Mary E. Norton, MD

Trisomies 21, 18, and 13 are the most common autosomal trisomies. Triploidy and deletions and duplications of portions of chromosomes also occur. With the advent of chromosomal microarray analysis, it is now possible to identify submicroscopic abnormalities associated with significant genetic diseases.

All pregnant women, regardless of their age, should be offered prenatal screening and diagnostic testing for detection of chromosomal abnormalities.

Chorionic villus sampling is typically performed at 10 to 14 weeks’ gestation, whereas genetic amniocentesis is performed at 15 to 20 weeks.

cfDNA testing, performed after
10 weeks’ gestation, is more than 99% accurate for detection of fetal trisomy 21 and 98% for trisomy 18 with a combined false-positive rate of 0.13% to 0.25%.

Expanded cfDNA panels, which are available from some laboratories, have not been clinically validated and are not recommended.

About 85% of trisomy 21 cases can be detected at 10 to 14 weeks’ gestation, based on a combination of maternal age, NT sonography, PAPP-A, and hCG. NT sonography should be performed only by credentialed sonographers and physicians.

Sonographic markers of aneuploidy that may be visible in the first trimester include cystic hygroma, absent nasal bone, abnormal Doppler blood flow in the ductus venosus, and abnormal blood flow across the tricuspid valve with evidence of tricuspid regurgitation. However, first-trimester evaluation for these secondary markers is not recommended for general population screening.

The optimal time for a genetic sonogram is 18 to 22 weeks. Identification of a major structural malformation increases risk of trisomy 21 by
20- to 30-fold and should trigger
genetic amniocentesis.

Approaches to combined first- and second-trimester screening include sequential screening and integrated screening. A serum integrated screening approach has a relatively high detection rate but provides a
later result.

Articles

Protocol 5 - In this protocol, Norton reviews the pathophysiology of fetal aneuploidy and the wide range of tests for it. Included are perspectives on cell-free DNA testing, first-trimester combined screening, nuchal translucency (NT) sonography, and pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin (hCG), as well as quad marker screening in the second trimester in appropriate cases, and combined first- and second-trimester screening.

Protocols for High-Risk Pregnancies, 7th Edition Prenatal testing for chromosomal abnormalities

While most genetic disorders occur in patients with no relevant family history or risk factors, patients who have a family history of concern often benefit from genetic counseling.Â For more information on genetic testing:Â New tools for counseling on prenatal genetic testing

Slideshows

While most genetic disorders occur in patients with no relevant family history or risk factors, patients who have a family history of concern often benefit from genetic counseling.

7 elements of pretest counseling

In some cases, it’s prudent to refer a patient to a genetic counselor for discussion of testing options. However, it’s neither practical nor realistic to send every prenatal patient for formal genetic counseling. Therefore, obstetricians need to have a strategy to provide basic pretest education and counseling to their pregnant patients.

For more information on genetic testing: 

New tools for counseling on prenatal genetic testing

These are eight indications for referral to genetic counseling:

1.  Family history of a known or suspected genetic disorder
	2.  Known carrier of a genetic condition
	3.  Consanguinity (blood relationship of parents, first cousins, or closer)
	4.  Fetal structural anomaly on prenatal ultrasound
	5.  Abnormal screening test result either traditional serum screening or cell-free DNA screening.
	6.  Known teratogenic exposure
	7.  Recurrent pregnancy loss (3 or more first-trimester losses, stillbirth, or neonatal or fetal loss with structural anomalies)
	8.  Patient request for additional information regarding genetic test options

Obstetricians need to have a strategy to provide basic pretest education and counseling to their pregnant patients.

Eight indications for referral to genetic counseling

In a busy obstetrical practice, use of a family history questionnaire or checklist is usually the most practical means of assessment. Asking patients to complete the questionnaire prior to the clinic visit can ensure that patients have time to contact family members as needed to collect more accurate information. 

