The clinical content of preconception care: genetics and genomics

All individuals 

Obtaining a complete 3-generation family medical history that includes ethnicity information about both sides of the family is arguably the single best genetic “test” that is applicable to preconception care. Additionally, a discussion of obstetric and medical history and parental age at anticipated delivery are critical aspects of a preconception healthcare visit. Family history and other historic data provide an inexpensive and noninvasive assessment of conditions that might affect pregnancy. Learning about these risks in the preconception period is ideal. Improved knowledge about the heritability of a disorder can allow individuals to make informed reproductive decisions and can improve prenatal care during pregnancy. Options that are available to couples before conception include adoption, surrogacy, use of donor sperm, preimplantation genetic diagnosis after in vitro fertilization with transfer of unaffected embryos, and avoidance of pregnancy. Future technologic advances likely will broaden further the choices that will be available to couples.3, 4, 5, 6, 7

Providers of preconception care should also urge women to take a multivitamin, with at least 400 μg of folate, daily beginning at least 1 month before conception. Folate has been shown to reduce the incidence of neural tube defects and may also reduce the incidence of other malformations such as orofacial clefting, limb deficiencies, cardiac defects, urinary tract defects, and omphalocele. Women with a history of medical conditions such as epilepsy or diabetes mellitus or a previous gestation with a neural tube defect may require increased folate intake.8, 9, 10

Finally, in addition to the testing discussed in Table 1, all couples, regardless of ethnicity, should be made aware of the availability of cystic fibrosis–carrier screening.11

TABLE 1. Recommended counseling/testing by race/ethnicity

	Ethnicity (of at least 1 member of the couple)	Disorders with recommended counseling/testing	Type of test
	White	Cystic fibrosisa	DNA testing of CFTR gene11
	European	Cystic fibrosisa	DNA testing of CFTR gene11
	Ashkenazi Jewish	Canavan disease, cystic fibrosis,a familial dysautonomia, Tay-Sachs disease, Gaucher's disease, Niemann-Pick disease Type A, Bloom syndrome, mucolipidosis IV, Fanconi anemia Group C	Canavan disease: DNA testing of ASPA gene13, 15, 19
			Cystic fibrosis: DNA testing of CFTR gene11, 13, 15, 19, 20
			Familial dysautonomia: DNA testing of IKBKAP gene13, 15, 19
			Tay-Sachs disease: enzyme assay for hexosaminidase-A level or DNA testing of HEXA gene13, 15, 19
			Gaucher's disease: DNA testing of GBA gene13, 15, 19
			Niemann-Pick disease Type A: DNA testing of SMPD1 gene13, 15, 19
			Bloom syndrome: DNA testing of BLM gene13, 15, 19
			Mucolipidosis IV: DNA testing of MCOLN1 gene13, 15, 19
			Fanconi anemia Group C: DNA testing of FANCC gene13, 15, 19
	French-Canadian	Tay-Sachs disease	Enzyme assay for hexosaminidase-A level or DNA testing of HEXA gene12, 14, 19
	Cajun	Tay-Sachs disease	Enzyme assay for hexosaminidase-A level or DNA testing of HEXA gene12, 14, 19
	African	Sickle cell disease/trait, thalassemia	Complete blood count with red blood cell indices (RBC), iron indices, hemoglobin electrophoresis16, 17, 18
	Mediterranean	Thalassemia	Complete blood count with red blood cell indices and iron indices; hemoglobin electrophoresis if anemia and normal iron indices16, 17, 18
	Asian	Thalassemia	Complete blood count with red blood cell indices and iron indices; hemoglobin electrophoresis if anemia and normal iron indices; DNA testing of alpha-globin genes for alpha thalassemia if Southeast Asian with low mean corpuscular volume anemia but normal iron studies16, 17, 18

Solomon. The clinical content of preconception care: genetics and genomics. Am J Obstet Gynecol 2008.

a Cystic fibrosis should be discussed with patients of all races/ethnicities.

Couples with ethnicity-based genetic risk factors 

Ancestry influences the probability of being a carrier of many disorders that affect pregnancy. Typically, carriers themselves will not show any signs of a genetic disorder, and there is often no known family history of the condition. The guidelines for testing by ethnicity include conditions for which there is evidence that testing is effective or for which there is strong expert opinion that testing should be performed. However, this is not meant to imply that these conditions do not occur or should be ignored in populations of other ethnicities. Individuals of mixed ancestry or ethnicity should consider carrier testing that is recommended for any component ethnicity. A formal referral could be considered if practitioners are unsure which disorders should be tested. Table 1 contains a summary of counseling/testing by ethnicity.11, 12, 13, 14, 15, 16, 17, 18, 19, 20

Carrier testing can have important psychologic consequences for an individual and should only occur after informed consent is obtained. Choosing the appropriate test and interpreting results of testing can be complex and may vary between different ethnic groups. For example, with the current recommended mutation panel, negative carrier testing for cystic fibrosis in an Ashkenazi Jewish couple would result in a different chance of having an affected child than negative testing in an African American couple. Depending on the provider's proficiency in genetics, carrier testing may necessitate referral to genetic services.11, 13, 15, 19, 20

