of Obstetricians and Gynecologists, 2017.


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Obstentrics_Williams. Expanded from American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2017; American College of Obstetricians and Gynecologists, 2017. other than D (American College of Obstetricians and Gynecologists, 2016; Koelewijn, 2008). hese are also known as minor antigens. Kell antigens are among the most frequent. Other antigens with potential to cause severe alloimmunization include Duy group A_Fya, MNS, and Kidd-Jka (de Hass, 2015; Moise, 2008). Most cases of sensitization to minor antigens result from incompatible blood transfusions. However, if an IgG red cell antibody is detected and there is any doubt as to its significance, the clinician should err on the side of caution, and the pregnancy should be evaluated for hemolytic disease.


Obstentrics_Williams

Obstentrics_Williams. Only a few blood group antigens pose no fetal risk. Lewis antibodies-Lea and Leb, as well as I antibodies, are cold agglutinins. They are predominantly IgVl and are not expressed on fetal red cells (American College of Obstetricians and Gynecologists, 2016). Another antibody that does not cause fetal hemolysis is Duy group B-Fl. Kell Alloimmunization. Approximately 90 percent of nonHispanic white Americans and up to 98 percent of African Americans are Kell negative. Kell type is not routinely determined. Transfusion history is important, as nearly 90 percent of Kell sensitization cases result from transfusion with Kellpositive blood. .


Obstentrics_Williams

Obstentrics_Williams. Kell sensitization may develop more rapidly and may be more severe than with sensitization to D and other blood group antigens. his is because Kell antibodies attach to erythrocyte precursors in the fetal bone marrow, thereby impairing the normal hemopoietic response to anemia. With fewer erythrocytes produced, there is less hemolysis, and severe anemia may not be predicted by the maternal Kell antibody titer. One option is to use a lower critical titer-l:8-for Kell sensitization (Moise, 2012). he American College of Obstetricians and Gynecologists (2016) has recommended that antibody titers not be used to monitor Kell-sensitized pregnancies.


Obstentrics_Williams

Obstentrics_Williams. Incompatibility for the major blood group antigens A and B is the most common cause of hemolytic disease in newborns, but it does not cause appreciable hemolysis in the fetus. Approxi mately 20 percent of newborns have ABO blood group incom patibility, yet only 5 percent are afected clinically. And in such cases, the resulting anemia is typically mild.


Obstentrics_Williams

Obstentrics_Williams. The condition difers from CDE incompatibility in several respects. First, ABO incompatibility is often seen in firstborn neonates, whereas sensitization to other blood group antigens is not. This is because most group 0 women have developed antiA and anti-B isoagglutinins before pregnancy from exposure to bacteria displaying similar antigens. Second, ABO alloimmunization rarely becomes more severe in successive pregnancies. Last, ABO incompatibility is considered a pediatric diseaserarely of obstetrical concern. his is because most anti-A and anti-B antibodies are IgM and do not cross the placenta. Fetal red cells also have fewer A and B antigenic sites than adult cells and are thus less immunogenic. Consequently, fetal surveillance and early delivery are not indicated in pregnancies with prior ABO incompatibility. Careful neonatal observation is essential, however, because hyperbilirubinemia may require treatment with phototherapy or occasionally transfusion (Chap. 33, p. 626).


Obstentrics_Williams

Obstentrics_Williams. • Management of the Alloimmunized An estimated 25 to 30 percent of fetuses from D-alloimmunized pregnancies will have mild-to-moderate hemolytic anemia. And without treatment, up to 25 percent will develop hydrops (Tannirandorn, 1990). If alloimmunization is detected and the titer is below the critical value, the titer is generally repeated every 4 weeks for the duration of the pregnancy (American College of Obstetricians and Gynecologists, 2016). Importantly, if a prior pregnancy was complicated by alloimmunization, serial titer assessment is not indicated, and the pregnancy is assumed to be at risk regardless of titer. Management of such pregnancies is discussed subsequently. In any pregnancy in which an antibody titer has reached a critical value, there is no beneit to repeating it. The pregnancy is at risk even if the titer drops, and further evaluation is still required.


Obstentrics_Williams

Obstentrics_Williams. Up to 40 percent of D-negative pregnant women carry a D-negative fetus. he presence of anti-D antibodies relects maternal sensitization but does not indicate whether the fetus is D-positive. If a woman became sensitized in a prior pregnancy, her antibody titer might rise to high levels during the current pregnancy even if the current fetus is D-negative, due to an amnestic response. In a non-Hispanic white couple in which the woman is D-negative, there is an 85-percent chance that the man is D-positive. But, in 60 percent of these cases, he will be heterozygous at the D-Iocus. And, if he is heterozygous, then half of his children will be at risk for hemolytic disease. Transfusion history is relevant. Alloimmunization to a red cell transfusion in the past, and if that antigen is not present on paternal erythrocytes, the pregnancy is not at risk.


Obstentrics_Williams

Obstentrics_Williams. Initial evaluation of alloimmunization begins with determining the paternal erythrocyte antigen status. Provided that paternity is certain, if the father is negative for the red cell antigen to which the mother is sensitized, the pregnancy is not at risk. In a D-alloimmunized pregnancy in which the father is D-positive, it is helpful to determine paternal zygosity for the D antigen using DNA-based analysis. If the father is heterozygous-or if paternity is not known-the woman should be ofered assessment of fetal genotype. Traditionally, this was done with amniocentesis and PCR testing of uncultured amniocytes, which has a positive-predictive value of 100 percent and negative-predictive value of approximately 97 percent (American College of Obstetricians and Gynecologists, 2016; Van den Veyver, 1996). Fetal testing for other antigens-such as E/e, C/c, Duy, Kell, Kidd, and �1/N-is also available with this method. Chorionic villus sampling is not recommended because of greater risk for


Obstentrics_Williams

Obstentrics_Williams. 1996). Fetal testing for other antigens-such as E/e, C/c, Duy, Kell, Kidd, and �1/N-is also available with this method. Chorionic villus sampling is not recommended because of greater risk for fetomaternal hemorrhage and subsequent worsening of alloimmunization.


