Prenatal Diagnosis and Fetal Therapy 

Updated: May 11, 2016
  • Author: Shelley C Springer, JD, MD, MSc, MBA, FAAP; Chief Editor: Harsh Grewal, MD, FACS, FAAP  more...
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Practice Essentials

Fetal medicine is a complex undertaking that involves a multidisciplinary team for prenatal diagnosis and fetal therapy. Several issues, including ethical and legal considerations, are particular to fetal medicine; fetal treatment centers may provide solutions to many of these.

Fetal team and issues to consider

A multidisciplinary team in fetal medicine generally consists of the following members:

  • An obstetrician
  • A maternal-fetal medicine specialist
  • A geneticist or genetic counselor
  • A neonatologist
  • A pediatric surgeon
  • An obstetric sonologist
  • Relevant pediatric subspecialists (eg, cardiologists, cardiothoracic surgeons, neurosurgeons, urologists)

Some issues that are of particular significance to fetal medicine include the following:

  • Unclear team leadership
  • Inadequate traditional roles and skills
  • Incompletely resolved issues
  • Knowledge gaps

Ethically, the fetus as a patient is thought of in different, often competing ways; the lack of legal clarity further confounds decision making, such as the following:

  • Maternal beneficence and autonomy versus fetal beneficence and autonomy
  • Vagaries of the legal status of the fetus as a person
  • Identifying viable and previable fetuses as candidates for treatment

Prenatal testing

Prenatal screening tests

Screening tests screen for various fetal metabolic, chromosomal, and anatomic defects.

First-trimester screening tests may include the following:

  • Beta human chorionic gonadotropin (β-hCG): To detect and diagnose pregnancy; in quantitative analysis, β-hCG levels lower than expected for presumed gestation can alert the clinician to an ectopic pregnancy or threatened abortion
  • Pregnancy-associated plasma protein-A (PAPP-A): To detect trisomy 18 and 21 cases (in conjunction with β-hCG and ultrasonography for nuchal translucency)

Second-trimester screening tests may include the following:

  • Maternal serum alpha-fetoprotein (MSAFP)
  • Serum β-hCG
  • Unconjugated estriol (uE3)
  • Inhibin A
  • Maternal hexosaminidase test
  • Fetal cells in maternal circulation

The “triple screen” includes MSAFP, serum β-hCG, and uE3; the addition of inhibin A results in the “quadruple screen.” The panel findings, along with gestational age, can suggest a number of fetal abnormalities, depending on the results pattern.

Prenatal diagnostic tests

Diagnostic tests are indicated when conditions that increase the risk of chromosomal anomaly are present or suspected (eg, advanced maternal age, suggestive fetal ultrasonographic findings). Genetic counseling by trained professionals in a timely and sensitive fashion is an essential adjunct to prenatal diagnosis.

First-trimester diagnostic tests may include the following:

  • Fetal ultrasonography
  • Chorionic villus sampling
  • Early amniocentesis
  • Preimplantation biopsy: Controversial; performed for preimplantation diagnosis in a fetus of parents with substantial risk of a known genetic disorder and in women with repeated miscarriages due to chromosomal translocation
  • Coelocentesis: Considered investigational due to reportedly high rates of pregnancy loss

Second-trimester diagnostic tests may include the following:

  • Midtrimester amniocentesis
  • Percutaneous umbilical blood sampling or cordocentesis
  • Late chorionic villus sampling
  • Fetal muscle and liver biopsy

For timely and appropriate intervention, assessment of fetal well-being in the third trimester, when preterm birth appears imminent, and in labor may include the following diagnostic tests:

  • Amniocentesis
  • Nonstress test (NST)
  • Biophysical profile test: Combines the NST with an assessment of amniotic fluid volume (AFV), fetal breathing movements, fetal activity, and fetal muscle tone
  • Contraction stress test
  • Doppler study: Assesses fetal umbilical arterial blood flow velocity or resistance to flow

Radiologic studies

Diagnostic imaging modalities include the following:

  • Ultrasonography: Single most valuable modality for identifying fetal and/or placental structural anomalies
  • Magnetic resonance imaging (MRI): Important adjunct to ultrasonography
  • Computed tomography (CT) scanning: Limited applications in prenatal diagnosis
  • Fetal magnetocardiography: Prenatal detection of a prolonged QT interval or Wolff-Parkinson-White syndrome

Fetal management

The following are options for medical and surgical fetal therapy to manage various fetal malformations:

  • Termination of the pregnancy
  • Elective cesarean delivery
  • Preterm delivery
  • Prenatal medical treatment
  • Prenatal invasive fetal surgery

Fetal disorders that require treatment include the following:

  • Neural tube defects
  • Congenital adrenal hyperplasia
  • Thyrotoxicosis
  • Hypothyroidism
  • Methylmalonic acidemia
  • Multiple carboxylase deficiency
  • Lung prematurity
  • Maternal HIV infection
  • Immune hydrops
  • Fetal thrombocytopenia
  • Fetal hemoglobinopathies, immune deficiency diseases, inborn errors of metabolism
  • Congenital heart disease
  • Certain fetal arrhythmias (eg, sustained supraventricular extrasystoles, atrial flutter), supraventricular tachycardias, and congenital complete heart block

Surgical interventions in invasive fetal therapy include the following three approaches:

  • Ultrasonography-guided vesicoamniotic and, less commonly, thoracoamniotic shunt placement
  • Fetoscopic techniques for ligation of umbilical cords in acardiac twins, selective laser photocoagulation of communicating vessels in twin-to-twin transfusions, and ablation of posterior urethral valves
  • Open fetal surgery

The above surgical inventions are considered appropriate for the following nine lesions:

  • Obstructive uropathy
  • Hydrocephalus
  • Pleural effusion
  • Twin-to-twin transfusion syndrome
  • Amniotic band syndrome
  • Congenital diaphragmatic hernia
  • Congenital high airway obstruction syndrome
  • Sacrococcygeal teratoma
  • Congenital cystic adenomatoid malformations
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Fetus as Patient

Multidisciplinary approach

Only in the past few decades has the fetus been considered a patient and become the subject of extensive scientific study and attempts at treatment. Technological advances have facilitated our ability to access and manipulate the fetus. Fetal medicine is a complex multidisciplinary undertaking with a team consisting of the following:

  • An obstetrician, who manages the pregnancy and who may perform minimally invasive interventions such as percutaneous shunt and catheter placement
  • A maternal-fetal medicine specialist, otherwise known as a perinatologist, who specializes in diagnosis and treatment of the high-risk maternal-fetal dyad
  • A geneticist or genetic counselor, who focuses on prenatal diagnosis, prognosis, genetic counseling, and the procedures involved in prenatal diagnosis
  • A neonatologist, who counsels the pregnant patient and her family prenatally with respect to expectations and outcomes and prepares to continue care for the baby after birth
  • A pediatric surgeon, who, in conjunction with the neonatologist, continues postnatal management of the fetal disease process and formulates the fetal treatment plan
  • An obstetric sonologist who has expertise in defining the fetal diagnosis and its severity and guiding diagnostic and therapeutic procedures
  • Pediatric subspecialists, such as cardiologists, cardiothoracic surgeons, neurosurgeons, and urologists, depending on the lesion

The following problems are of particular significance to fetal medicine:

  • Unclear team leadership - The physician who takes responsibility for a particular procedure may be different from the one who made the diagnosis or the team taking care of the mother
  • Inadequate traditional roles and skills - The obstetrician may find that closing an empty uterus is entirely different from closing a gravid uterus; surgeons who are accustomed to excising the posterior urethral valves in the neonate may find the same procedure difficult to perform in a half-exteriorized fetus
  • Incompletely resolved issues - These include the optimal agent and depth of anesthesia for both the fetus and mother and the best methods to control bleeding, to maintain fetal exposure, to monitor both patients, to prevent preterm labor, and to prevent the leak of amniotic fluid
  • Knowledge gaps - The maternal-placental-fetal physiology and metabolism presents distinct challenges that preclude mere extrapolation of common medical fundamentals

Fetal treatment center

The fetal treatment center has been established as a solution to these problems. These centers offer many advantages.

One such advantage is that the fetal treatment center is staffed with fetal surgeons, either obstetricians or surgeons, who have acquired broad training and skills for treating the fetus. They have specific knowledge of fetal physiology and procedural problems in the fetus. These specialists have been trained on similar lesions in an animal model with the same team.

Another advantage is that the various perinatal specialists are in close proximity and have a working relationship. A high-risk obstetric unit and a neonatal intensive care unit are in the same center.

Moreover, in such a center, clinical care and research coexist. Given that all fetal procedures are still at an early, even experimental stage, the results must be analyzed periodically by the team and reported to the larger medical community. In such centers, standard protocols can be established and informed consent obtained. In addition, institutional board review of selection criteria, timing, and results of therapy can be conducted. Bioethicists and geneticists are also available to counsel and support families and the team.

Another important aspect of the fetal treatment center is regular multidisciplinary meetings that include nurses and social workers who review each case, follow up on the treatment given, seek expert opinion from inside and outside the center, and communicate with the referring physician.

Ethical and legal considerations

Ethically, the fetus as a patient is thought of in different, often competing ways; the lack of legal clarity further confounds decision-making. Key considerations include the following:

  • Maternal beneficence and autonomy versus fetal beneficence and autonomy
  • Vagaries of the legal status of the fetus as a person
  • Identifying viable and previable fetuses as candidates for treatment

The physician's legal duties to the previable fetus depend on the mother assigning the fetus "patient status" by continuing the pregnancy. The ethical concept is that beneficence-based obligations to the fetal patient should be negotiated in the context of the beneficence and autonomy of the mother.