For more information on prenatal genetic testing - 

New Tools For Counseling On Prenatal Genetic Testing

Resources for collecting family history information (modified from UpToDate)

Tool for patients to create their own family tree (Available in English and Spanish)

In a busy obstetrical practice, use of a family history questionnaire or checklist is usually the most practical means of assessment.

Resources for collecting family history information 

Obstetricians and their patients are faced with an increasingly complex array of prenatal screening and diagnostic testing options. With the benefit of more options comes the challenge of providing patients with the information they need to make an informed choice about testing that is consistent with their clinical situation and personal values. In a busy clinical setting, it’s often unrealistic to review the recommended content of pretest counseling as described by professional societies. In some cases, it’s prudent to refer a patient to a genetic counselor for discussion of testing options (Table 1); the National Society of Genetic Counselors and the American College of Medical Genetics and Genomics both provide information that can be helpful in locating genetic counseling services.

 However, it’s neither practical nor realistic to send every prenatal patient for formal genetic counseling. Therefore, obstetricians need to have a strategy to provide basic pretest education and counseling to their pregnant patients. This article discusses the important elements of pretest counseling that should be provided to every prenatal patient, and some suggestions on how to do such counseling in a manner that is adequate and yet realistic.
	 

The American College of Obstetricians and Gynecologists (ACOG) makes several recommendations regarding patient counseling about testing for aneuploidy, as well as for carrier screening.  According to ACOG, “[a]neuploidy screening or diagnostic testing should be discussed and offered to all women early in pregnancy…”.

  ACOG also recommends that all women be offered carrier screening that includes, at a minimum, cystic fibrosis (CF) and spinal muscular atrophy (SMA); additional tests may also be recommended depending on the patient’s race and ethnicity.

  Genetic testing should be an informed patient choice, with an underlying foundation of shared decision making that fits the patient’s clinical circumstances, values, interests, and goals. Clearly, complying with these recommendations is challenging in the context of an initial prenatal visit that must also address other important aspects of prenatal care. 


	While most genetic disorders occur in patients with no relevant family history or risk factors, patients who have a family history of concern often benefit from genetic counseling. ACOG recommends that all women have a family history evaluation for inherited risk.

 Genetic counselors typically assess family history by creating a three-generation pedigree, but there are also tools available to collect family history information (Tables 2,3).

  In a busy obstetrical practice, use of this type of family history questionnaire or checklist is usually the most practical. Asking patients to complete the questionnaire prior to the clinic visit can ensure that patients have time to contact family members as needed to collect more accurate information. Any positive responses should be followed up to obtain more detail, including the relationship of the affected family member(s) to the patient, exact diagnosis, age at onset, and severity of disease. Concern is generally greatest when there is an affected first-degree relative (parent or sibling) and less commonly when a more distant relative (aunt, uncle, grandparent, or cousin) has a genetic disorder. An exception is with X-linked disorders, in which case a genetic variant can be passed through unaffected female relatives. Concerns in first-degree relatives, or for X-linked disorders related through female relatives, should prompt consideration of referral for formal genetic counseling.

Importantly, simply ordering expanded carrier screening is not adequate to assess risk for a familial genetic disorder. While expanded carrier screening may include testing for a gene or genes that cause a particular disorder, such panels may not include all variants in a given gene. Therefore, the detection rate of expanded carrier panels is usually lower than targeted testing. Ideally, the specific variant in the family should be identified in order to provide accurate genetic counseling and prenatal testing.

What is the purpose of prenatal genetic testing? Does every patient want such information?


	The purpose of prenatal genetic testing is to determine if a fetus has a genetic disorder. Obtaining such information can serve several purposes; for most women, results are normal and they receive reassurance. For some fetal disorders, prenatal diagnosis allows the family to prepare for the birth of a child with special needs. Early detection of conditions such as cystic fibrosis may ensure early institution of appropriate care after birth. For a few conditions, prenatal detection may lead to a change in pregnancy management or delivery location. In many cases, however, the family is faced with a decision regarding pregnancy termination when no perinatal interventions are available to improve outcomes. 