Obstentrics_Williams

Obstentrics_Williams. Noninvasive fetal D genotyping has been performed using cell-free DNA (cfDNA) from maternal plasma (Chap. 13, p. 273). The reported sensitivity exceeds 99 percent, the speciicity exceeds 95 percent, and positive-or negative-predictive values are similarly very high (de Haas, 2016; Johnson, 2017; Moise, 2016; Vivanti, 2016). Fetal D genotyping with cDNA is routinely used in parts of Europe. There are two potential indications in D-negative pregnant women: (1) in women with D alloimmunization, testing can identiY fetuses that are also D-negative and do not require anemia surveillance, and (2) in women without D alloimmunization, anti-D immune globulin might be withheld if the fetus is D negative. In the case of the latter, the American College of Obstetricians and Gynecologists (2017) does not recommend routine cDNA screening in D-negative pregnancies until it becomes cost-efective.


Obstentrics_Williams

Obstentrics_Williams. Management of the alloimmunized pregnancy is individualized and may consist of maternal antibody titer surveillance, sonographic monitoring of the fetal MCA peak systolic velocity, amnionic luid bilirubin studies, or fetal blood sampling. Accurate pregnancy dating is critical. The gestational age at which fetal anemia developed in prior pregnancies is important because anemia tends to occur earlier and be sequentially more severe. Middle Cerebral Artery Doppler Velocimetry. Serial measurement of the peak systolic velocity of the fetal MCA is the recommended test for detection of fetal anemia (Society for Maternal-Fetal Medicine, 20 15a). he anemic fetus shunts blood preferentially to the brain to maintain adequate oxygenation. he velocity rises because of increased cardiac output and decreased blood viscosity. The technique is discussed Fetus without anemia or with mild anemiac� nE 120 • Fetus with severe anemia .-u .�::100 u ..o� )� . ) 40n� �u


Obstentrics_Williams

Obstentrics_Williams. Fetus without anemia or with mild anemiac� nE 120 • Fetus with severe anemia .-u .�::100 u ..o� )� . ) 40n� �u FIGURE 15-1 Doppler measurements ofthe peak systolic velocity in the middle cerebral artery (MeA) in 165 fetuses at risk for severe anemia. The blue line indicates the median peak systolic velocity in normal pregnancies, and the red line shows 1.5 multiples ofthe median. (Reproduced with permission from Oepkes 0, Seaward PG, Vandenbussche et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia, N Engl J Med. 2006 Jul 13;355(2):156-164.) in Chapter 10 (p. 214) and requires training and experience (American College of Obstetricians and Gynecologists, 2016).


Obstentrics_Williams

Obstentrics_Williams. In a landmark study, Mari and coworkers (2000) measured the MCA peak systolic velocity serially in 111 fetuses at risk for anemia and in 265 normal control fetuses. he threshold value of 1.5 multiples ofthe median (MoM) for gestational age correctly identiied all fetuses with moderate or severe anemia. his provided a sensitivity of 100 percent, with a false-positive rate of 12 percent.


Obstentrics_Williams

Obstentrics_Williams. he MCA peak systolic velocity is followed serially, and values are plotted on a curve like the one shown in Figure 15-1. If the velocity is between 1.0 and 1.5 MoM and the slope is rising-such that the value is approaching 1.5 Movf-surveillance is generally increased to weekly Doppler interrogation. If the MCA peak systolic velocity exceeds 1.5 \10M and the gestational age is younger than 34 or 35 weeks, fetal blood sampling should be considered and followed by fetal transfusion if needed (Society for Maternal-Fetal Medicine, 2015a). he false-positive rate of MCA peak systolic velocity increases signiicantly beyond 34 weeks, due to the normal augmentation in cardiac output that develops at this gestational age (Moise, 2008; Zimmerman, 2002).


Obstentrics_Williams

Obstentrics_Williams. Amnionic Fluid Spectral Analysis. This test is included for historical interest. More than 50 years ago, Liley (1961) demonstrated the utility ofamnionic fluid spectral analysis to measure bilirubin concentration and to thereby estimate hemolysis severity. Amnionic luid bilirubin concentration was measured by a spectrophotometer and was represented as the change in optical density absorbance at 450 nm-10D450. The likelihood of fetal anemia was determined by plotting the 10D45o value on a graph that was divided into zones. hese zones roughly correlated with fetal hemoglobin concentration, and thus with anemia severity. he original Liley graph was valid from 27 to 42 weeks' gestation and was subsequently modiied by Queenan (1993) to include gestational ages as early as 14 weeks. However, the amnionic luid bilirubin level is normally high in midpregnancy, limiting the reliability ofthis technique.


Obstentrics_Williams

Obstentrics_Williams. Middle cerebral artery velocimetry is more accurate than 10D45o assessment and does not confer risks for increased alloimmunization associated with amniocentesis. It has replaced 10D45o assessment for this purpose.


Obstentrics_Williams

Obstentrics_Williams. If there is evidence of severe fetal anemia, because of either elevated MCA peak systolic velocity or development of fetal hydrops, management is strongly inluenced by gestational age. Fetal blood sampling and intrauterine transfusion are generally performed prior to 34 to 35 weeks (Society for Maternal-Fetal Medicine, 2015a). Intravascular transfusion into the umbilical vein under sonographic guidance is the preferred method of fetal transfusion. Transfusion into the fetal peritoneal cavity may be necessary with severe, early-onset hemolytic disease in the early second trimester, a time when the umbilical vein is too narrow to readily permit needle entry. With hydrops, although peritoneal absorption is impaired, some prefer to transfuse into both the fetal peritoneal cavity and the umbilical vein.