The pregnant woman has an ethical obligation to accept fetal therapy for a viable fetus if treatment to prevent a serious disease or handicap would benefit or save the life of the fetus, if mortality or injury to the fetus is unlikely, and if mortality or morbidity in the mother is unlikely. Unfortunately, however, every decision-point word is subjective and open to interpretation. The following questions commonly arise:

  • When is a fetus "viable"?
  • What constitutes "serious disease or handicap"?
  • What kind of "benefit" is required to justify the decision?
  • What constitutes "unlikely" with respect to morbidity or mortality of either the mother or the fetus?
  • What role does the biologic father have in these decisions, and does this role differ if the parents are married?
  • What happens when a mother's decisions are contrary to the reasonable best interests of the fetus?

If the therapy being offered to the pregnant woman is experimental, the ethical construct is from the fetal perspective.

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Options for Prenatal Diagnosis

Prenatal diagnosis of fetal disorders and structural malformations is becoming increasingly important for several reasons. Approximately 3% of all pregnancies result in the delivery of an infant with a genetic disorder or birth defect. Such anomalies are also the biggest cause of infant mortality in the United States. Minor malformations are found in an additional 7%-8% of neonates.

Over the last four decades, we have developed an understanding of the genetic basis of an increasing number of diseases. Safe and effective fetal diagnostic techniques are being developed, and earlier detection is expanding therapeutic options. With prenatal diagnosis of fetal abnormalities, the parents, obstetric team, geneticist, and other subspecialists can discuss options ranging from abortion to intrauterine medical and surgical treatments. In concert with the neonatologists, the optimal time, mode, and place of delivery can be determined. Parents can be prepared for short- and long-term postnatal expectations. If appropriate, genetic counseling can assist with further reproductive planning.

Prenatal testing is divided into two types—screening and diagnostic (see Prenatal Screening Tests and Prenatal Diagnostic Tests). Different tests are performed at different stages of gestation and have different risk-benefit profiles.

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Prenatal Screening Tests

Screening tests are safe, minimally invasive studies performed in large, low-risk populations to detect conditions in which a timely intervention can alter outcomes. Screening tests typically have a high sensitivity so as to identify all patients who might be affected. Because specificity may be low, further diagnostic tests are required to confirm the diagnosis in any patient with a positive screening result. Because a positive screening result modifies risk perception, it provides a reasonable indication for invasive, but more specific, diagnostic tests such as amniocentesis.

Prenatal screening tests screen for various fetal metabolic, chromosomal, and anatomic defects. Until relatively recently, pregnant women older than 35 years (ie, of "advanced maternal age") were counseled to proceed directly to diagnostic tests rather than to undergo screening tests first because of elevated risk. A 2007 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG), reaffirmed in 2011, issued prenatal testing recommendations that include offering screening tests to all pregnant women, regardless of age. [1]

First trimester

Beta human chorionic gonadotropin

Beta human chorionic gonadotropin (β-hCG) is produced by the developing trophoblast in the earliest stages of pregnancy and forms the basis for urine and serum pregnancy tests. By the time the first menstrual period is missed, maternal β-hCG levels should be high enough to allow detection and diagnosis of pregnancy—usually about 6-7 weeks postmenstrual age (PMA). In quantitative analysis, β-hCG levels lower than expected for presumed gestation can alert the clinician to an ectopic pregnancy or threatened abortion.

β-hCG is also a component of the traditional triple screen (or the more contemporary quadruple screen) discussed below. Elevated β-hCG levels, especially in conjunction with elevated levels of maternal alpha-fetoprotein (AFP; see below), suggest trisomy 21; markedly elevated levels can indicate a molar pregnancy. Further testing is indicated in both situations.

Pregnancy-associated plasma protein-A

Pregnancy-associated plasma protein-A (PAPP-A) can be measured in maternal blood at approximately 11-13 weeks PMA. When combined with β-hCG and ultrasonography for nuchal translucency (see below), more than 80% of trisomy 18 and 21 cases can be detected (decreased PAPP-A levels and increased β-hCG levels). A home collection kit is available for PAPP-A that allows patients to send their blood samples from home. Results can then be available for the next office visit, when ultrasonography can be performed to measure nuchal fold thickness, another indicator of Down syndrome.

Second trimester

Triple and quadruple screen

The triple screen test includes the following:

  • Maternal serum AFP (MSAFP)
  • Serum β-hCG
  • Unconjugated estriol (uE3)

The quadruple screen test includes all three of these and adds inhibin A.

The panel findings, along with gestational age, can suggest a number of fetal abnormalities, depending on the results pattern (see Table 1 below). Maternal weight, race, and multiple pregnancies may affect the risk calculation.

Table 1. Patterns of Triple Screen Test Results and Their Interpretations (Open Table in a new window)

Condition MSAFP level uE3 level hCG level
NTD Increased Normal Normal
Trisomy 21 Low Low Increased
Trisomy 18 Low Low Low
Molar pregnancy Low Low Very high
Multiple gestation Increased Normal Increased
Fetal death (stillbirth) Increased Low Low

The developing fetus produces two circulating proteins: albumin and AFP. Because adults display only circulating albumin, any AFP found in a pregnant woman is presumed to be of fetal origin. Quantitative AFP measured in the maternal blood at 16-20 weeks' gestation, alone and in conjunction with other markers, is used to screen for various fetal abnormalities. The implications of an elevated MSAFP level vary with gestation, and the most common reason for an abnormal level is incorrect gestational age. Elevated levels can also indicate multiple fetuses. If an abnormal MSAFP level is found, further, more specific testing (eg, ultrasonography, amniocentesis) is performed to distinguish among the possible etiologies.

Causes of an elevated MSAFP level include the following:

  • More advanced gestational age
  • Multiple gestation
  • Neural tube defects (NTDs)
  • Open abdominal wall defects
  • Aneuploidy
  • Renal diseases such as congenital nephrosis, infantile polycystic disease, and bilateral renal agenesis
  • Skin diseases such as ectodermal dysplasia and aplasia cutis congenita
  • Cystic adenomatoid malformation of the lung
  • Maternal hepatic and ovarian tumors
  • Uterine and placental anomalies
  • Fetomaternal hemorrhage
  • Fetal demise

Causes of low MSAFP levels include the following:

As discussed above, β-hCG is produced by the placenta; quantitative measurements used alone and in conjunction with other serum markers increase the reliability of screening diagnostics.

uE3 is a global indicator of a viable fetus supported by a functioning placenta in a well mother. The fetal adrenal gland produces dehydroepiandrosterone (DHEA), which is converted to estriol by the placenta and crosses into maternal circulation. The maternal liver then conjugates the compound and secretes it in bile. Thus, normal levels of uE3 require a functioning fetal adrenal gland, placenta, and maternal liver. Maternal levels of uE3 can also be used in the third trimester as a measure of fetal well-being.

Inhibin A is a protein produced by the placenta and corpus luteum that can be found in maternal blood. Elevated levels suggest trisomy 21.

As quoted by ACOG, quadruple screening yields detection rates of 67% for trisomy 18, 80% for trisomy 21, and 80%-85% for NTDs and/or abdominal wall defects. About 60% of cases of Smith-Lemli-Opitz syndrome, a chromosomally mediated cholesterol synthesis abnormality, can also be detected. The addition of the first trimester PAPP-A and nuchal translucency tests increases detection rates of trisomy 18 to 79% and trisomy 21 to 85%. However, these additions do not improve detection rates for the other conditions.

Maternal hexosaminidase test

Tay-Sachs disease, a genetic disorder more common among confined populations (eg, Ashkenazi Jews), is an autosomal-recessive deficiency of the enzyme that hydrolyzes hexosaminidase A, leading to increased serum levels of this substance. Homozygous individuals display progressive neurologic dysfunction leading to death in the first few years of life; carriers are asymptomatic. Maternal hexosaminidase levels increase in pregnancy and can reflect a fetal origin. [2]

Historically, it was thought that rising maternal hexosaminidase levels could be used to diagnose affected fetuses. Whereas maternal levels are now known to be inconclusive with respect to conclusively identifying homozygotic fetuses, population screening programs have been effective in identifying carriers, including couples whose offspring are at risk. Couples with identified genetic risk can be counseled to undergo definitive invasive testing, such as chorionic villus sampling or amniocentesis (discussed below). [3]

Fetal cells in maternal circulation

Building on the awareness that fetal cells can be found in the maternal circulation (the basis of the Kleihauer-Betke test for maternal-fetal transfusion), researchers have attempted for many years to develop a maternal blood screening test for fetal disorders. Most promising is the ability to diagnose aneuploidy in a male fetus; because the mother has no Y chromosomes in her genetic material, any circulating cells demonstrating a Y chromosome must be of fetal origin. Harvesting and analyzing these cells could lead to noninvasive fetal diagnosis.

In another technique, direct micromanipulator isolation of histochemically identified fetal hemoglobin (HbF)-positive nucleated red cells is followed by fluorescent in situ hybridization (FISH) analysis for chromosomal aneuploidies. The results are obtained in 72 hours and have been shown to correlate highly with amniocentesis results. Although this approach not yet ready for clinical implementation, advances continue to be made in this arena. [4, 5]

A technique has been described that uses methylated DNA immunoprecipitation methodology and real-time quantitative polymerase chain reaction (PCR) to determine the fetal chromosome dosage. The technique uses an antibody specific for 5-methylcytidine to capture methylated sites. Using this noninvasive technique, the study group analyzed fetal-specific differentially methylated regions present in maternal peripheral blood and identified 14 cases of trisomy 21 and 26 normal cases. [6]

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Prenatal Diagnostic Tests

For the most part, diagnostic tests are invasive and resource-intensive, but they directly analyze fetal material and confirm diagnoses. Because the fetal/placental unit is invaded, these tests pose risks of pain, infection, bleeding, fetal scarring, and fetal loss. Multiple recently published large-scale national and international case series have analyzed the fetal risks of the two most common tests: chorionic villus sampling and amniocentesis.