Related - Should Genomic Testing Be Routine After Stillbirth?

As patients consider prenatal testing, it is important that they understand the reasons that women choose to undergo, or in some cases to decline, prenatal genetic testing. This part of the conversation can be done with a simple explanation and a question: “There are a number of genetic tests that are available to test for different types of birth defects or genetic disorders. There is a range of conditions that we can find, and some are treatable, while for others, no treatment is available. It is your choice whether to have such testing, or if you would like more information about different tests and options. Are you interested in learning more about testing for birth defects?” Some women may decline testing altogether, and that is an acceptable decision that should be supported and documented in the medical record. For women who are uncertain, or want to hear more about options, the next step is a discussion of the difference between screening and diagnostic testing.  

What is the difference between screening and diagnostic testing?


	One of the most important basic concepts of genetic testing is the difference between screening tests, which help a patient refine her risks, and diagnostic tests, which tell a patient for certain if her fetus is affected with a genetic disorder.  As a general rule, screening tests are noninvasive and include ultrasound, such as nuchal translucency; maternal serum tests (such as first- or second-trimester screening); and cell-free DNA (cfDNA) screening.  Diagnostic testing, in contrast, generally requires an invasive procedure such as amniocentesis or chorionic villus sampling for fetal karyotyping or chromosomal microarray. Diagnostic tests are far more comprehensive and accurate, while screening tests carry no miscarriage risk.  

Many patients who undergo cfDNA screening are confused by the nomenclature “noninvasive prenatal testing,” which implies that it is a noninvasive alternative to diagnostic testing. In fact, it is more appropriately presented as an alternative to other screening options (“cell-free DNA screening”). In addition to presenting a simple explanation of the difference between these types of tests, there are patient education tools available through ACOG. A short video available through the Washington State Department of Public Health also explains the difference between prenatal screening and diagnostic tests.  The Perinatal Quality Foundation’s Genetic Education Modules (GEM) also discuss the different prenatal screening and diagnostic tests that are available, with a “test at a glance” page that clearly illustrates the differences (Table 4). 

Regardless of whether a provider refers patients to one of these tools, or explains the tests in person, ensuring that pregnant women understand the difference between screening and diagnostic testing is one of the most important concepts in pre-test counseling (Table 5).  Patients who undergo screening may incorrectly assume that they are diagnostic and that such tests indicate with certainty either that a fetus is “normal” with a guarantee that no anomalies are present or is affected with a congenital disorder because a screening test suggests an increased risk.  Women should be counseled that all positive screening tests require diagnostic confirmation before irreversible actions (such as pregnancy termination) are undertaken.
	 

Review of prenatal screening and diagnostic tests for aneuploidy


	Once assured that a patient understands the difference between screening and diagnostic testing, a provider can then discuss options with a more targeted approach. Different patients, providers, and practices may have access to different test options. ACOG recommends that “[a]ll women should be offered the option of aneuploidy screening or diagnostic testing for fetal genetic disorders, regardless of maternal age,” but does not require that specific tests need to be offered. In the past, women under 35 years old were commonly offered aneuploidy screening, while women 35 and older were often referred to genetic counseling for a comprehensive review of genetic testing options or were offered the options of aneuploidy screening versus diagnostic testing. In contrast, recent recommendations note that while “maternal age may be helpful in adjusting an individual woman’s risk of having a fetus with aneuploidy, it should not be used as the sole determinant of whether aneuploidy screening or diagnostic testing is offered.” Most important is that all women are offered testing, and that the offer of testing be consistent in the practice. Many tools are available that compare and contrast testing options for patients, including the PQF GEM module, the ACOG FAQs or the Washington state video (Table 4). Practices may also create their own brochures, videos, or other tools to describe available options.