Obstentrics_Williams

Obstentrics_Williams. Transfusion is generally recommended only if the fetal hematocrit is <30 percent (Society for Maternal-Fetal Medicine, 2015a). Once hydrops has developed, the hematocrit is generally 15 percent or lower. The red cells transfused are type 0, D-negative, cytomegalovirus-negative, packed to a hematocrit of approximately 80 percent to prevent volume overload, irradiated to prevent fetal graft-versus-host reaction, and leukocyte-poor. he fetal-placental volume allows rapid infusion ofa relatively large quantity ofblood. Before transfusion, a paralytic agent such as vecuronium may be given to the fetus to minimize movement. In a nonhydropic fetus, the target hematocrit is generally 40 to 50 percent. he volume transfused may be estimated by multiplying the estimated fetal weight in grams by 0.02 for each 10-percent rise in hematocrit needed (Giannina, 1998). In the severely anemic fetus at 18 to 24 weeks' gestation, less blood is transfused initially, and another transfusion may be planned


Obstentrics_Williams

Obstentrics_Williams. for each 10-percent rise in hematocrit needed (Giannina, 1998). In the severely anemic fetus at 18 to 24 weeks' gestation, less blood is transfused initially, and another transfusion may be planned for approximately 2 days later. Subsequent transfusions usually take place every 2 to 4 weeks, depending on the hematocrit.


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Obstentrics_Williams. The MCA peak systolic velocity threshold for severe anemia is higher following an initial transfusion-1.70 MoM rather than 1.50 MoYI (Society for Maternal-Fetal Medicine, 2015a). It is hypothesized that the change in threshold compensates for the contribution ofdonor cells in the initial transfusion, because donor cells (from adults) have a smaller mean corpuscular volume. Alternately, the timing ofsubsequent transfusions is based on anemia severity and posttransfusion hematocrit. Following transfusion, the fetal hematocrit generally drops by approximately 1 percent per day. A more rapid initial decline may be encountered in the setting of fetal hydrops.


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Obstentrics_Williams. Outcomes. Procedure-related complications have declined signiicantly at experienced centers in recent years, with overall survival rates exceeding 95 percent (Zwiers, 2017). Complications include fetal death in approximately 2 percent, need for emergent cesarean delivery in 1 percent, and infection and preterm rupture of membranes in 0.3 percent each, respectively. The stillbirth rate exceeds 15 percent if transfusion is required before 20 weeks (Lindenberg, 2013; Zwiers, 2017). Considering that fetal transfusion is potentially lifesaving in severely compromised fetuses, these risks should not dissuade therapy. Van Kamp (2001) reported that if hydrops had developed, the survival rate approached 75 to 80 percent. However, of the nearly two thirds with resolution of hydrops following transfu sion, more than 95 percent survived. he survival rate was < 40 percent if hydrops persisted.


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Obstentrics_Williams. Lindenberg (2012) reviewed long-term outcomes following intrauterine transfusion in a cohort of more than 450 alloimmunized pregnancies. Alloimmunization was secondary to anti-D in 80 percent, anti-Kell in 12 percent, and anti-c in 5 percent. Approximately a fourth of afected fetuses had hydrops, and more than half also required exchange transfusion in the neonatal period. Among nearly 300 children aged 2 to 17 years who participated in neurodevelopmental testing, fewer than 5 percent had severe impairments. hese included severe developmental delay in 3 percent, cerebral palsy in 2 percent, and deafness in 1 percent. • Prevention of Anti-D Alloimmunization


Obstentrics_Williams

Obstentrics_Williams. • Prevention of Anti-D Alloimmunization Anti-D immune globulin is one of the success stories of modern obstetrics. It has been used for nearly five decades to prevent D alloimmunization. In countries without access to anti-D immune globulin, up to 10 percent of D-negative pregnancies are complicated by hemolytic disease of the fetus and newborn (Zipursky, 2015). With immunoprophylaxis, however, the alloimmunization risk is reduced to <0.2 percent. Despite long-standing and widespread use, its mechanism of action is not completely understood.


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Obstentrics_Williams. As many as 90 percent of alloimmunization cases occur from fetomaternal hemorrhage at delivery. Routine postpartum administration of anti-D immune globulin to at-risk pregnancies within 72 hours of delivery lowers the alloimmunization rate by 90 percent (Bowman, 1985). Additionally, provision of anti-D immune globulin at 28 weeks' gestation reduces the third-trimester alloimmunization rate from approximately 2 percent to 0.1 percent (Bowman, 1988). Whenever there is doubt whether to give anti-D immunoglobulin, it should be given. If not needed, it will not cause harm, but failure to provide it when needed can have severe consequences.


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Obstentrics_Williams. Current preparations of anti-D immune globulin are derived from human plasma donated by individuals with hightiter anti-D immunoglobulin D antibodies. Formulations prepared by cold ethanol fractionation and ultrailtration must be administered intramuscularly because they contain plasma proteins that could result in anaphylaxis if given intravenously. However, formulations prepared using ion exchange chromatography may be administered either intramuscularly or intravenously. his is important for treatment of significant fetomaternal hemorrhage, which is discussed subsequently. Both preparation methods efectively remove viral particles, including hepatitis and human immunodeiciency viruses. Depending on the preparation, the half-life of anti-D immune globulin ranges from 16 to 24 days, which is why it is given both in the third trimester and following delivery. he standard intramuscular dose of anti-D immune globulin-300 I-Lg or 1500 IU-will protect the average-sized mother from a fetal


Obstentrics_Williams

Obstentrics_Williams. is why it is given both in the third trimester and following delivery. he standard intramuscular dose of anti-D immune globulin-300 I-Lg or 1500 IU-will protect the average-sized mother from a fetal hemorrhage of up to 30 mL of fetal whole blood or 15 mL of fetal red cells.


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Obstentrics_Williams. In the United States, anti-D immune globulin is given prophylactically to all D-negative, unsensitized women at approximately 28 weeks' gestation, and a second dose is given after delivery if the newborn is D-positive (American College of Obstetricians and Gynecologists, 2017). Before the 28-week dose of anti-D immune globulin, repeat antibody screening is recommended to identiy individuals who have become alloimmunized (American Academy of Pediatrics, 2017). Following delivery, anti-D immune globulin should be given within 72 hours. Recognizing that 40 percent of neonates born to D-negative women are also D negative, administration of immune globulin is recommended only after the newborn is conirmed to be D positive (American College of Obstetricians and Gynecologists, 2017). If immune globulin is inadvertently not administered following delivery, it should be given as soon as the omission is recognized, because there may be some protection up to 28 days postpartum (Bowman, 2006).