The global experience has shown that the risk of fetal loss (defined as miscarriage < 24 weeks PMA) has declined over time, is lessened when performed by more experienced clinicians, is similar between the two procedures, and is generally found to be less than 2%. Since the mid 1970s, amniocentesis has been used routinely to test for Down syndrome, which is by far the most common, nonhereditary, genetic birth defect, affecting about one in every 1,000 babies. By 1997, approximately 800 different diagnostic tests were available, most of them for hereditary genetic disorders such as Tay-Sachs disease, sickle cell anemia, hemophilia, muscular dystrophy, and cystic fibrosis.

Indications

Conditions that increase the risk of chromosomal anomaly include the following:

  • Advanced maternal age (>35 years), the most common indication
  • Previous offspring with chromosomal anomalies or other birth defects
  • Parental balanced translocation, inversion (manifests as recurrent pregnancy loss), or both
  • Suggestive fetal ultrasonographic findings
  • Positive maternal screening test findings
  • Mother having a disease or being exposed to drugs, medications, or infections known to be associated with congenital malformations in the fetus
  • Mendelian genetic trait in the parents
  • Molecular DNA diagnosis (cystic fibrosis, fragile X)
  • Enzymatic activities in villi, amniocytes, or both

Genetic counseling

Genetic counseling offered by trained professionals in a timely and sensitive fashion is an essential adjunct to prenatal diagnosis. Families must be informed about the diagnosis, severity, prognosis, and available options for treatment and continuation of pregnancy.

Some question the value of prenatal diagnosis and postulate that it produces unnecessary anxiety with no ultimate benefit. The value to the clinician is obvious. Knowledge about the fetus' condition allows counseling and transfer of information that may be of tremendous importance to the family.

Some families faced with a lethal fetal anomaly may choose to terminate the pregnancy. Fetal therapies may be available to families who opt to continue gestation. Information regarding fetal abnormalities allows for the proper team of caregivers to become involved in the pregnancy, to optimize maternal and fetal treatment plans, to prepare for the impending birth and any specialized care that may be required in the neonatal period, and to allow the family to adjust and prepare for the birth of an affected child.

First trimester

Fetal ultrasonography

Fetal ultrasonography in the first trimester is the most reliable method of dating naturally conceived fetuses, as cell division and growth during the earliest part of development proceed at a predictable rate. The so-called fetal "anatomic survey" that traditionally occurs in the mid-second trimester can be used to reliably diagnose anatomic abnormalities such as NTDs and abdominal wall defects, congenital diaphragmatic hernia, limb abnormalities, and cardiac defects.

With the advent of first-trimester ultrasonography screening for nuchal lucency in conjunction with PAPP-A measurements to diagnose trisomy 21, some experts are advocating performing the anatomic survey contemporaneously with the nuchal lucency assessment. Improved ultrasonographic resolution and technique have improved fetal visualization, and several series have shown first-trimester anatomic surveys to be as accurate in identifying anatomic abnormalities as the more traditional examinations at 18-22 weeks. Given the significance of many of the defects that can be identified, the advantages of earlier detection are apparent.

Chorionic villous sampling

Chorionic villous sampling (CVS) is the technique of choice for prenatal diagnosis prior to 12 weeks' gestation for detection of a chromosomal anomaly, DNA molecular diagnosis of classic genetic disorders, and the detection of defects in lysosomal enzymes or mucopolysaccharidoses.

A diagnosis of enzymatic defects, such as 21-hydroxylase deficiency, which causes congenital adrenal hyperplasia, can be made with an allele-specific amplification analysis technique of DNA obtained with CVS. For technical reasons, it is difficult to perform on multiple gestations. The test cannot be used to diagnose anatomic abnormalities, such as NTDs and abdominal wall defects, nor is it useful in diagnosis of Smith-Lemli-Opitz syndrome.

Preliminary ultrasonography is performed to establish fetal viability, gestation, and anatomy and to determine the placental location. A sample of placental tissue is obtained via a 16-gauge polyethylene catheter for analysis under ultrasonographic guidance. The test is usually performed at 8-12 weeks' gestation.

The approach is based on the placental location. A transabdominal approach is preferred for anterior and fundal placentas after 13 weeks' gestation and in active vaginal and cervical infections. The sample is smaller than that obtained with the transcervical method. The transcervical approach is indicated in cases with interposed bowel loops or uterine retroversion and a posterior or low-lying placenta. The transvaginal approach has limited application and is used when the placenta is placed posteriorly, the uterus is retroverted and retroflexed, and the cervical canal points toward the abdomen.

Chromosomal analysis of the sample is performed in two ways, as follows:

  • The direct method evaluates the metaphysis from the outer layer of cytotrophoblasts in the chorionic villi; this method provides results in 2 days
  • A long-term culture of the inner mesenchymal layer of trophoblasts provides results in 10-14 days; these results more closely correlate with the true karyotype

An abnormal direct result has to be confirmed with long-term cultures of trophoblasts, amniotic cells, or fetal lymphocytes. Rarely, a normal direct result is followed by abnormal culture findings, which are confirmed with fetal tissue results. Chromosomal mosaicism occurs in 1.2-2.5% of the samples and may cause diagnostic error. The mosaicism is purely extraembryonic in 70-80% of the cases, and it is more common in direct preparations. If found in both direct preparation and long-term cultures, a follow-up ultrasonographic level 2 screening for anomalies and amniocentesis or cordocentesis are indicated to verify mosaicism in the fetal blood. Maternal cell contamination may also distort the results.

Complications associated with first-trimester CVS include the following:

  • There is a pregnancy loss risk that is approximately twice the natural pregnancy loss risk; although it was once thought that the pregnancy loss risk was higher with first-trimester CVS than with midtrimester amniocentesis, several retrospective studies have found the aggregate loss rates to be similar; limb reduction defects and oromandibular malformations are more likely in some studies, especially if the procedure is performed prior to 10 weeks' gestation [7, 8, 9, 10]
  • Fetomaternal transfusion can occur regardless of the approach used; thus, Rh isoimmunization is considered a relative contraindication, and Rh immunoprophylaxis is administered to Rh-negative women after the procedure

Early amniocentesis

This technique is performed preferably at 15-22 weeks' gestation (see below) but can be performed as early as 14 weeks PMA. It is preferred to CVS when CVS is not reliable, as is the case in higher-order multiple pregnancies, in twins with fused placentae, and in certain biochemical disorders. Chromosomal anomalies can be diagnosed with 99% certainty on the basis of karyotyping of fetal cells. AFP and acetylcholinesterase studies yield a 90-95% sensitivity rate for NTDs and omphalocele. AFP levels are elevated in both conditions, whereas acetylcholinesterase levels are high in NTDs but absent in abdominal wall defects. These studies are not useful for diagnosing Smith-Lemli-Opitz syndrome.

The procedure consists of the aspiration of amniotic fluid (approximately 1 mL/week of gestation) from an amniotic fluid pocket with a 22-gauge needle under ultrasonographic guidance.

Complications associated with amniocentesis include the following:

  • Uterine bleeding (1.9%)
  • Uterine cramping
  • Leakage of amniotic fluid (2.9%)
  • Pregnancy loss (1.4-4.2%)
  • Increased risk of clubfoot when performed prior to 12 weeks' gestation
  • Procedural failure due to tenting of the membranes ahead of the needle
  • Culture failure rates of 1% overall and 5% if the procedure is performed prior to 12 weeks' gestation

Pseudomosaicism and maternal contamination are less likely than with CVS.

Preimplantation biopsy

This controversial procedure is performed for preimplantation diagnosis in a fetus of parents with substantial risk of a known genetic disorder and in women with repeated miscarriages due to chromosomal translocation.

At the eight-cell stage of the embryo, a single cell is removed and analyzed (blastomere biopsy) for X-linked recessive diseases. Only XX embryos are transferred following in-vitro fertilization. More trophectodermal cells can be removed from the blastocyst for analysis. Because it has the same genetic constitution as the ovum, the second polar body can also be analyzed for diseases with known gene defects such as cystic fibrosis, hemophilia, and α1-antitrypsin deficiency.

Coelocentesis

Coelocentesis, defined as coelomic fluid aspiration, can be performed as early as 6-10 weeks' gestation but is still considered investigational because of the high rate of pregnancy loss reported.

Second trimester

Midtrimester amniocentesis

Amniocentesis performed at 16-18 weeks' gestation is the criterion standard of prenatal diagnostic techniques in both efficacy and safety. It is offered to all women older than 35 years as an alternative to initial prenatal screening tests or in those with abnormal findings on quadruple screens. Genetic counseling to evaluate genetic risks and detailed ultrasonography to estimate gestation, placental location, and amount of amniotic fluid are important prior to the procedure.

The procedure is the same as that for amniocentesis in early gestation, except that 20-30 mL of amniotic fluid is aspirated for analysis.

The amniotic fluid phase can be analyzed for several substances, as follows:

  • AFP and acetylcholinesterase levels are used to identify a fetus with NTD or abdominal wall defects, with upwards of 90% sensitivity
  • Bilirubin levels in amniotic fluid are elevated in isoimmune hemolysis, and the risk to the fetus can be predicted on the basis of bilirubin level and gestational age; because bilirubin is a pigmented compound, its concentration in the amniotic fluid can be determined by measuring the optical density of the aspirated fluid, and this value is then plotted on the standard Liley curve to determine fetal risk; fetal therapy is available for those with severe hemolysis
  • Enzyme analysis and measurement of metabolite levels, used for the diagnosis of urea cycle disorders and of other inborn errors of metabolism, may also be performed on the amniotic fluid at this stage

Fetal cells can be extracted from amniotic fluid samples and analyzed for a number of chromosomal and genetic disorders via several methods. Chromosome analysis through direct metaphase visualization is the traditional method; results are obtained in 1-2 weeks. If termination is an option, the study must be performed early enough to allow for results prior to the fetus achieving viability. FISH, when used in addition to standard cytogenetics, can analyze fetal cells for abnormalities in chromosomes 21, 18, 13, X, and Y and provide results in 48-72 hours. FISH can also detect microdeletions found in Prader-Willi, DiGeorge, Williams, and Angelman syndromes.

