9
Risk Assessment in Preconception and Maternal Care
Jill Fonda Allen, Lisa M. Freese, Quannetta T. Edwards, and Charles J. Macri
Genetics is the primary cause or plays an important role in many medical conditions and birth defects. Given that approximately 3% of newborns have a birth defect or genetic condition, many more develop significant conditions after birth, and more and more women with genetic conditions are having children, medical genetics is of prime importance in obstetric care. Evaluation of risk, identification of appropriate screening and testing options, and the ethical and psychological factors revolving around pregnancy may be encountered at any prenatal, preconception, or primary care visit for women of childbearing age and their families. It is essential that advanced practice registered nurses (APRNs) are knowledgeable about risk assessment and steps that follow when providing preconception and obstetrical (OB) care.
Objectives
1. Describe how RISK elements can be used when providing a genetic/genomic risk assessment for preconception care (PCC)
2. Discuss ancillary and laboratory measures in obstetrics that are used as part of the genetic risk assessment for screening and diagnosis of the fetus
100The genomic risk assessment during preconception and prenatal care is more than evaluation of the risk for a single disorder; rather, it warrants a comprehensive assessment of medical, behavioral, environmental, and other factors that can impact maternal/infant outcomes. In this chapter, RISK elements are discussed as each applies to APRNs in conducting risk assessment when providing preconception or OB care. Before this discussion, Table 9.1 presents definitions of terms commonly used in obstetrics as it pertains to genetic testing.
Review of Data
Review of data as it relates to the personal history provides important information that can impact maternal/fetal outcomes prior to pregnancy. A comprehensive personal history should consist of (a) current age; (b) time period of pregnancy interest and age at time of expected delivery; (c) in-depth past and current medical and surgical history; (d) past and current medications including over-the-counter medications and contraceptives; (e) nutritional history; (f) lifestyle, behaviors, and environmental exposures; (g) psychosocial assessment; (h) immunization history; (i) prior gynecological and OB history including history of miscarriages, pregnancy outcomes during prenatal and postnatal period, as well as status of infant; and (j) reproductive plan. Undiagnosed, untreated, or poorly controlled medical conditions should be evaluated, including specific medications used and evaluation of teratogenic effects as should be employed as part of PCC and the risk assessment process (American College of Obstetricians and Gynecologists [ACOG], 2005; Nypayer, Arbour, & Niederegger, 2016). A comprehensive physical exam should be conducted and any abnormal findings that can impact maternal and fetal outcomes documented. Evaluation for infectious diseases (sexually transmitted infections) that can impact the pregnancy and neonate should also be conducted and pertinent counseling and management of care implemented. Carrier screening for genetic disorders (e.g., hemoglobinopathy, cystic fibrosis [CF] screen) is another important measure that should be offered based on the individual and partner’s ancestry/ethnicity and family history. Sickle cell disease, for example, occurs more frequently in individuals of African descent with approximately one in 10 with the trait and one in 300 to 500 African American newborns with sickle cell disease (ACOG Committee on Genetics, 2017). Optimally, carrier screening should be part of PCC or the first OB visit. Carrier screening options should be based on professional guidelines from the ACOG and the American College of Medical Genetics and Genomics (ACMG). For example, individuals of Mediterranean, Asian, Middle Eastern, Hispanic, and West Indian descent are more likely to have mutations in beta thalassemia; alpha thalassemia is commonly found among individuals of Southeast Asian, African, West Indian, and Mediterranean ancestry. Currently, the ACOG Committee on Genetics (2017) recommends a complete blood count with red blood cell indices performed on all women to assess for anemia and hemoglobinopathies, with hemoglobin electrophoresis performed, in addition to complete blood count based on ethnicity described, if there is a suspicion for hemoglobinopathy (ACOG Committee on Genetics, 2017). In addition, CF carrier screening should be conducted for all women as part of PCC, or on women who are currently pregnant (ACOG Committee on Genetics, 2017). Carrier screening is discussed in more detail in the following.
Preconception Care (PCC) and Risk Assessment
101TABLE 9.1 Selected Terms Commonly Used in Obstetrics as They Relate to Genetic Assessment
Term | Description |
Aneuploidy | Abnormality in the chromosomal number from the usual 46 (e.g., trisomy 21)a |
Carrier screening | Screening conducted to identify individuals who have one copy of a gene mutation that, when present in two copies, causes a genetic disorder (e.g., autosomal recessive disorders)b |
Noninvasive prenatal testing—after 10 weeks (10–22 weeks). Also known as cell-free DNA screening or aneuploidy | Cell-free DNA analyzed from the maternal blood for detection of pregnancies at increased risk for fetal aneuploidy and, if requested, sex chromosome compositionc, d |
Predictive testing | Testing used to detect gene mutations associated with disorders that usually occur later in lifeb |
Prenatal diagnosis | Diagnostic testing done on fetal cells obtained from amniocentesis, chorionic villus sampling, or fetal blood sampling (rare) using varied techniquesb,e |
Types of prenatal testing Chromosome analysis DNA analysis Microarray analysis | Testing that can be done on amniocytes, villi, or fetal blood to detect changes in the chromosomes or genesb |
Preimplantation testing or screening (PGD and PGS) | Assessment of “embryos” (blastocysts) obtained via assisted reproductive measures (e.g., in vitro fertilization [IVF]) to detect genetic changes to allow transfer of an unaffected embryo to improve the success rate for IVF and/or to reduce the risk of miscarriage or of having an infant with a particular genetic or chromosomal disorderb |
PGD, preimplantation genetic diagnosis; PGS, preimplantation genetic screening.