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Obstentrics_Williams. globulin is inadvertently not administered following delivery, it should be given as soon as the omission is recognized, because there may be some protection up to 28 days postpartum (Bowman, 2006). Anti-D immune globulin is also administered after pregnancyrelated events that could result in fetomaternal hemorrhage (see Table 15-2).


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Obstentrics_Williams. Anti-D immune globulin may produce a weakly positive-1: 1 to 1 :4-indirect Coombs titer in the mother. This is harmless and should not be confused with development of alloimmunization. Additionally, as the body mass index increases above 27 to 40 kg/m2, serum antibody levels decrease by 30 to 60 percent and may be less protective (MacKenzie, 2006; Woelfer, 2004). D-negative women who receive other types of blood products-including platelet transfusions and plasmapheresis-are also at risk of becoming sensitized, and this can be prevented with anti-D immune globulin. Rarely, a small amount of antibody crosses the placenta and results in a weakly positive direct Coombs test in cord and infant blood. Despite this, passive immunization does not cause signiicant fetal or neonatal hemolysis.


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Obstentrics_Williams. It is estimated that in 2 to 3 per 1000 pregnancies, the volume of fetomaternal hemorrhage exceeds 30 mL of whole blood (American College of Obstetricians and Gynecologists, 2017). A single dose of anti-D immune globulin would be insuicient in such situations. If additional anti-D immune globulin is considered only for women with risk factors such as those shown in Table 15-2, then hafof those who require additional immune globulin may be missed. For this reason, all D-negative women should be screened at delivery, typically with a rosette test, followed by quantitative testing if indicated (American College of Obstetricians and Gynecologists, 20i17).


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Obstentrics_Williams. he rosette test is a qualitative test that identiies whether fetal D-positive cells are present in the circulation of a D-negative woman. A sample of maternal blood is mixed with anti-D antibodies that coat any D-positive fetal cells present in the sample. Indicator red cells bearing the D-antigen are then added, and rosettes form around the fetal cells as the indicator cells attach to them by the antibodies. hus, if rosettes are visualized, there are fetal D-positive cells in that sample. In the setting of D incompatibility, or any time a large fetomaternal hemorrhage is suspected-regardless of antigen status, a Kleihauer-Betke test or flow cytometry test are used. These are discussed on page 307.


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Obstentrics_Williams. The dosage of anti-D immune globulin is calculated from the estimated volume of the fetal-to-maternal hemorrhage, as described on page 307. One 300-�g dose is given for each 15 mL of fetal red cells or 30 mL of fetal whole blood to be neutralized. If using an intramuscular preparation of anti-D immune globulin, no more than five doses may be given in a 24-hour period. If using an intravenous preparation, two ampules-totaling 600 �g-may be given every 8 hours. To determine if the administered dose was adequate, the indirect Coombs test may be performed. A positive result indicates that there is excess anti-D immunoglobulin in maternal serum, thus demonstrating that the dose was suicient. Alternatively, a rosette test may be performed to assess whether circulating fetal cells remain.


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Obstentrics_Williams. Formerly called D") these are the most common antigenic D variants in the United States and Europe. Serological weak D phenotypes have been further refined into two general categories using molecular analysis-RHD genotyping. Molecular weak D phenotypes carry reduced numbers of intact D antigens on the red cell surface. Those designated partial D types have protein deletions associated with abnormal D antigens that lack epitopes (Sandler, 2017). When this distinction is known, it can have clinical consequences in terms of sensitization risk and need for anti-D immune globulin.


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Obstentrics_Williams. Traditionally, serological weak D individuals have been considered to be D-positive or -negative depending on the clinical situation. For the purposes of blood donation, they are categorized as D-positive, whereas transfusion recipients with weak D are considered D-negative. In pregnancy, weak D has also been considered D-negative, so that individuals receive immune globulin and avoid potential sensitization (American College of Obstetricians and Gynecologists, 2017; Sandler, 2015).


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Obstentrics_Williams. Many non-Hispanic white Americans who test positive for weak D have weak D phenotypes 1, 2, or 3. Individuals with these phenotypes may be managed as though they are D-positive. Because they are not at risk for alloimmunization, anti-D immune globulin is not needed (Sandler 2015, 2017). In contrast, individuals with partial D antigens may be at risk for D-sensitization and do require immune globulin. Molecular RHD genotyping has been suggested for pregnant women with weak D phenotype, bur cost-benefit analysis of this strategy is presently lacking (American College of Obstetricians and Gynecologists, 2017). f molecular genetic testing has not been peormed in those with serologic weak D phenoype) D immunoprophylaxis should be administered to those with weak D phenotype.


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Obstentrics_Williams. A small amount of fetomaternal bleeding likely occurs in all pregnancies, and in two thirds, this may be suicient to provoke an antigen-antibody reaction. As shown in Figure 15-2, the incidence increases with advancing gestation and the 80 0.19 mL 70 )> 60;;)>C 50)C·uE 40 FIGURE 15-2 Incidence of fetal-to-maternal hemorrhage during pregnancy. The numbers at each data point represent total volume of fetal blood estimated to have been transferred into the maternal circulation. (Data from Choavaratana, 1997.) volume of fetal blood in the maternal circulation. Fortunately, a large blood loss-true fetomaternal hemorrhage-is rare. In one series of more than 30,000 pregnancies, fetomaternal hemorrhage ::150 mL occurred in 1 per 2800 births (de Almeida, 1994). he prevalence of fetomaternal hemorrhage of at least 30 mL-the volume of fetal blood covered by a standard 300 �g dose of anti-D immune globulin-is estimated to be 3 per 1000 pregnancies (Wylie, 2010).