Direct DNA analysis is done with PCR gene amplification, followed by Southern blot analysis to detect gene deletions. Allele-specific oligonucleotide (ASO) analysis measures the specific binding of labeled probes to normal DNA or mutant sequences to detect gene mutations. This technique is important in identifying disorders in which multiple mutations have to be screened for, such as cystic fibrosis and thalassemia, or in which a restriction site is not created, such as Duchenne muscular dystrophy, Tay-Sachs disease, and phenylketonuria.

Indirect DNA methods, such as linkage analysis with restriction fragment length polymorphisms (RFLPs), are performed in affected individuals and multiple other family members. This can facilitate diagnosis of diseases in which the exact gene defect and location are not known. Crossover changes between the gene and the RFLP probe can distort the results.

Survival motor neuron (SMN) analysis for gene deletion in the family of an affected patient is useful in the prenatal diagnosis of spinal muscular atrophy. Molecular analysis of the fibroblast growth factor receptor 3 gene with direct and restriction enzyme analysis can help to diagnose thanatophoric dysplasia. Fetal DNA obtained by amniocentesis can be analyzed for the same deletion as that of the index case.

Complications of second-trimester amniocentesis include the following:

  • Pregnancy loss (0.3-1%)
  • Amniotic fluid leakage (1-2%) - In rare cases, this may lead to infection, oligohydramnios, arthrogryposis, and pulmonary hypoplasia
  • Amnionitis (0.1%)
  • Rh isoimmunization (1% above baseline risk) - Rh immunoprophylaxis is recommended for Rh-negative nonsensitized women
  • Mosaicism on cytogenetic analysis (1%) - True fetal mosaicism is relatively rare, and fetal blood sampling is required for confirmation

Percutaneous umbilical blood sampling or cordocentesis

The greatest advantage of this technique is that it provides a direct fetal sample and access to the fetus for treatment in utero. With ultrasonographic guidance, a sample of fetal blood is obtained from the umbilical vessel close to the cord insertion near the placenta. A 20- to 27-gauge needle is used; the approach can be transplacental in an anterior placenta or transamniotic in a posterior placenta.

Diagnostic studies that can be performed include the following:

  • Direct karyotyping of fetal lymphocytes can provide results within 24-72 hours
  • DNA studies can be used to diagnose metabolic diseases
  • Hematologic problems (eg, thalassemias, hemophilia, von Willebrand disease, and alloimmune thrombocytopenia) are especially amenable to this technique; in Rh-isoimmunized fetuses, diagnosis and treatment of fetal anemia and thrombocytopenia is possible, as is intrauterine transfusion
  • Immunologic tests can be performed on blood samples for diagnosis of fetal infections (eg, specific immunoglobulin M [IgM] for toxoplasmosis, rubella, cytomegalovirus [CMV], varicella zoster, HIV); viral DNA can be detected by using PCR for certain infections, such as parvovirus B19
  • Fetal arterial oxygen tension (PaO 2), carbon dioxide tension (PCO 2), and pH - These can provide critical indicators of fetal well-being in a growth restricted or compromised fetus and thus can help guide management decisions

Complications associated with cordocentesis are more common in posterior placentae and when the procedure is performed prior to 19 weeks' gestation. These include the following:

  • Fetal loss (1-2.3%)
  • Preterm labor (5-9%)
  • Hematoma of the umbilical cord and placental abruption
  • Chorioamnionitis (0.6%)
  • Fetal exsanguination from the procedure site
  • Rh isoimmunization - Rh immunoprophylaxis is mandatory in all Rh-negative nonsensitized women after the procedure

Placenta penetration during cordocentesis has been associated with a higher risk for fetal loss, preterm birth, and low birth weight. [11]

Late chorionic villus sampling

The technique of placental biopsy is equally effective in the second and third trimesters, and karyotyping is possible with small amounts of placental tissue. It has the advantage of being as accurate as amniocentesis, and it provides rapid results.

Fetal muscle and liver biopsy

Muscle biopsy is used in rare cases of Duchenne muscular dystrophy in which findings from all previous investigations are nondiagnostic. Dystrophin levels are measured in myoblasts by in situ hybridization. Fetal liver biopsies have also been performed to measure enzyme levels of glucose-6-phosphatase and ornithine transcarbamylase in patients with suspected glycogenesis and urea cycle disorders when direct DNA techniques are not sensitive.

Third trimester and labor

The purpose of prenatal diagnosis in the third trimester is to confirm fetal growth, well-being, and lung maturity, as well as to evaluate for infection. For timely and appropriate intervention, fetal well-being must be assessed in the third trimester, when preterm birth appears imminent, and particularly in labor.

Fetal movement is monitored on the basis of maternal perception, which, in nonrandomized studies, has been found to a more accurate indicator of fetal well-being than external fetal monitoring. Lack of fetal movement for longer than 30 minutes suggests possible fetal compromise. Fetal lung maturity is determined in case of an impending preterm delivery and helps in deciding whether to induce preterm labor for any indication.

Amniocentesis

Pulmonary surfactant and surface-active phospholipids are measured in amniotic fluid to evaluate fetal pulmonary maturity. A lecithin-to-sphingomyelin ratio greater than 2, as measured chromatographically in an uncontaminated sample, suggests lung maturity, except in fetuses of mothers with diabetes; this usually occurs in fetuses older than 34 weeks PMA.

Other fetal lung maturity assays measure the surfactant-to-albumin ratio with fluorescent polarization technology and provide early results. Both of these tests are affected by contamination with blood or meconium, and results are unreliable in fetuses of mothers with diabetes or preeclampsia or in cases of intrauterine asphyxia. The presence of phosphatidyl glycerol in amniotic fluid indicates lung maturity, particularly in fetuses of mothers with diabetes. Saturated phosphatidylcholine is unaffected by contamination with blood. A combination of these tests provides a more accurate indication of lung maturity.

Mothers presenting in preterm labor or with premature rupture of membranes may have occult chorioamnionitis, and imminent delivery may be indicated. Amniotic fluid can be sent for fluid analysis and culture; glucose levels less than 20 mg/dL, cloudiness, presence of white blood cells, and bacteria found on Gram stain are worrisome findings.

Nonstress test

Nonstress testing is a simple low-risk procedure in which the fetal heart rate is monitored with Doppler ultrasonography or electrodes on the maternal abdomen or a fetal scalp electrode placed after rupture of membranes, in conjunction with the simultaneous recording of uterine activity with a tocodynamometer. After 32 weeks' gestation, the fetus responds to uterine contractions with tachycardia. The criteria for reactive test results are the following:

  • Heart rate of 120-160 beats/min - Fetal tachycardia may be due to fever, drugs, or fetal arrhythmias or hypoxemia
  • Normal beat-to-beat variability of more than 5 beats/min - Decreased beat-to-beat variability suggests fetal hypoxia, sleep, prematurity, maternal sedation, or narcotic use
  • Two accelerations of more than 15 beats/min lasting more than 20 seconds each within a 15-minute test period

 A reactive test is reassuring, with a high chance of intrauterine survival over the next 7 days. A nonreactive test, which does not meet these criteria, necessitates further testing for confirmation. The disadvantage of the test is variable reproducibility; nonreactivity may be a late sign of fetal hypoxia, a benign pattern, or the result of a prior asphyxial event.

Biophysical profile test

The biophysical profile (BPP) combines the nonstress test with an assessment of amniotic fluid volume (AFV), fetal breathing movements, fetal activity, and fetal muscle tone. It gives a reliable indication of fetal acid-base balance; fetal acidemia has been linked to poor outcomes.

A score of 0 or 2 is given for each of the following parameters observed on ultrasonography:

  • At least one pocket of amniotic fluid greater than or equal to 1 cm depth - 2 points
  • At least one episode of fetal breathing of 60 seconds' duration within 30 minutes - 2 points
  • Three or more discrete episodes of fetal movement - 2 points
  • At least one episode of extension and flexion of extremities or spine - 2 points
  • A reactive nonstress test - 2 points

Scores of 8 or higher indicate a low risk of impending stillbirth (0.8 per 1000 in one series), and weekly retesting is recommended. A score of 6 is equivocal and warrants further investigation. Whereas the false-positive rate of a BPP has been measured as high as 75%, fetal death rates can be increased 14 times in the absence of fetal movement and 18 times in the absence of fetal breathing. Scores of 0-4 correlate well with a fetal blood pH of less than 7.20 and, along with oligohydramnios, may be indications for immediate delivery.

Test results can be adversely affected by prematurity, maternal drugs, or a sleeping fetus. Vibroacoustic stimulation (VAS) has been shown to improve the BPP in more than 80% of cases, without affecting predictive values. [12]

In an attempt to decrease the resources consumed in performing a full BPP, modifications have been proposed. One such modified BPP in frequent clinical use employs the nonstress test with AFV assessment. According to one series, when the nonstress test is reactive and AFV is greater than 2 cm, the risk of stillbirth within the subsequent week is estimated to be 0.186%, and weekly testing is recommended. If either value is abnormal, a full BPP is indicated.

Contraction stress test

The contraction stress test (CST) is used to monitor fetal heart rate in response to uterine contractions that are spontaneous or induced with oxytocin. The contraction should occur within 30 minutes and last 40-60 seconds with a frequency of 3 in 10 minutes. In a healthy fetus, uterine contractions cause transient hypoxia and hypoperfusion of the intervillous space, which is relatively well tolerated. Early decelerations start with the onset of uterine contractions, reach the nadir at the time of peak of the contraction, and end simultaneously. These are benign and are seen in late labor from fetal head compression.