Source: aGriffiths et al. (2000); bLister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, National Institutes of Health, Department of Health & Human Services (2017); cNational Coalition for Health Professional Education in Genetics (2012); dAmerican College of Obstetricians and Gynecologists (ACOG, 2015a); eACOG (2014).
102Family history of the patient and her partner should be conducted and include preferably a three-generation pedigree (including siblings, niece/nephews, aunt/uncles, first cousins) to visualize potential 103relationships or patterns that may indicate genetic conditions. Assessment for the presence of mental retardation, birth defects, known or suspected hereditary conditions, or infant loss is central to determining what PCC genetic carrier screening should be implemented. Carrier screening is available for many autosomal recessive disorders (e.g., spinal muscular atrophy). A family history of mental retardation is an indication to offer fragile X carrier screening. Referral for genetic counseling should be made when further investigation is needed into the family history, when specialized carrier screening is warranted, or when one individual is identified as a carrier and carrier screening is needed on the partner.
Identification of Risk
Identification of risk should be based on information obtained from the comprehensive history. Table 9.2 provides a list of modifiable elements of risk or red flags based upon maternal history that warrant intervention.
Selecting the Probability of Risk
Selecting the probability of risk should be based upon identified risk factors (red flags) obtained from the history data and the evidence to support adverse outcomes to the mother and infant.
Keep the Patient Up to Date
Keep the patient up to date on data obtained from the history through risk communication and appropriate management of risk based upon identified red flags. Timely communication of results allows more time for follow-up (e.g., institution of folic acid supplements, or carrier testing of one’s partner). Shared decision making that is culturally sensitive should be implemented with the goal of healthy maternal/infant outcomes. Although pregnancy outcomes cannot be guaranteed, providing evidence-based strategies should be communicated and implemented as part of PCC with the purpose of optimizing the chances for a healthy pregnancy and newborn.
104TABLE 9.2 Elements of Modifiable Risk Based on Maternal History for Preconception Care
Potential Elements of Risk (Red Flags) | Interventions for Preconception Care |
Unmanaged medical conditions (e.g., diabetes, hypertension) | Referral/consultation for management of care before pregnancy includes appropriate counseling of potential pregnancy risks |
Current medication use with potential adverse fetal effects | Referral/consultation for possible medication substitution, change in dose, or reassurance regarding the relative safety of medical treatment |
Nutritional deficiencies including overweight/obesity; underweight | Nutritional consultation a. Initiation of folic acid supplementation 1 month prior to pregnancy |
Unhealthy behaviors or lifestyles (e.g., smoking, alcohol, drug use) | Management of behavioral risk before pregnancy attempt |
Nonimmunized (e.g., rubella) | Immunization assessment and offer of vaccination counseling and immunize where applicable |
Ancestry/heritage with specific carrier screening recommendations | Appropriate carrier screening or referral for genetic counseling |
Family history of known or suspected genetic condition | Appropriate carrier screening or referral for genetic counseling |
Application of Medical Genetics in Modern OB Care
Given the great number and wide variability of birth defects and genetic conditions, applying modern genetics to OB care is a challenge. It is necessary for OB care providers to be well versed with standard screening methods, integrate new screening options, be comfortable with prenatal 105diagnostic testing, and be familiar with specialized evaluation. It is also important for providers to be prepared to make appropriate referrals and know how to find genetic resources for their patients. This section focuses on practical application of these new and not-so-new developments.
Review History
An in-depth personal history is an important part of risk assessment and general OB/prenatal care. Current and maternal age at the time of delivery is important because advanced maternal age is a risk factor for Down syndrome, trisomies 13 and 18, as well as other maternal and fetal risks. Maternal age options are discussed in more detail under screening methods. Figure 9.1 presents a graphic display of the risk of trisomy disorders (aneuploidy) as a consequence of maternal age.