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Obstentrics_Williams. Selected causes of fetomaternal hemorrhage are shown in Table 15-2. It also may occur with placenta previa, placental chorioangioma, or vasa previa (Giacoia 1997; Rubod, 2007). In each of these circumstances, however, fetomaternal hemorrhage is extremely uncommon if not rare. And, in more than 80 percent of cases, no cause is identified. With significant hemorrhage, the most common presenting complaint is decreased fetal movement (Bellussi, 2017; Wylie, 2010). A sinusoidal fetal heart rate pattern is infrequently seen but warrants immediate evaluation (Chap. 24, p. 464). Sonography may demonstrate elevated MCA peak systolic velocity, and indeed this is reported to be the most accurate predictor (Bellusi, 2017; Wylie, 2010). Hydrops is an ominous inding. If fetomaternal hemorrhage is suspected, an elevated MCA peak systolic velocity or sonographic evidence of hydrops prompts consideration of urgent fetal transfusion or delivery.


Obstentrics_Williams

Obstentrics_Williams. One limitation of quantitative tests for fetal cells in the maternal circulation is that they do not provide information regarding hemorrhage timing or chronicity (Wylie, 2010). In general, anemia developing gradually or chronically, as in alloimmunization, is better tolerated by the fetus than acute anemia. Chronic anemia may not produce fetal heart rate abnormalities until the fetus is moribund. In contrast, significant acute hemorrhage is poorly tolerated by the fetus and may cause profound fetal neurological impairment from cerebral hypoperfusion, ischemia, and infarction. In some cases, fetomaternal hemorrhage is identified during stillbirth evaluation (Chap. 35, p. 646). FIGURE 15-3 Kleihauer-Betke test demonstrating massive fetalto-maternal hemorrhage. After acid-elution treatment, fetal red cells rich in hemoglobin F stain darkly, whereas maternal red cells with only very small amounts of hemoglobin F stain lightly.


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Obstentrics_Williams. Once fetomaternal hemorrhage is recognized, the volume of fetal blood loss should be estimated. he volume is essential to calculate the appropriate dose of anti D-immune globulin if the woman is D-negative, and it may inluence obstetrical management. The most commonly used quantitative test for fetal red cells in the maternal circulation is the acid elution or Kleihauer-Betke (KB) test (Kleihauer, 1957). Fetal erythrocytes contain hemoglo bin F, which is more resistant to acid elution than hemoglobin


Obstentrics_Williams

Obstentrics_Williams. A. After exposure to acid, only fetal hemoglobin remains, such that after staining, the fetal erythrocytes appear red and adult erythrocytes appear as "ghosts" (Fig. 15-3). he fetal cells are then counted and expressed as a percentage of adult cells. he KB test is labor intensive. Importantly, there are two scenarios in which it may not be accurate: (1) maternal hemoglobinopathies such as �-thalassemia in which the fetal hemoglobin level is elevated and (2) pregnancies at or near term, when the fetus has already started to produce hemoglobin A. he volume of fetomaternal hemorrhage is calculated from the KB test result using the following formula:


Obstentrics_Williams

Obstentrics_Williams. One method is to estimate the maternal blood volume (MBV) as 5000 mL for a normal-size, normotensive women at term. Thus, for 1.7 -percent positive KB-stained cells in a woman of average size with a hematocrit of 35 percent and whose fetus has a hematocrit of 50 percent: 5000 X 0.35 X 0.017 0.5 he fetal-placental blood volume at term approximates 125 mLlkg. For a 3000-g fetus, that would equate to 375 mL. Thus, this fetus lost approximately 15 percent (60 -375 mL) of the fetal-placental volume. Because the hematocrit is 50 percent in a term fetus, this 60 mL of whole blood represents 30 mL of red cells lost into the maternal circulation. This loss should be well tolerated hemodynamically but would require two 300-lLg doses of anti-D immunoglobulin to prevent alloimmunization. A more precise method to estimate the maternal blood volume includes a calculation based on the maternal height, weight, and anticipated physiological maternal blood volume accrual (Table 41-1, p. 756).


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Obstentrics_Williams. Fetomaternal hemorrhage can also be quantified using low cytometry, which uses monoclonal antibodies to hemoglobin F or to the D antigen, followed by quantiication of luorescence (Chambers, 2012; Welsh, 2016). Flow cytometry is an automated test that can analyze a greater number of cells than the KB test. Further, it is unafected by maternal levels of fetal hemoglobin or by fetal levels of hemoglobin A. Flow cytometry has been reported to be more sensitive and accurate than the KB test, however, it uses specialized technology not routinely available in many hospitals (Chambers, 2012; Corcoran, 2014; Fernandes, 2007).


Obstentrics_Williams

Obstentrics_Williams. This condition is also referred to as neonatal alloimmune throm cytopenia (FNAIT). Alloimmune thrombocytopenia (AIT) is the most common cause of severe thrombocytopenia among term newborns, with a frequency of 1 to 2 per 1000 births (Kamphuis, 2010; Pacheco, 2013; Risson, 2012). FNAIT is caused by maternal alloimmunization to paternally inherited fetal platelet antigens. he resulting maternal antiplatelet anti bodies cross the placenta in a manner similar to red cell allo immunization (p. 301). Unlike immune thrombocytopenia, the maternal platelet count is normal with FNAIT. And, unlike anti-D alloimmunization, severe sequelae may afect the initial at-risk pregnancy.


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Obstentrics_Williams. Maternal platelet alloimmunization is most often against human platelet antigen-1a (HPA-1a). It accounts for 80 to 90 percent of cases and is associated with the greatest severity (Bussel, 1997; Knight, 2011; Tiller, 2013). his is followed in order of frequency by HPA-5b, HPA-1b, and HPA-3a. Alloimmunization to other antigens accounts for only 1 percent of reported cases.