Variable decelerations vary in their timing and relation with uterine contractions and occur in response to cord compression. They are benign unless they are associated with severe or prolonged bradycardia, are less than 60 beats/min, last more than 60 seconds, are associated with an overshoot acceleration lasting more than 1 minute after a variable deceleration, or have poor beat-to-beat variability.

Under conditions of uteroplacental insufficiency, a late deceleration is induced. A late deceleration begins 10-30 seconds after the onset of uterine contraction, the nadir is later than the peak of the contraction, and it returns to baseline after the contraction ceases.

A CST result is positive if late decelerations are present with 50% or more of contractions. A CST finding is equivocal if decelerations are inconsistent. A negative CST result, defined as the absence of late decelerations, is associated with a risk of fetal demise of 0.4 cases per 1000 within the week. Drawbacks of the test are its duration (~90 minutes) and the need for oxytocin.

Doppler study

A Doppler study of fetal umbilical arterial blood flow velocity or resistance to flow is another modality used to assess placental function, particularly to monitor high-risk fetuses. Decreased flow velocity during diastole indicates placental insufficiency, and, in severe cases, diastolic flow may stop completely or even reverse. Therefore, a systolic-to-diastolic umbilical blood flow ratio higher than 3 after 30 weeks' gestation is associated with fetal compromise.

Researchers are still investigating the utility of measuring fetal arterial velocity in assessing redistribution in the hypoxic fetus and as indicators of placental circulation in pathologic placental processes, such as pregnancy-induced hypertension.

Fetal scalp pH is used to accurately determine fetal hypoxia and acidosis. A pH level lower than 7.25 is considered abnormal, and a pH level lower than 7.1 mandates immediate delivery by the quickest route.

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Prenatal Diagnostic Imaging

Ultrasonography

Ultrasonography is the single most valuable modality in the identification of fetal and/or placental structural anomalies. It is also useful in the detection of abnormal growth patterns in the fetus, in estimating gestation, and in assessing fetal well-being in the third trimester and during labor and delivery. It is important in guiding the operator during procedures such as amniocentesis and cordocentesis.

Ultrasonography is widely available and has no known adverse effects. Current techniques, including high-resolution multiplanar imaging, three-dimensional (3D) imaging, and Doppler imaging, have improved its yield. As resolution improves, we are finding fetal conditions that would be pathologic in an infant, such as choroid plexus cysts or fetal hydronephrosis, and are no longer visible after birth. Disadvantages include beam attenuation with maternal adipose tissue and poor images with an engaged fetal head or oligohydramnios. In addition, its success is operator-dependent.

Fetal gestation

Gestation is best estimated in the first trimester, with an error range of 3-5 days. The range increases to 1 week at 12 weeks' gestation and 3 weeks at 36 weeks' gestation.

In the first trimester, the crown-rump length is the most accurate measure of gestation. This is measured from the top of the head to the bottom of the torso or the longest dimension of the fetus excluding the yolk sac and extremities. In the second and third trimesters, parameters used to estimate gestation are the biparietal diameter (BPD), head circumference, abdominal circumference, and femur lengths.

BPD is measured on the transaxial view of the head from the outer edge of the cranium nearest the transducer to the inner edge of the cranium farthest from the transducer. BPD, which is measured at the level of the thalami, including the cavum septum pellucidum, should not be used in cases of hydrocephalus or abnormal head shape or late in the third trimester when the head may be engaged. Measures such as a corrected BPD have been devised to take into account differences in head shape.

Abdominal circumference is the length of the outer perimeter of the fetal abdomen measured at the level of the stomach and intrahepatic umbilical vein on a transverse scan. This measure should not be used in cases of fetal growth abnormality in which the head size may be relatively preserved or in a fetus with diaphragmatic hernia or abdominal wall defect.

In comparison, femoral length is more affected by caliper placement and technically more difficult. Femoral length may be affected by skeletal dysplasias, Down syndrome, and fetal growth abnormalities. Only the length of the diaphysis is measured for femur length.

A combination of these measurements yields the most accurate results.

Abnormal fetal growth patterns

Serial ultrasonography can be used to monitor the rate of increase in fetal biparietal diameter, abdominal circumference, and femoral length, thereby helping to identify a growth-restricted fetus with intrauterine growth restriction (IUGR).

In the third trimester, ratios of morphometric measures such as abdominal circumference and femoral length are used to diagnose IUGR.

Oligohydramnios and a poor biophysical score support the diagnosis of growth restriction secondary to uteroplacental insufficiency. This is most commonly the result of maternal disease such as hypertension. Oligohydramnios is defined as the absence of amniotic fluid pockets or the presence of an amniotic fluid index (AFI; defined as the sum of the vertical distance of the largest pocket in each of four equal uterine quadrants) lower than 5.

Estimated fetal weights, derived by combining several parameters (usually head, abdominal, and femur measurements), are useful. However, they are inaccurate at the extremes of birth weight. Fetuses with IUGR can demonstrate either a symmetric or asymmetric growth pattern. Symmetric growth restriction involves all three anthropometrics (ie, head circumference, weight, length), whereas an asymmetric pattern displays sparing and typically progresses from low weight to restricted length with relative head sparing.

Classic teaching suggests that symmetric IUGR begins early in gestation and is caused by chromosomal or genetic anomalies or intrauterine infections; asymmetric growth restriction presents later and is the result of maternal conditions or nutrition. However, neonatologists have learned from experience that these axioms are not always reliable and that unexplained small size for gestational age (SGA; the neonatal corollary to fetal IUGR) in an infant merits a diagnostic evaluation.

Serial ultrasonography can be used to measure the ratio of abdominal circumference to head circumference and thereby detect macrosomia.

Fetal central nervous system anomalies

Ultrasonography is 95% sensitive in the diagnosis of hydrocephalus and myelomeningocele. Ventriculomegaly has been defined in some studies by a measurement at the atrium of the lateral ventricle of more than 10 mm at any time during pregnancy.

In myelomeningocele, diagnosis is made by noting a divergence of the pedicles of the vertebrae or the presence of a fluid-filled sac. Some intracranial signs are associated, such as ventriculomegaly, small BPD, biconcave frontal bones at 18-24 weeks, a distorted position of the cerebellum, and obliteration of the cisterna magna, especially if associated with Chiari II malformation.

Diagnosis of anencephaly, encephalocele, craniosynostosis, and brain malformations, such as porencephaly, can be made on the basis of ultrasonographic findings. Fetuses with hydrocephalus or meningomyelocele should be evaluated for chromosomal abnormalities or anatomic defects in the cardiac, renal, and skeletal systems. Associated defects are present in 90-95% of cases.

Fetal chest abnormalities

Pulmonary hypoplasia, pleural effusions, cystic adenomatoid malformations, sequestration, and bronchogenic cysts are all pulmonary lesions that can be diagnosed on the basis of ultrasonographic findings.

Diagnosis of congenital diaphragmatic hernia (CDH) is based on the presence of bowel or liver in the thorax with the accompanying blood supply, mediastinal shift, and pulmonary hypoplasia. Polyhydramnios may be present. After the diagnosis, serial ultrasonography should be performed to monitor fetal growth and hydramnios and to evaluate for cardiac anomalies. Workup may include ultrafast magnetic resonance imaging (MRI), echocardiography, and karyotyping with amniocentesis to exclude associated anomalies. Hydrops is a predictor of a poor outcome.

Fetal cardiac abnormalities

Detailed cardiac ultrasonography is indicated in fetuses with the following:

  • Chromosomal anomalies
  • Hydrops
  • Oligohydramnios or polyhydramnios
  • Exomphalos
  • Diaphragmatic hernia
  • Defects in other systems with known cardiac associations

Other indications for cardiac echocardiography antenatally include the following:

  • Family history of congenital heart defect
  • Maternal diabetes or systemic lupus erythematosus (SLE)
  • Maternal lithium, alcohol, or progesterone intake
  • Fetal arrhythmias

M-mode echocardiography is used to measure chamber size, cardiac rhythm, pericardial effusions, and wall thickness and motion. Cross-sectional echocardiograms show the heart position and situs and the atrioventricular (AV) connections. Doppler echocardiograms show the direction and pattern of blood flow, and they can depict valvular regurgitation or stenotic lesions.

Prenatally diagnosed heart disease has been associated with reduced early neurologic morbidity in certain lesions, such as a hypoplastic left heart. Conversely, whereas a poorer prognosis was reported earlier in prenatal cohorts because more severe lesions are more likely to be detected, especially when they are associated with a structural or chromosomal defect.

Fetal gastrointestinal anomalies

Gastroschisis and omphalocele are easily detected on ultrasonography. Ultrasonography has low sensitivity in the diagnosis of obstruction, which is indirectly indicated by the presence of polyhydramnios, poorly visualized gut distal to the obstruction, and a fluid-filled portion proximal to it. An echogenic bowel, meconium peritonitis, and pseudocyst formation are suggestive of cystic fibrosis. All of these findings indicate the need for further cytogenetic evaluation of the fetus.

Fetal genitourinary tract anomalies

Ultrasonography can be used to detect renal agenesis, cystic disease, obstructive lesions (uteropelvic junction obstruction and posterior urethral valves), and renal tumors. Renal dimensions, parenchymal thinning and cysts, ratios of renal circumference to abdominal circumference, pelvic diameters, and urinary ascites can be assessed, along with urethral and bladder anatomy. The amniotic fluid volume provides an indication of renal function. Oligohydramnios is associated with a poor prognosis.