	Advances in sequencing techniques have made carrier screening for single-gene disorders more comprehensive and less costly, as well as much more complex. As noted above, ACOG recommends that all women be offered some type of carrier screening that includes, at a minimum, cystic fibrosis (CF) and spinal muscular atrophy (SMA); additional tests may also be recommended depending on the patient’s race and ethnicity.

 Each provider should determine an approach to screening that best fits their population: ethnicity-based, pan ethnic, or expanded carrier screening. In traditional 

, the conditions included are targeted to those associated with a specific ethnic group, such as Ashkenazi Jewish disease screening or hemoglobinopathy screening for patients of African, Mediterranean, or Middle Eastern ancestry. Due to growing admixture of ethnicities, some are moving towards pan ethnic screening, in which a panel of recommended conditions is offered to all patients regardless of their ancestry. 

is the most comprehensive carrier screening option, with screening panels that can include well over 100 recessively inherited conditions.  

Regardless of the approach an obstetrician chooses for his or her practice, it is critical that patients be informed of the benefits and limitations of testing, including a reminder that results cannot completely rule out carrier status, though a negative result significantly reduces the chance that an individual is a carrier. One must also bear in mind that, unlike aneuploidy screening in which only the pregnant woman needs to undergo testing, carrier screening may require testing of the reproductive partner. It is important that a woman knows before undergoing screening that if she is found to be a carrier of an autosomal-recessive condition, testing of the biological father also will be recommended. It should also be noted that the larger the screening panel, the higher the screen-positive rate (up to 60% with very large panels) and the higher the likelihood of needing to test the partner. If the biological father is unknown, not available or unwilling to be tested, that might affect a woman’s decision to pursue carrier screening. As with aneuploidy screening, a woman must also know that if carrier status is confirmed in both members of the couple, diagnostic testing of the fetus would require invasive testing (CVS or amniocentesis). Once again, decisions should take into account a woman’s values, needs and desires.

Discussion of patient’s values and preferences


	Final decisions about prenatal genetic testing must consider individual patients’ values and preferences. Patients should not have blood drawn for genetic tests as part of their routine prenatal labs without a conversation and consent. For many women, initial discussions about the purpose of prenatal testing may lead to a mutual decision that the best option is to forgo genetic testing altogether. Others value the certainty and comprehensive nature of diagnostic testing, while many women want to refine their risk with screening tests as a first step. 

For some women, it may be helpful to complete a decision aid, such as that available through the PQF GEM website (Tables 4 and 5). Answering questions about the relative value of the information obtained can help women better consider the best option for them. 

The prenatal genetic testing landscape has expanded significantly. While that is often daunting to patients and providers, tools are available to help navigate this process. Reviewing the available tools, and deciding which are most appropriate for each practice, can be helpful in streamlining this component of prenatal care, while ensuring that all patients have access to appropriate information.

The authors report no potential conflicts of interest with regard to this article.

National Society of Genetic Counselors home page. Available at 

American College of Medical Genetics and Genomics home page. Available at 

American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine.  Practice Bulletin No. 163: Screening for Fetal Aneuploidy. 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: Carrier Screening in the Age of Genomic Medicine. 

Committee Opinion No. 478: Family history as a risk assessment tool.  American College of Obstetricians and Gynecologists Committee on Genetics. 

Raby BA, Kohlman W, Venne V.  (2018) Genetic counseling: Family history interpretation and risk assessment.  Tirnauer JS, ed. UpToDate. Waltham, MA: UpToDate Inc. 

As new screening options become available, ob/gyns must be able to counsel their pregnant patients appropriately.

Polyhydramnios, or hydramnios, is an abnormal increase in the volume of amniotic fluid. Identification of polyhydramnios should prompt a search for an underlying etiology. The two most common pathologic causes of polyhydramnios are maternal diabetes mellitus and fetal anomalies. When no etiology for the excess amniotic fluid is identified, polyhydramnios is termed “idiopathic,” or unexplained. Idiopathic polyhydramnios accounts for approximately 60% to 70% of cases of polyhydramnios in published series and is identified in nearly 1% of pregnancies. This summary of SMFM Consult Series #46 reviews major considerations in evaluation and management of polyhydramnios (Table 1).