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Obstentrics_Williams. Approximately 85 percent of non-Hispanic white individuals are HPA-1a positive. Two percent are homozygous for HPA-1b and thus at risk for alloimmunization. Importantly, however, only 10 percent of homozygous HPA-1 b mothers who carry an HPA-1a fetus will produce anti-platelet antibodies. Approximately a third of afected fetuses or neonates will develop severe thrombocytopenia, and 10 to 20 percent of those with severe thrombocytopenia sustain an intracranial hemorrhage (ICH) (Kamphuis, 2010). As a result, population-based screening studies have identified FNAIT-associated ICH in 1 per 25,000 to 60,000 pregnancies (Kamphuis, 2010; Knight, 2011).


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Obstentrics_Williams. FNAIT may present in various ways. In some cases, neonatal thrombocytopenia may be an incidental finding or the newborn may manifest petechiae. In the other extreme, a fetus or neonate may develop devastating ICH-often before birth. Of 600 pregnancies with FNAIT identified through a large international registry, fetal or neonatal ICH complicated 7 percent of cases (Tiller, 2013). Hemorrhage afected the irst-born child in 60 percent and occurred before 28 weeks' gestation in half. A third of afected children died soon after birth, and 50 percent of survivors had severe neurological disabilities. Bussel and coworkers (1997) evaluated fetal platelet counts before therapy in 107 fetuses with FNAIT. Thrombocytopenia severity was predicted by a prior sibling with perinatal ICH, and 98 percent of cases were identiied this way. he initial platelet count was <20,000/�L in 50 percent. In cases in which the platelet count was initially >80,000/�L, they noted that it dropped by more than 1


Obstentrics_Williams

Obstentrics_Williams. of cases were identiied this way. he initial platelet count was <20,000/�L in 50 percent. In cases in which the platelet count was initially >80,000/�L, they noted that it dropped by more than 1 O,OOO/�L each week in the absence of therapy.


Obstentrics_Williams

Obstentrics_Williams. Alloimmune thrombocytopenia is typically diagnosed following delivery of a neonate with severe and unexplained thrombocytopenia to a woman whose platelet count is normal. Rarely, the diagnosis is ascertained after identiYing fetal ICH. he condition recurs in 70 to 90 percent of subsequent pregnancies, is often severe, and usually develops earlier with each successive pregnancy. Traditionally, fetal blood sampling was performed to detect fetal thrombocytopenia and to tailor therapy, with transfusion of platelets if the fetal platelet count was < 50,000/�L. Because of procedure-related complications, however, experts recommend abandoning routine fetal platelet sampling in favor of empirical treatment with intravenous immune globulin (IVIG) and prednisone (Berkowitz, 2006; Pacheco, 2011).


Obstentrics_Williams

Obstentrics_Williams. herapy is stratified according to whether a prior afected pregnancy was complicated by perinatal ICH, and if so, at what gestational age (Table 15-3). Pioneering work by Bussel (1996) and Berkowitz (2006) and their colleagues demonstrated the eicacy of such treatment. In one series of 50 pregnancies with fetal thrombocytopenia secondary to FNAIT, IVIG raised the platelet count by approximately 50,000/�L, and no fetus developed ICH (Bussel, 1996). Among pregnancies at particularly high risk-based on a platelet count <20,000/�L or sibling with FNAIT-associated ICH-the addition of corticosteroids to IVIG increased the platelet count in 80 percent of cases (Berkowitz, 2006). Cesarean delivery has been recommended at or near term. A noninstrumental vaginal delivery is generally considered only if fetal blood sampling has demonstrated a platelet count > 100,000/�L (Pacheco, 2011).


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Obstentrics_Williams. Additional considerations include risks and costs associated with therapy. Side efects ofIVIG may include fever, headache, nausea/vomiting, myalgia, and rash. Maternal hemolysis also has been described (Rink, 2013). Costs for IVIG may exceed $70 per gram or nearly $10,000 for each weekly 2-g/kg infusion for an average-size pregnant woman (Pacheco, 2011).


Obstentrics_Williams

Obstentrics_Williams. lso known as immune or idiopathic thrombocytopenic 2urpura (ITP), this autoimmune disorder is characterized by antiplatelet IgG antibodies that attack platelet glycoproteins. In pregnancy, these antibodies may cross the placenta and cause fetal thrombocytopenia. Maternal ITP is discussed in Chapter 56 (p. 1086). Fetal thrombocytopenia is usually mild. However, neonatal platelet levels may fall rapidly after birth, with a nadir at 48 to 72 hours of life. Neither the maternal platelet count, identification of anti platelet antibodies, nor treatment with corticosteroids efectively predicts fetal or neonatal platelet counts (Hachisuga, 2014). Importantly, fetal platelet counts are usually adequate to allow vaginal delivery without an increased risk of ICH. In a recent review of more than 400 pregnancies TABLE 15-3. Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT) Treatment Recommendations


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Obstentrics_Williams. TABLE 15-3. Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT) Treatment Recommendations Maternal anti-HPA antibody screening and cross-matching with paternal platelets at 12,s24, and 32 weeks' gestation; no treatment for negative test results Beginning at 20 wks: IVIG 1 g/kg/wk and prednisone 0.5 mg/kg/d or IVIG 2 g/kg/wk Beginning at 32 weeks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d. Beginning at 12 wks: IVIG 1 g/kg/wk Beginning at 20 wks: either increase IVIG to 2 g/kg/wk or add prednisone 0.5 mg/kg/d Beginning at 28 wks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d. Beginning at 12 wks: IVIG 2 g/kg/wk Beginning at 20 wks: add prednisone 1 mg/kg/d Continue both until delivery HPA human platelet antigen; ICH intracerebral hemorrhage; IVIG intravenous immunoglobulin G. Data from Pacheco, 2011s.


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Obstentrics_Williams. Beginning at 20 wks: add prednisone 1 mg/kg/d Continue both until delivery HPA human platelet antigen; ICH intracerebral hemorrhage; IVIG intravenous immunoglobulin G. Data from Pacheco, 2011s. with ITP, there was no case of fetal or neonatal ICH and no infant with any central nervous system abnormality (Wyszynski, 2016). Fetal bleeding complications are considered rare, and fetal blood sampling is not recommended (Neunert, 201i1). Delivery mode is based on standard obstetrical indications.