Fetal skeletal anomalies

A detailed fetal ultrasonography is used in an attempt to rule out skeletal dysplasias, achondroplasia, osteogenesis imperfecta, polydactyly, and absence of a bone. Long bones are evaluated for size, shape, symmetry, and proportions of the different segments, and the skull is evaluated for shape and deformity. Examination of the spine and ribs helps in the delineation of the disorder.

Identification of a skeletal dysplasia and prognosis are relatively accurate; however, in one study, a specific antenatal diagnosis was made in 60% of cases, but these were incorrect in 19% postnatally. According to some reports, 3D ultrasonography seems to provide additional visualization of skeletal deformities and abnormal spatial relations, such as short ribs and absent bones, and to enable specific diagnosis.

Fetal chromosomal anomalies

In one meta-analysis, nuchal thickening was found to be the most accurate marker in the second trimester. It was associated with a 17-fold increased risk of Down syndrome.

Nuchal thickening in the first trimester has a sensitivity of 60-70% for the detection of Down syndrome, with a 5% false-positive rate, whereas ultrasonography and biochemical screening, in combination, improve the sensitivity to 80%. Other single subtle markers (eg, choroid plexus cysts, shortened long bones, echogenic bowel) are not sensitive.

Magnetic resonance imaging

MRI is an important adjunct to ultrasonography. It is used mainly in the assessment of cases with equivocal ultrasonographic findings or when prenatal ultrasonography is not reliable in the identification of fetal anomalies (eg, in the setting of maternal obesity or oligohydramnios). One meta-analysis showed that ultrafast MRI in the third trimester, as compared with ultrasonography, provided additional information for fetal diagnosis in 23-100% of cases, particularly those involving the posterior fossa of the head.

The main advantage of current fast and ultrafast sequence MRI techniques is that they have minimized motion artifacts; thus, sedation is not needed. Various sequences have been used, including echoplanar, half-Fourier single-shot turbo spin-echo (HASTE), and fast spin-echo sequences. Of these, HASTE has proven to be an excellent method of fetal imaging.

Advantages of MRI include the following:

  • Absence of ionizing radiation
  • Multiplanar capability
  • Large field of view
  • Superior soft-tissue contrast enhancement
  • Good image quality in oligohydramnios
  • More precise volumetric measurement
  • Better intracranial delineation

Limitations of MRI include the following:

  • Spatial resolution inferior to that of ultrasonography
  • Poor depiction prior to 20 weeks' gestation
  • Safety question - It is not approved by the Food and Drug Administration (FDA) in this setting, but there is no known significant risk beyond the first trimester

MRI may be used if other nonionizing imaging modalities are inadequate or if ionizing radiation would otherwise be required for further evaluation.

Indications for MRI evaluation include the following:

  • Fetal cerebral anomalies - MRI has been most successful in the identification of posterior fossa abnormalities, migrational anomalies (eg, lissencephaly, polymicrogyrias, schizencephaly) at 30-32 weeks' gestation, agenesis of the corpus callosum, white-matter disease, hydrocephalus, and ischemic or hemorrhagic lesions
  • Volumetric analysis - The size of the fetus or individual organs, such as the liver, can be determined; in CDH, volumetric measurements of the right fetal lung and the position of the left hepatic lobe appear to be good prognostic indicators and help in planning therapeutic interventions
  • Congenital high airway obstruction syndrome - MRI can be used to confirm upper airway obstruction by demonstrating hyperinflation of both lungs and dilated fluid-filled airways below the level of obstruction; it can identify fetal neck masses such as cystic hygromas and teratomas, allowing early intervention when indicated
  • Congenital hemochromatosis - T2-weighted MRI can be used to confirm the diagnosis
  • Amniotic band syndrome - MRI provides an accurate diagnosis

Retroactive analysis of a small series by Guillemette-Artur et al suggested that prenatal MRI could identify severe cerebral damage in fetuses exposed to intrauterine Zika virus infection. [13]  The lesions resembled those of severe congenital CMV and lymphocytic choriomeningitis virus infections.

A retrospective sudy by Kheiri et al found that T2-weighted fetal MRI may be useful for prenatal diagnosis of bowel malpositioned bowel, even when the malpositioning is not suspected on the basis of ultrasonography. [14]

Computed tomography

Computed tomography (CT) has limited applications in prenatal diagnosis. It is used mainly when MRI is contraindicated in the mother (eg, if she has a pacemaker, an intraocular metallic foreign body, or intracranial ferromagnetic surgical clips).

The primary advantage of CT is that it delineates fetal bony anatomy better than other imaging modalities do. Its limitations include possible teratogenesis due to ionizing radiation if it is performed in the first trimester and a risk of cancer induction. In children, a risk of mortality from cancer of 1 per 220-440 cases has been reported.

Indications for CT include pelvimetry and CT amniography to confirm monoamnionicity if ultrasonography provides inconclusive data.

Fetal magnetocardiography

A prolonged QT interval or Wolff-Parkinson-White syndrome can be detected in the prenatal period on fetal magnetocardiograms by evaluating T waves and obtaining current arrow maps. A weak, prolonged T wave is likely a good indicator of the condition.

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Options for Fetal Therapy

In the past two decades, the goal of prenatal diagnosis has changed from merely deciding about terminating the pregnancy to possible active intervention for improving the long-term outcome of the fetus. Medical and surgical fetal therapy has emerged as an option for the management of various fetal malformations.

Termination of the pregnancy is an option for families in cases involving serious malformations that are incompatible with life. Examples of these conditions include severe chromosomal abnormalities known to be incompatible with long-term survival (eg, trisomy 13, trisomy 18), certain metabolic conditions, and anatomic defects, especially of the brain and kidneys.

Elective cesarean delivery is indicated in fetal malformations that can cause dystocia or in cases in which immediate surgical correction in a sterile environment is likely to improve outcome or when successful elective delivery of an affected fetus is unlikely to be achieved by the vaginal mode. Conjoined twins, large omphaloceles, severe hydrocephalus, ruptured meningomyelocele, large sacrococcygeal teratoma, and large cystic hygroma are some examples.

Preterm delivery is indicated in a maternal or fetal disorder in which the risk of continued gestation on the function of the involved organ system or to the viability of the fetus is greater than the risk of preterm delivery. Ideally, the delivery will occur at the site where early correction after delivery is available and is of proven benefit to the fetus. Urinary tract obstruction, progressive hydrocephalus, hydrops fetalis, and progressive fetal growth restriction with disturbed umbilical blood flow are examples of such lesions.

Prenatal medical treatment is beneficial in a variety of diseases (see Fetal Therapy: Medical). With the availability of easier and safer access to the fetus, deficient nutrients, hormones, and substrates can be provided, and certain blocked metabolic pathways may be bypassed. Before a case is selected for fetal therapy, the fetal anomaly should be correctly diagnosed and its severity assessed. The benefits of treatment should outweigh both the risks if the anomaly is left untreated and the risks that the procedure itself poses to the fetus and mother. Other serious malformations should be excluded and pulmonary maturity ascertained prior to delivery, and adequate follow-up care should be provided after the intervention.

Prenatal invasive fetal surgery may be beneficial in select conditions amenable to this developing therapy (see Fetal Therapy: Surgical). Currently, these procedures are being performed in a select group of specialized fetal therapy centers on an expanding array of fetal conditions. Therapeutic approaches include palliative maneuvers to facilitate improved fetal organ development; definitive repair of various congenital malformations continues as a long-term goal.

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Fetal Therapy: Medical

Neural tube defects

Perhaps the best known and most extensively studied pharmacologic intervention is folic acid. It has been proven to reduce the incidence of NTDs in women with one or more previously affected children and in women who have no risk factors.

All women are advised to take folic acid prior to conception (0.4 mg/day PO for 3 months), and 4 mg/day is recommended for women with a previously affected child, beginning at least 1 month prior to conception through 3 months of pregnancy.

Congenital adrenal hyperplasia

Because the differentiation of external genitalia begins at 7 weeks' gestation, the mothers of all fetuses at risk (those with a previously affected child) are given dexamethasone (0.25 mg PO qid) at 7-9 weeks.

Direct studies using probes or linkage DNA studies are performed with CVS. Affected female fetuses are identified at a rate of 1 case per 8 carrier parents.

Treatment is continued until term only in affected fetuses. Stress-dose glucocorticoids are administered at delivery and gradually tapered in the mother after delivery. The long-term outcome of patients treated in utero is still being assessed. The treatment has proven effective in preventing masculinization.

Thyrotoxicosis

Fetal thyrotoxicosis is usually seen in infants of mothers with Grave disease or autoimmune thyroiditis. The diagnosis is made with cordocentesis. Maternal treatment with propylthiouracil (300 mg/day PO initially, subsequently titrated according to effect) or methimazole is associated with a good fetal outcome.

Hypothyroidism

Fetal hypothyroidism is linked to maternal hyperthyroidism, use of radioactive iodine, drugs, and excessive maternal iodine intake. Fetal status is evaluated at ultrasonography and by direct cordocentesis. Intra-amniotic L-thyroxine (500 μg every 2 weeks, initiated at 34 weeks' gestation) has been shown to cause regression of fetal goiters and normalization of hormone levels.

Methylmalonic acidemia

This is caused be a deficiency of methylmalonyl CoA mutase or its coenzyme, adenosylcobalamin, which results in an accumulation of methylmalonic acid and its precursors in body fluids. Clinically, patients present in the first few weeks of life with poor feeding, vomiting, hypotonia, lethargy, dehydration, ketosis and acidosis.

Prenatal cyanocobalamin has been empirically administered orally to the mother at a dose titrated to achieve high maternal plasma B12 levels and normal maternal urinary methylmalonic acid excretion. The long-term effects on fetal development have not been studied extensively.

Multiple carboxylase deficiency

This disorder is caused by a deficiency of holocarboxylase synthetase or biotinidase, two enzymes essential to rendering the carboxylases functional. The carboxylase enzymes are involved in the metabolic pathways of isoleucine, leucine, and valine.