Q| How is amniotic fluid volume assessed? 

After 20 weeks’ gestation, amniotic fluid volume is assessed by using 

either the deepest vertical pocket (DVP) or the amniotic fluid index (AFI). In multiple gestations, the DVP is used. When the single DVP is used, polyhydramnios is defined as a measurement ≥ 8.0 cm. When AFI is used, the threshold is generally considered to be 24 cm or 25 cm, depending on whether a 95th or 97th percentile is selected. 

Polyhydramnios is most often identified in the third trimester. Idiopathic polyhydramnios is usually detected in the third trimester, at a mean gestational age of 31 to 36 weeks across various series. 

The degree of polyhydramnios is frequently categorized as mild, moderate, or severe, based on an AFI of 24.0 to 29.9 cm, 30.0 to 34.9 cm, and ≥ 35 cm, or a DVP of 8 to 11 cm, 12 to 15 cm, or ≥ 16 cm, respectively. Mild polyhydramnios accounts for approximately 65% to 70% of cases, moderate polyhydramnios for 20%, and severe polyhydramnios for < 15%.    

Q| What are the underlying causes of polyhydramnios? 

When an etiology of polyhydramnios is identified, it is most commonly a fetal anomaly or maternal diabetes. Other potential causes of apparently isolated polyhydramnios in a structurally normal fetus include alloimmunization and congenital infection. Physiologically, the fluid increase in many of these cases can be attributed to either (1) impaired fetal swallowing or (2) overproduction of fetal urine due to a high-output cardiac state, renal abnormality, or osmotic fetal diuresis. In general, any anomaly severe enough to cause nonimmune hydrops fetalis (NIHF) may result in polyhydramnios, as these entities are often associated with each other. With maternal diabetes, maternal hyperglycemia leads to fetal hyperglycemia, with subsequent osmotic diuresis into the amniotic fluid compartment. 

Alloimmunization can lead to fetal anemia with resultant NIHF and polyhydramnios. Congenital infections, such as parvovirus, cytomegalovirus, or syphilis, can lead to polyhydramnios by a variety of mechanisms, including anemia or cardiac dysfunction.

Q| What evaluation should be performed when polyhydramnios is detected?

Idiopathic polyhydramnios is a diagnosis of exclusion. While the cause may be unexplained during pregnancy, the underlying risk that a structural or genetic abnormality is identified after birth in a pregnancy associated with apparently idiopathic polyhydramnios is 9% in the neonatal period to as high as 28% when infants were followed up to age 1 year.

 Initial evaluation for polyhydramnios involves targeted ultrasonography to assess for fetal abnormalities. It is important to assess fetal growth because idiopathic polyhydramnios may be associated with macrosomia, and fetal growth restriction associated with polyhydramnios presents a high risk for an underlying fetal abnormality, including trisomy 13 or 18. 

Not all of the abnormalities associated with polyhydramnios are detectable by ultrasound. Fetal esophageal atresia and tracheoesophageal fistula are among the most common polyhydramnios-associated abnormalities and may be difficult to diagnose by ultrasound. Disorders associated with apparently isolated polyhydramnios also include genetic syndromes for which there may be no sonographic findings or no screening or diagnostic test available.

Diabetes, alloimmunization, and congenital infection should be considered in a structurally normal fetus with mild polyhydramnios. Routine prenatal care includes screening for diabetes and alloimmunization, as well as testing for syphilis. Congenital infection usually presents with additional sonographic findings, such as NIHF, hepatomegaly, splenomegaly, or placentomegaly. In cases of polyhydramnios associated with NIHF or additional sonographic features, evaluation for fetal anemia and congenital infection is recommended. 