Obstentrics_Williams

Obstentrics_Williams. This term refers to excessive accumulation of serous fluid. Strictly defined, hydrops etalis is edema of the fetus. Traditionally, the diagnosis was made after delivery of a massively edematous neonate, often stillborn (Fig. 1i5-4). With sonography, hydrops has become a prenatal diagnosis. It is deined as two or more fetal efusions-pleural, pericardial, or ascites-or one efusion plus anasarca. As hydrops progresses in severity, edema is invariably a component, and is usually accompanied by placentomegaly and hydramnios. Clinically significant edema is defined sonographically as skin thickness > 5 mm, and placentomegaly if the placenta thickness is at least 4 em in the second trimester or 6 em in the third trimester (Bellini, 2009; Society for Maternal-Fetal Medicine, 2015b). Hydrops may result from a wide range of conditions with varying pathophysiologies, each with the potential to make the fetus severely ill. It is divided into two categories. If found in association with red cell


Obstentrics_Williams

Obstentrics_Williams. result from a wide range of conditions with varying pathophysiologies, each with the potential to make the fetus severely ill. It is divided into two categories. If found in association with red cell alloimmunization, it is termed immune, otherwise, it is nonimmune.


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Obstentrics_Williams. he incidence of immune hydrops has dramatically declined with the advent of anti-D immune globulin, MCA Doppler studies for detection of severe anemia, and prompt fetal transfusion when needed (p. 304). However, fewer than 10 percent of hydrops cases are caused by red cell alloimmunization (Bellini, 2012; Santolaya, 1992). The pathophysiology underlying hydrops remains unknown. Immune hydrops is postulated to share several physiological abnormalities with nonimmune hydrops. As shown in


Obstentrics_Williams

Obstentrics_Williams. FIGURE 15-4 Hydropic, macerated stillborn infant and characteristically large placenta. The etiology was B1o9 parvovirus infection. (Used with permission from Dr. April Bleich.) 15-5, these include decreased colloid oncotic pres sure, increased hydrostatic (or central venous) pressure, and enhanced vascular permeability. Immune hydrops results from transplacental passage of maternal antibodies that destroy fetal red cells. The resultant anemia stimulates marrow erythroid hyperplasia and extramedullary hematopoiesis in the spleen and liver. The latter likely causes portal hypertension and impaired hepatic protein synthesis, which lowers plasma oncotic pressure (Nicolaides, 1985). Fetal anemia also may raise central venous pressure (Weiner, 1989). Finally, tissue hypoxia from anemia may increase capillary permeability, such that luid collects in the fetal thorax, abdominal cavity, andlor subcutaneous tissue. he degree of anemia in immune hydrops is typically severe.


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Obstentrics_Williams. he degree of anemia in immune hydrops is typically severe. In a series of 70 pregnancies with fetal anemia from red cell alloimmunization, Mari and coworkers (2000) found that all those with immune hydrops had hemoglobin values <5 g/dL. As discussed on page 304, immune hydrops is treated with fetal blood transfusions.


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Obstentrics_Williams. At least 90 percent of cases of hydrops are nonimmune (Bellini, 2012; Santolaya, 1992). The prevalence estimate is 1 per 1500 second-trimester pregnancies (Heinonen, 2000). The number of specific disorders that can lead to nonimmune hydrops is extensive. Etiologies and the proportion of births within each hydrops category from a review of more than 6700 afected pregnancies are summarized in Table 1i5-4. A cause is identified in at least 60 percent prenatally and in more than 80 percent postnatally (Bellini, 2009; Santo, 2011). Currently, approximately 20 percent of cases remain idiopathic (Bellini, 2015). As shown in Figure 15-5, several diferent pathophysiological processes are proposed to account for the inal common pathway of hydrops fetalis.


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Obstentrics_Williams. Importantly, the etiology of non immune hydrops varies according to when in gestation it is identified. Of those diagnosed prenatally, aneuploidy accounts for approximately 20 percent, cardiovascular abnormalities for 15 percent, and infections for 14 percent-the most common of these being parvovirus B19 (Santo, 2011). Overall, only 40 percent of pregnancies with nonimmune hydrops result in a liveborn neonate, and of these, the neonatal survival rate is only about 50 percent. Sohan and colleagues (2001) reviewed 87 pregnancies with hydrops and found that 45 percent of those diagnosed before 24 weeks' gestation had a chromosomal abnormality. The most frequent aneuploidy was 45,X-Turner syndrome, and in such cases, the survival rate was <5 percent (Chap. 13, p. 259). If hydrops is detected in the irst trimester, the aneuploidy risk is nearly 50 percent, and most have cystic hygromas (Fig. 10-22, p. 198).


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Obstentrics_Williams. Although the prognosis of nonimmune hydrops is guarded, it is heavily dependent on etiology. In large series from Thailand and Southern China, aA-thalassemia is the predominant cause of nonimmune hydrops, accounting for 30 to 50 percent of cases and conferring an extremely poor prognosis (Liao, 2007; Ratanasiri, 2009; Suwanrath-Kengpol, 2005). In contrast, treatable etiologies such as parvovirus, chylothorax, and tachyarrhythmias, which each comprise about 10 percent of Anemia Red cell alloimmunization Fetomaternal hemorrhage Hematological disorder Infection Selected fetal anomalies Placental abnormality Volume overload or Extramedullary hematopoiesis Impaired venous return Hepatic dysfunction, Metabolic disorders impaired protein synthesis Infection Tissue hypoxia ? Heart failure Increased hydrostatic pressure Lymphatic abnormality Decreased plasma oncotic pressure Increased capillary permeability Decreased lymphatic flow Increased interstitial fluid Hydrops fetalis