Clinically, patients present in the first few weeks of life or later in childhood with hypotonia, seizures, vomiting, failure to thrive, dermatitis, developmental delay, hearing loss, and acidosis. Maternal biotin supplementation may prevent neonatal complications.

Lung maturity induction

In multiple studies, maternal corticosteroid therapy, used to induce lung maturity and surfactant synthesis in the fetus, has been proven effective in significantly reducing respiratory distress syndrome (RDS) in the neonatal period. Controlled studies have shown a reduction from 20.2% to 11.2%. In the extremely premature fetus, antenatal steroids also decrease the incidence of neonatal intraventricular hemorrhage, one of the major causes of cerebral palsy in infants who were born premature.

Betamethasone (12 mg IM q24hr for two doses) or dexamethasone (6 mg IM q12hr for four doses) is recommended for fetuses at less than 34 weeks' gestation who are at risk of preterm delivery. The onset of action in the fetus occurs 48 hours after administration of the first dose.

Repeated courses of antenatal steroids have been linked to neurologic disability in the infant, independent of degree of prematurity. The previous practice of weekly courses has been replaced with a single course given whenever preterm delivery before 34 weeks appears possible. A 2009 multicenter, randomized, placebo-controlled trial showed that the benefit of a single rescue course of steroids given prior to 33 weeks' gestation outweighs the fetal/neonatal risks. [15]

Maternal HIV infection

Maternal administration of zidovudine (AZT), started by 14 weeks' gestation, continued throughout pregnancy, and given IV during labor, followed by treatment of the neonate for the first 6 weeks, has been documented to decrease the rate of vertical transmission from 25% to 8%.

Immune hydrops

Hemolytic disease of the fetus is a condition of fetal anemia caused by Rh isoimmunization. An antibody screen, performed periodically in a sensitized mother, can detect the presence and titer of maternal antibodies.

If the paternal screen for the antigen is positive, PCR can determine fetal blood group from samples obtained at amniocentesis or cordocentesis. Reverse transcriptase (RT)-PCR of fetal cells in maternal blood is also being used for the same purpose.

The fetuses at risk are then monitored with serial ultrasonography (for evidence of hydrops) and Doppler assessment of the velocity of blood flow in the middle cerebral artery (higher in anemic fetuses), starting at 16-18 weeks' gestation and repeated every 1-2 weeks until 35 weeks' gestation.

Alternatively, one can perform amniocentesis serially (10-day to 2-week intervals) with measurement of bilirubin, beginning at 18 weeks, and determine when the result is abnormal from the Queenan and Liley charts.

Serial cordocentesis is indicated for severely affected fetuses for direct measurement of hematocrit, reticulocyte count, and bilirubin.

Intrauterine transfusions can be performed as indicated by the results of the diagnostic tests. Direct intravascular transfusions through umbilical vein puncture or a combination of intraperitoneal and intravascular transfusions can be used. The combination achieves a more stable hematocrit and delays the time to the next transfusion.

The volume of intraperitoneal transfusion can be calculated as follows:

  • Intraperitoneal transfusion volume (mL) = gestational age (wk) – 20 × 10

This is repeated at 2-week intervals until fetal erythropoiesis decreases.

Monitor this with Kleihauer Betke stains and size of fetal liver and spleen on ultrasonography as indicators of extramedullary hematopoiesis. Repeat at 3- to 4-week intervals, with monitoring of the fetal hematocrit.

The intravascular transfusion alone aims to achieve a fetal hematocrit of 35-40%. The intraperitoneal transfusion provides a reservoir of blood and achieves a final hematocrit of 50-60%.

A fetus with hydrops requires careful transfusion until the hematocrit reaches 25%. Transfusion is repeated in 2 days and then weekly to achieve the final hematocrit.

O-negative, CMV-negative allogenic or maternal blood is tested for infection, washed, packed (hematocrit, 75-85%), filtered, irradiated with 25 Gy, and then transfused. Repeat transfusions are indicated until pulmonary maturity or a gestational age of 35 weeks is reached.

Fetal thrombocytopenia

Maternal thrombocytopenia has many causes, many of which do not place the fetus at risk of bleeding.

In idiopathic thrombocytopenic purpura, the fetus has a low risk for intracranial hemorrhage. Scalp electrodes, forceps, and vacuum are not used at the time of delivery. In early labor, a fetal platelet count may be obtained via cordocentesis or a scalp blood smear. If the count is lower than 20,000/μL, a cesarean delivery may be preferred.

Alloimmune thrombocytopenia is the most common type of platelet isoimmunization that occurs in a PLA1 Ag–negative mother, with an incidence of 1 per 5000. If a history of an affected sibling exists, the direct fetal platelet count is measured with blood sampling, and maternal platelets can be transfused with cordocentesis. Disadvantages are the short life span of the platelets, which makes frequent transfusions necessary, and the possibility of further sensitization. Maternal intravenous immunoglobulin G (IVIG; 1 g/kg/wk) coadministered with corticosteroids has been tried with some good results.

Fetal hematopoietic stem cell transplantation

Hematopoietic stem cell (HSC) transplantation in utero is an attractive theoretical option for the treatment of congenital disease that can be diagnosed antenatally and improved by engraftment of HSCs.

Before 14 weeks' gestation, the fetal bone marrow has not yet developed sites for hematopoiesis and is receptive to the engraftment of circulating hematopoietic stem cells. Thymic processing of self-antigens has not yet started, and differentiated T cells have not yet been released into the circulation.

At this stage, theoretically, foreign HSCs should engraft without inducing an immune rejection or graft-versus-host disease and without needing myeloablation. Human leukocyte antigen (HLA) matching is not required. Additionally, specific tolerance for donor antigen is induced, allowing additional cells or bone marrow to be transplanted postnatally from the same donor.

In-utero treatment may also preempt many clinical manifestations of the condition, such as recurrent infections, failure to thrive, and neurologic damage.

The disadvantages of the modality are the maternal and fetal risk from the procedures used to diagnose the disease and to perform the actual HSC transplantation, the technical expertise needed for the procedure, and the expense.

Diseases theoretically amenable to HSC transplantation are hemoglobinopathies such as sickle cell disease and thalassemias, immune deficiency diseases, and inborn errors of metabolism.

Congenital heart disease

The precise diagnosis of congenital heart lesions with the aid of newer echocardiographic techniques has created the potential for prenatal surgery or interventional catheterization. In the treatment of hypoplastic left heart syndrome, umbilical vessel catheterization and balloon valvuloplasty in utero for aortic stenosis are being attempted, with equivocal results. In critical pulmonary stenosis, experimental valvotomy in utero may prevent right ventricular hypoplasia.

At present, the major goal of prenatal diagnosis of congenital heart lesions is genetic counseling and delivery at a tertiary center, where early and optimal management is possible in the neonatal period.

Fetal arrhythmias

Most fetal arrhythmias are benign, and 90% are atrial extrasystoles. These should be observed twice weekly to exclude sustained supraventricular extrasystoles or atrial flutter. In ventricular extrasystoles, myocardial ischemia and tumors (eg, rhabdomyomas) must be excluded.

Prerequisites prior to starting antiarrhythmic therapy include the following:

  • An understanding of the electrophysiologic basis of the abnormal rhythm and its natural history
  • Good understanding of the pharmacokinetics of the agent in the mother, fetus, and placenta
  • Maternal consent for treatment
  • Presence of hydrops fetalis with a sustained supraventricular arrhythmia
  • Early gestation with a sustained arrhythmia in which the risk for development of hydrops is perceived to be high

The disadvantages include early and late mortality in the mother and fetus.

Supraventricular tachycardias

These must be treated if they are sustained and associated with hydrops or upon evidence of left atrial preexcitation and a small foramen ovale.

Inpatient maternal treatment is started after 12-24 hours of fetal cardiac monitoring. Maternal workup includes electrocardiography (ECG) to exclude a maternal Wolff-Parkinson-White syndrome and a determination of electrolyte, blood urea nitrogen (BUN), and creatinine levels prior to digoxin loading.

Digoxin is the first-line drug. Propranolol, procainamide, and quinidine have also been used. All fetal antiarrhythmic medications are associated with risks of proarrhythmia and mortality in both mother and fetus. Carefully select patients for treatment and monitor drug levels and toxicity. Structural defects, such as Ebstein anomaly and mitral insufficiency, must be excluded.

Congenital complete heart block

This is associated with major congenital heart disease in approximately 50% of cases. Diagnoses have included left atrial isomerism, physiologically corrected transposition, atrioventricular canal defects, and ventricular septal defects. This group has a high incidence of congestive heart failure or cyanosis and requires postnatal permanent pacemakers. The remaining cases (50%) are associated with maternal autoimmune diseases (eg, systemic lupus erythematosus, Sjögren disease). Experimental protocols have used immunosuppressives, β-mimetics, and inotropes, with variable results.

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Fetal Therapy: Surgery

Anesthesia

As new intrauterine surgical techniques have been developed, anesthesia for the procedures has also evolved. The major objectives are to ensure maternal and fetal safety. Specific goals are the prevention of maternal hypoxia and hypotension, together with the maintenance of optimal uterine blood flow. Lower doses of epidural and spinal anesthetic agents are needed in pregnant women because of increased epidural pressure and a lower volume of cerebrospinal fluid in the vertebral space.

To promote fetal safety, procedures are generally performed in the second trimester, if possible, to avoid potential teratogenicity from the anesthetic agents.

To prevent fetal asphyxia. normal maternal PaO2 should be maintained, and blood pressure should be maintained (with intravenous fluids and, if necessary, ephedrine, a vasopressor with central adrenergic stimulant action).