Severe polyhydramnios presenting earlier in gestation should raise a greater concern for an underlying etiology. In severe cases, especially early in gestation, it is important to review the medical and family history, in addition to obtaining a detailed ultrasound examination. Genetic counseling and consideration of testing for neurologic disorders such as congenital myotonic dystrophy should be considered, especially with decreased fetal movement.

Q| How is a pregnancy with polyhydramnios managed?

Polyhydramnios severe enough to cause maternal respiratory compromise, significant discomfort, or preterm labor often has an underlying etiology, whereas idiopathic polyhydramnios, because it is usually mild and does not present until the mid-third trimester, does not typically require treatment. In selected cases, however, amnioreduction may be considered in an effort to relieve maternal dyspnea or discomfort. Overall, in cases of severe polyhydramnios that results in maternal respiratory compromise such that amnioreduction is considered, an underlying fetal abnormality is usually present. In addition, polyhydramnios usually recurs after amnioreduction, making its efficacy somewhat limited. 

Indomethacin, which is often used for tocolysis, decreases fetal urine production. Due to reported neonatal complications, and in the absence of data on improved maternal or neonatal outcomes, we recommend that indomethacin not be used for the sole purpose of decreasing amniotic fluid in the setting of polyhydramnios.

Likelihood of an underlying fetal abnormality is significantly higher with greater degrees of polyhydramnios, and progression of the condition is suggestive of an underlying etiology. In pregnancies with an identified underlying etiology, the degree of polyhydramnios is associated with an increased likelihood of preterm birth (PTB), a small-for-gestational age infant, macrosomia, and perinatal mortality. 

Rates of PTB are not generally increased with idiopathic polyhydramnios (which is usually mild) but PTB is associated with more severe polyhydramnios. Reported data on whether perinatal mortality is increased with idiopathic polyhydramnios have been inconsistent. Idiopathic polyhydramnios is associated with infant birthweight > 4000 g in approximately 15% to 30% of cases. 

The most recent guidance from the American College of Obstetricians and Gynecologists on antepartum fetal surveillance does not specifically address isolated polyhydramnios or list it as an indication for surveillance. Although antepartum surveillance is often performed in this setting, there are no data to suggest that such assessment decreases perinatal mortality. The role and frequency of follow-up ultrasonography is unclear, but the imaging may be warranted in cases where there is concern for progression of polyhydramnios or to evaluate fetal growth. 

Regarding timing of delivery, there are no data to suggest that induction of labor or PTB are associated with an improved outcome in the setting of mild idiopathic polyhydramnios. Labor should be allowed to occur spontaneously at term and the mode of delivery should be determined based on usual obstetric indications. If an induction is planned, it should not occur at < 39 weeks’ gestation in the absence of other indications.  

Rates of fetal nonvertex presentation are reported to increase as severity of polyhydramnios increases. Clinical or sonographic determination of the fetal presenting part should be performed upon presentation in labor. External version for nonvertex fetal presentation may be considered if there are no contraindications to this procedure.

Rates of dysfunctional labor are increased in the presence of polyhydramnios. Studies have also demonstrated that women with pregnancies complicated by idiopathic polyhydramnios are significantly more likely to undergo a cesarean delivery for failure to progress. Rates of caesarean delivery for women with pregnancies complicated by idiopathic polyhydramnios range from 35% to 55%. An increased risk of operative vaginal delivery in the presence of polyhydramnios has also been reported. Some investigators report a higher frequency of nonreassuring fetal heart rate tracings and postpartum hemorrhage. 

Planning for care of the neonate is necessary in cases of polyhydramnios. As noted previously, there is an increased rate of structural abnormalities or genetic syndromes in the neonate following a gestation complicated by polyhydramnios. Idiopathic polyhydramnios has also been associated with an increased risk of neonatal intensive care unit admission. Pediatric support should be available at delivery for women with mild, idiopathic polyhydramnios; for women with severe polyhydramnios, delivery at a tertiary center is recommended. 

This summary of SMFM Consult Series #46 reviews major considerations in evaluation and management of polyhydramnios.