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Obstentrics_Williams. FIGURE 15�5 Proposed pathogenesis of immune and nonimmune hydrops fetalis. (Adapted from Bellini, 2009; Lockwood, 2009.) cases, can result in survival in two thirds of cases with fetal therapy (Sohan, 2001). Hydrops is readily detected sonographically. As noted, two efusions or one efusion plus anasarca are required for diagnosis. Edema may be particularly prominent around the scalp, or equally obvious around the trunk and extremities. Efusions are visible as luid outlining the lungs, heart, or abdominal viscera (Fig. 15-6). In many cases, targeted sonographic and laboratory evaluation will identiy the underlying cause of fetal hydrops. hese include cases due to fetal anemia, arrhythmia, structural abnormality, aneuploidy, placental abnormality, or complications of monochorionic twinning. Depending on the circumstances, initial evaluation includes the following: 1. 2. Targeted sonographic fetal and placental examination, including:


Obstentrics_Williams

Obstentrics_Williams. 2. Targeted sonographic fetal and placental examination, including: A detailed anatomical survey to assess for the structural abnormalities listed in Table 15-4 MCA Doppler peak systolic velocity to assess for fetal anemia Fetal echocardiography with M-mode evaluation 3. Amniocentesis for fetal karyotype and for parvovirus B19, cytomegalovirus, and toxoplasmosis testing as discussed in Chapter 64. Consideration of chromosomal microarray analysis if fetal anomalies are present 4. Kleihauer-Betke test for fetomaternal hemorrhage if anemia is suspected, depending on findings and test results 5. Consideration of testing for alpha-thalassemia and/or inborn errors of metabolism.


Obstentrics_Williams

Obstentrics_Williams. Kleihauer-Betke test for fetomaternal hemorrhage if anemia is suspected, depending on findings and test results 5. Consideration of testing for alpha-thalassemia and/or inborn errors of metabolism. Isolated Efusion or Edema. Although one efusion or anasarca alone is not diagnostic for hydrops, the above evaluation should be considered if these are encountered, as hydrops may develop. For example, an isolated pericardial eusion may be the initial finding in fetal parvovirus B19 infection (Chap. 64, p. 1217). n isolated pleural efusion may represent a chylothorax, which is amenable to prenatal diagnosis, and for which fetal therapy may be lifesaving if hydrops develops (Chap. 16, p. 324). Isolated ascites also may be the initial inding in fetal parvovirus B 19 infection, or it may result from a gastrointestinal TABLE 15-4. Categories and Etiologies of Nonimmune Hydrops Fetalis


Obstentrics_Williams

Obstentrics_Williams. TABLE 15-4. Categories and Etiologies of Nonimmune Hydrops Fetalis Structural defects: Ebstein anomaly, Fallot tetralogy with absent pulmonary valve, hypoplastic left or right heart, premature closure of ductus arteriosus, arteriovenous malformation (vein of Galen aneurysm) Bradycardia, as may occur in heterotaxy syndrome with endocardial cushion defect or with anti-RolLa antibodies Cystic hygroma, systemic lymphangiectasis, pulmonary lymphangiectasis Parvovirus B19, syphilis, cytomegalovirus, toxoplasmosis, rubella, enterovirus, varicella, herpes simplex, coxsackievirus, listeriosis, leptospirosis, Chagas disease, Lyme disease Skeletal dysplasia with very small thorax Meconium peritonitis, gastrointestinal tract obstruction Congenital (Finnish) nephrosis, Bartter syndrome, mesoblastic nephroma Placental, Twin, and Cord Abnormalities 5


Obstentrics_Williams

Obstentrics_Williams. Meconium peritonitis, gastrointestinal tract obstruction Congenital (Finnish) nephrosis, Bartter syndrome, mesoblastic nephroma Placental, Twin, and Cord Abnormalities 5 Placental chorioangioma, twin-twin transfusion syndrome, twin reversed arterial perfusion sequence, twin anemia polycythemia sequence, cord vessel thrombosis Inborn errors of metabolism: Gaucher disease, galactosialidosis, GM1 gangliosidosis, sialidosis, mucopolysaccharidoses, mucolipidoses Tumors: sacrococcygeal teratoma, hemangioendothelioma with Kassabach-Merritt syndrome apercentages reflect the proportion within each category from a systematic review of 6775 pregnancies with nonimmune hydrops. Modified from Bellini, 2015.


Obstentrics_Williams

Obstentrics_Williams. Modified from Bellini, 2015. FIGURE 15-6 Hydropic features. A. This profile of a 23-week fetus with nonimmune hydrops secondary to B 19 parvovirus infection depicts scalp edema (arrowheads) and ascites (*). B. This 34-week fetus had hydrops secondary to an arteriovenous malformation in the brain, known as a vein of Galen aneurysm. In this coronal image, prominent pleural effusions (*) outline the lungs (L). Fetal ascites is also pres- ent (arrows), as is anasarca. C. This axial (transverse) image depicts a pericardial effusion (arrows) in a 23-week fetus with hydrops from B1o9 parvovirus infection. The degree of cardiomegaly is impressive, and the ventricular hypertrophy raises concern for myocarditis, which can accompany parvovirus infection. D. This axial (transverse) image depicts fetal ascites (*) in a 15-week fetus with hydrops secondary to large cystic hygromas. Anasarca is also seen (bracket).


Obstentrics_Williams

Obstentrics_Williams. abnormality such as meconium peritonms. Finally, isolated edema, particularly involving the upper torso or the dorsum of the hands and feet, may be found in Turner or Noonan syndrome or may represent congenital lymphedema syndrome (Chap. 13, p. 259). An association between fetal hydrops and development of maternal edema in which the fetus mirrors the mother is attributed to Ballantyne. He called the condition triple edema because the fetus, mother, and placenta all became edematous. he etiology of the hydrops is not related to development of mirror syndrome. It has been associated with hydrops from D alloimmunization, twin-twin transfusion syndrome, placental chorioangioma, and with fetal cystic hygroma, Ebstein anomaly, sacrococcygeal teratoma, chylothorax, bladder outlet obstruction, supraventricular tachycardia, vein of Galen aneurysm, and various congenital infections (Braun, 2010).