Couples with genetic risk factors that are based on specific family history 

If at least 1 member of a couple has a family history of developmental delay, congenital anomalies, or other known or suspected genetic conditions, the couple should be referred to a qualified healthcare provider for appropriate counseling and potential testing.2, 4 If a disorder in the individual's family has been identified as having a genetic cause, it may be possible to test an individual to determine whether the couple is at risk for having an affected child. For example, a family history of known genetic conditions such as cystic fibrosis or Tay-Sachs disease should prompt the offer of testing for at least the person with affected relatives. If the person is found to have inherited a gene that could cause the disorder in their children, the partner could be tested to quantify the overall risk. In the case of an X-linked disorder such as hemophilia, sex selection should be discussed.2, 21, 22, 23, 24, 25, 26 Table 2 gives information about examples of family history findings that should prompt further counseling/testing.

TABLE 2. Details from personal or family history that should prompt further counseling

	Chromosomal disorders (eg, Trisomy 21)
	Clotting disorders
	Deafness
	Developmental delay/mental retardation (eg, Fragile X syndrome)
	Early infant death
	Heart defects
	Other known genetic disorders (eg, phenylketonuria, Marfan syndrome)
	Neural tube defects
	Familial cancer syndromes (known or suspected)
	Family history of other congenital malformations
	Neural tube defects
	Orofacial clefts
	Recurrent miscarriages
	Sickle cell disease or trait
	Sudden infant death syndrome
	Thalassemia
	Thrombophilia

Solomon. The clinical content of preconception care: genetics and genomics. Am J Obstet Gynecol 2008.

Couples with genetic risk factors that are based on previous pregnancies 

A history of recurrent pregnancy loss (classically defined as > 2 spontaneous abortions) should prompt testing of both parents for genetic conditions such as chromosomal anomalies and hereditary thrombophilia.17, 27, 28 Testing for chromosomal anomalies can be performed by a test of peripheral blood for chromosome analysis (karyotyping).2 If a chromosomal anomaly such as a balanced translocation is found, providers should discuss the use of in vitro fertilization with preimplantation genetic diagnosis to increase the chance of an unaffected pregnancy.29, 30, 31

Individuals with risk factors caused by known genetic conditions 

Individuals with known genetic conditions should be counseled regarding optimal control of their condition and the chances of having affected offspring; these individuals should be aware of how the presence of a genetic disorder could affect both their health and the health of the fetus. For example, women with sickle cell disease have an increased risk of preterm labor and premature rupture of membranes; women with Marfan syndrome have an increased risk of aortic dissection during pregnancy.32, 33

In certain genetic disorders, there are specific recommendations for management in the preconception period. For example, women with sickle cell disease require increased amounts of folate; women with phenylketonuria should maintain low phenylalanine diets before conception, because infants who are born to women with phenylketonuria with phenylalanine levels of > 20 mg/dL are more likely to have microcephaly, developmental delay, growth restriction, and heart defects.17, 34, 35

Comment 

No provider is expected to be aware of every genetic condition that possibly could affect a pregnancy; however, it is important that all providers be able to do 2 things. First, providers should be able to ask the right questions to determine who might be at risk. This includes the ability to take a 3-generation family history. Second, providers should know when to refer a patient and to whom a patient should be referred. There is a wide array of excellent educational resources regarding genetic disorders and family history that are available on the web. Table 3 contains a list of resources. Finally, providers should keep in mind that this is a very rapidly expanding field. Researchers are unraveling the genetic causes of many conditions for which screening and testing may soon become available.36

TABLE 3. Further resources

	Resources	Comments
	American College of Medical Genetics (www.acmg.net)	Includes links to the latest standards and guidelines for clinical genetics laboratories, with disease/phenotype-specific standards and guidelines
	CDC National Office of Public Health Genomics (cdc.gov/genomics)	Resources on how human genomic discoveries can be used to improve health and prevent disease
	Gene tests (genetests.org)	Reviews about specific conditions, laboratory and clinical directories, handouts for patients
	Genetic Alliance (geneticalliance.org)	Information about specific disorders and advocacy, support, and discussion groups
	Genetic and Rare Diseases Information Center (rarediseases.info.nih.gov/html/resources/info_cntr.html)	Information about specific disorders, explanations for patients, financial assistance information, and access to specialists
	National Society of Genetic Counselors (nsgc.org)	Directory of genetic counselors, guidelines for counseling specific conditions
	Online Mendelian Inheritance in Man (ncbi.nlm.nih.gov/sites/entrez?db=omim)	Searchable database of genes and genetic disorders that targets healthcare professionals
	PubMed (ncbi.nlm.nih.gov/PubMed)	Medical literature database
	US Surgeon General's Family History Initiative (hhs.gov/familyhistory)	Education about family health history through tools such as My Family Health Portrait

Solomon. The clinical content of preconception care: genetics and genomics. Am J Obstet Gynecol 2008.