The uterine incision stimulates uterine contractions, which must be stopped before preterm labor sets in. The agents used for this purpose include indomethacin, magnesium sulphate, and terbutaline. Indomethacin is administered preoperatively and continued postoperatively for 3-5 days. Fetal adverse effects include premature closure of the ductus arteriosus.

Anesthetic agents commonly used are isoflurane inhalation with 100% oxygen along with muscle relaxants. For surgical procedures involving direct fetal manipulation, direct intramuscular fentanyl and pancuronium (a muscle relaxant and vagolytic) administered to the fetus have been tried prior to hysterotomy under ultrasonographic guidance.

Intraoperative and postoperative monitoring

The parameters monitored during and after surgery include the following:

  • Myometrial contractions and intrauterine pressures
  • Maternal blood pressure, ECG, and pulse oximetric and blood gas levels
  • Fetal pulse oximetric measurement (50-60% saturation), heart rate, blood gases, and ECG
  • Ultrasonographic findings in cases of fetoscopic surgery
  • Fetal temperature - Maintain temperature with continuous warm sodium chloride irrigation, minimized exposure, and increased ambient temperature

Approaches to fetal surgery

Three approaches are currently used for invasive fetal therapy, as follows [16] :

  • Ultrasound-guided shunt placement
  • Fetoscopy
  • Open surgery

Ultrasound-guided vesicoamniotic and, less commonly, thoracoamniotic shunt placement, is used in a fetus from 16 weeks' gestation to when lung maturity makes postnatal treatment the best option. Complications are inadequate function, migration, and iatrogenic gastroschisis.

Fetoscopic techniques now have a clinical application in the ligation of umbilical cords in acardiac twins, in selective laser photocoagulation of communicating vessels in twin-to-twin transfusions, and in the ablation of posterior urethral valves. The procedure is performed inside the uterus using endoscopes, with a much smaller hysterotomy than that needed for open procedures. This lessens the risks of preterm labor and fetal hypothermia and improves fetal hemostasis during the procedure.

The success of fetoscopic surgery depends on the use of both a transabdominal ultrasonographic intraoperative view and a simultaneous endoscopic view to guide placement of the trocars and cannulae. The drawbacks are the risks of bleeding (avoiding the transplacental route decreases this risk), rupture of membranes, and chorioamnionitis. Fetoscopy may also be difficult because of poor access to the fetus resulting from fetal position or polyhydramnios.

Open fetal surgery is currently performed at select centers in instances where the risk of the procedure to the mother and fetus is overridden by a diagnosis with a known poor outcome. Complications such as chorioamnionitis, preterm labor, bleeding, and direct trauma to the fetus are risks in most of these procedures.

These surgical techniques are considered appropriate for nine types of lesions, as discussed in more detail below.

Obstructive uropathy

Patients with severe obstructive uropathy with bilateral hydronephrosis and oligohydramnios revealed with ultrasonography should be evaluated for possible fetal therapy.

Prior to intervention, a cordocentesis is performed to document a normal karyotype and to exclude other major fetal anomalies. This is followed by serial fetal bladder aspirations of urine under ultrasonographic guidance, which can help in the diagnosis of progressive renal damage (tonicity and electrolyte levels in the urine) and can relieve pressure if performed prior to 20 weeks' gestation.

A vesicoamniotic shunt is indicated in persistent megacystis with adequate ultrasonographic and biochemical renal function to reduce pressure in the urinary tract and to improve pulmonary development and decrease uterine compression.

Fetoscopic techniques can be used for fulguration of posterior urethral valves, placement of vesicoamniotic shunts, and vesicostomy. If all of these procedures fail, open vesicostomy with marsupialization of the bladder wall to the abdomen may be attempted.

Open surgery has a high fetal mortality (45%). In a study evaluating long-term postnatal outcomes after fetal surgery for posterior urethral valves in 14 patients, eight patients lived to a follow-up period of 11.6 years. Chronic renal failure was present in five of them. This study emphasized that fetal intervention may assist in prolonging gestation to term, but the sequelae of the lesion on renal function may not be preventable. Fetuses with urethral atresia, despite vesicoamniotic shunts, have a poor prognosis, probably due to the severity and timing of the lesion.

Hydrocephalus

Ventriculoamniotic shunts used for the decompression of obstructive hydrocephalus have had poor results and have caused procedure-related complications. Thus, their use is not indicated.

Fetal surgical procedures, both open and endoscopic, have been performed to repair myelomeningocele in utero. The open procedure is performed at 24-30 weeks' gestation and is shown to reduce both hindbrain herniation and the number of patients requiring shunts for hydrocephalus postnatally.

A randomized study found that surgery before 26 weeks' gestation was associated with a decreased risk of death or shunting before age 12 months, as well as improved mental and motor function scores at 30 months of age. Secondary outcomes included lower degrees of hindbrain herniation and greater likelihood of independent walking. This study was stopped for efficacy as statistical significance was established. However, an increased risk of preterm delivery and uterine dehiscence at delivery was noted. [17]

An endoscopic procedure has been performed by the Vanderbilt group, which consists of maternal laparotomy, followed by placement of a split-thickness maternal skin graft over the exposed spinal cord and neural elements of the fetus. The skin graft is attached with fibrin glue prepared from autologous maternal cryoprecipitate. The procedure has been performed at 22-24 weeks' gestation, with the rationale that neurologic injury is partly acquired through exposure of neural elements to amniotic fluid and the uterine wall.

Pleural effusion

The use of thoracoamniotic shunts is indicated in a fetus with pleural effusion that reaccumulates after thoracocentesis and causes mediastinal shift. The aim of the shunt is to decompress the chest, promote pulmonary development, and treat the hydrops.

Twin-to-twin transfusion syndrome

Umbilical cord ligation may be indicated in some cases of twin-to-twin transfusion syndrome. In acardiac twins, twin reverse arterial perfusion (TRAP) is characterized by artery-to-artery and vein-to-vein communications between twins in a monozygotic placenta. The donor twin is at risk for congestive failure, and the recipient is acardiac and inadequately perfused.

Umbilical cord ligation is indicated in the acardiac twin or a nonviable twin involved in twin-to-twin transfusion after 21 weeks' gestation. Selective laser photocoagulation of the cord circulation, using an yttrium-aluminum-garnet (YAG) laser, can be performed prior to 21 weeks. In this procedure, an endoscope is introduced intra-amniotically through a port with ultrasonographic guidance.

Amniotic band syndrome

In amniotic band syndrome, attempts have been made to lyse amniotic bands using fetoscopic techniques when a high risk of limb amputation is present.

Congenital diaphragmatic hernia

Many investigators believe that intrauterine therapy is indicated in fetuses with CDH who have a poor prognosis. These patients have been defined as those with the liver in the chest and those with a low lung-to-head ratio (<1.0) on ultrasonography. Additional criteria for intervention include a singleton fetus, normal karyotype, diagnosis made prior to 25 weeks' gestation, and absence of associated anomalies.

The procedures that have been attempted since the early 1990s involved definitive repair by reduction of viscera from the chest, patch placement over the diaphragm, and abdominal silo construction to reduce intra-abdominal pressure. These carried a high mortality in patients with a poor prognosis and have since been abandoned.

The current fetal surgery for CDH is tracheal occlusion. This causes enlargement and real growth of the lungs, often pushing the abdominal viscera back into the abdomen. The trachea is occluded by external metal clips placed either fetoscopically or in an open fashion, delivering the head and neck through a hysterotomy.

Outcomes with fetoscopic and open methods have been comparable. Survival rates in these high-risk patients have been approximately 33%, compared to 10% with conventional postnatal therapy. Significant morbidity related to prematurity, atrial perforation, pulmonary insufficiency, and neurologic complications have been observed.

An ex-utero intrapartum (EXIT) procedure to remove the clips, aspirate lung fluid, administer surfactant, and intubate the trachea is then performed while the fetus is still on placental support, followed by delivery of the baby. The EXIT procedure is performed at 36 weeks' gestation or earlier if fetal hydrops or impending preterm labor is present.

Small trials of internal tracheal occlusion by a detachable balloon placed through a single uterine port using fetal bronchoscopy and ultrasonography have yielded good results. The advantage of the technique is that it is technically less demanding and has a lower risk of recurrent laryngeal nerve and tracheal injury.

Congenital high airway obstruction syndrome

When congenital high airway obstruction syndrome (CHAOS) is complicated by hydrops, an EXIT procedure to place a tracheostomy may be of use. Earlier, fetoscopic, intervention may also be reasonable. The usual causes are laryngeal or tracheal stenosis.

Sacrococcygeal teratoma

Fetuses with sacrococcygeal teratoma may develop hydrops from high output failure. Early attempts at open resection of the teratoma or radiofrequency ablation (RFA) of the tumor proved to be associated with high fetal mortality and maternal morbidity.

Coagulation or ligation of the feeding vessels at the base of the tumor directly at fetoscopy by laser is now possible at an early gestation. This treatment slows the vascular steal and reverses the high-output failure. Targeted RFA of the feeding vessels via a percutaneous probe under ultrasonic guidance is also effective. Potential risks include the following:

  • Gas emboli
  • Hyperkalemia
  • Thrombosis
  • Hemorrhage
  • Hemolysis
  • Burn injury to the adjacent tissue
  • Premature rupture of membranes

Fetal hemodynamic status requires monitoring during and immediately following the ligation because of an increase in afterload after ligation of the previously low-resistance tumor circuit.

Congenital cystic adenomatoid malformations

Of fetuses with congenital cystic adenomatoid malformations, 10% develop hydrops, and these have a mortality approaching 100%. They can be treated at open fetal surgery with resection of the cystic lobe prior to 32 weeks' gestation. In some instances, this improves lung growth and allows the hydrops to resolve. The macrocystic form of cystic adenomatoid malformation may be drained with pleuroamniotic shunts, thus ameliorating the space-occupying effects and improving lung growth.

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