Besides age, the process of data review discussed previously for personal history may identify genetic risk factors. An in-depth OB history should also be obtained including history of abortions/miscarriages, fetal anomalies, or other conditions that impacted the infant at birth or later during childhood. Other factors important to the genetic history include environmental exposures related to employment (e.g., day-care provider’s possible exposure to cytomegalovirus [CMV]), lifestyle (e.g., alcohol consumption), immunization status (e.g., rubella), medications (e.g., antiseizure), and travel history that may increase maternal/fetal risk (e.g., Zika virus). Questions should be carefully chosen to elicit a complete history. For example, “Have you or your partner traveled out of state or overseas in the past year? If yes, where did you travel? Did your travel(s) require premedication (e.g., antimalaria) or immunization(s)? Did you obtain the treatment or immunization prior to travel?” Although some of this inquiry may not directly relate to genetic disorders, the history may be important in order to differentiate inherited or chromosomal disorders from other environmental factors if a problem is found during or immediately after the pregnancy.
A family history should be taken to screen for genetic risk factors. Having the patient complete a family history questionnaire prior to the visit may help start this process. My Family Health Portrait, available via familyhistory.hhs.gov, is one resource that family members can use to obtain data relating to the family history. However, a personal interview will prompt a more complete history that might lead to discovery of a risk for inherited conditions. The family history should include general and specific inquiry about the health of immediate family members (children, siblings, and parents) and at least general and preferably specific inquiry regarding second-degree relatives (aunts, uncles, and cousins). General inquiry has been shown to be ineffective in identifying all potential risks, as patients may not consider a relative to have “mental retardation” or “birth defects” that could be attributed to inherited disorders (particularly recessive or X-linked disorders). Asking questions from the patient’s perspective, using nonmedical terminology such as “Were there any infants in the family history who did not survive or needed surgery at birth?” or “Were there any individuals who were not independent as adults?” might be more effective in obtaining a relevant history and elicit red flags that may be attributed to inherited or chromosomal disorders.
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107Identify Red Flags Through Screening Methods
The personal and family history is one way of identifying red flags that may suggest a risk for genetic disease, chromosomal disorders, or other potential risks to the fetus. However, there are a number of screening tests that may be done on a standard basis during pregnancy and other tests available for high-risk situations to evaluate the fetus’s status or well-being. These can generally be divided into screening tests and diagnostic tests. It is important to discuss these tests in advance with patients and clarify with them the purpose, limitations, and optional nature of each of these tests. This pretest discussion should be geared to enable informed consent and prepare patients for potential results. Approaching evaluation for possible genetic risk factors from a chronological standpoint during pregnancy provides a logical and practical framework for the practitioner. Most of the following tests should be offered based on the ACOG and the ACMG guidelines. Initial discussion should take place prior to or very early in pregnancy, preferably by 8 weeks gestation, to allow the patient time to consider and then schedule testing.
Genetic carrier screening should be offered to all patients based on the patient’s ancestry, heritage, or ethnicity as increased frequency of some genetic diseases is found to occur in higher rates among certain groups (Edwards, Seibert, Macri, Covington, & Tilghman, 2004; Nazareth, Lazarin, & Goldberg, 2015). It is important to assess ancestry/ethnicity for both the maternal and paternal lineages at the time of the preconception or initial obstetrics visit. As noted previously, ACOG/ACMG guidelines should be followed. For example, carrier frequency of Tay–Sachs disease, a severe 108progressive neurologic disease that causes death in early childhood, is one in 30 for Ashkenazi Jewish ancestry, compared to one in 300 in non-Jewish populations, with French Canadians and individuals of Cajun descent having higher frequency rates compared to general population (ACOG Committee on Genetics, 2017; Park et al., 2010). Tay–Sachs carrier screening using either DNA-based testing/mutation analysis or biochemistry (Hex A) should be offered to women who are or whose partner is of Ashkenazi Jewish or half Jewish ancestry, even if she or her partner is not. In addition, the ACOG Committee on Genetics (2017) recommends that carrier screening for Canavan disease, CF, and familial dysautonomia (using DNA) and other disorders should be discussed and offered to individuals of Ashkenazi Jewish descent. Carrier screening for alpha thalassemia should be offered to individuals of Asian heritage, especially those with anemia or conditions where the red blood cell size (MCV) or hemoglobin amount relative to the size of the cell (MCH) is low. CF is more common among non-Hispanic Whites compared with other racial/ethnic groups with a carrier frequency of one in 25; however, because of difficulty in assigning the disorder to one specific ethnic group, screening for CF is reasonable for all couples according to the ACOG Committee on Genetics (2017). It can be a challenge for the practitioner to stay current with genetic carrier screening practice guidelines, as the number and nature of carrier screening options changes with new advances (e.g., expanded carrier screening [ECS] panels).
Genetic carrier screening should be offered or a referral for genetic counseling to explore possible carrier screening should be made as indicated based on family history (e.g., if a family member is diagnosed with a specific condition or is known to be a carrier for a genetic condition). The presence of a family member with mental retardation or autistic spectrum disorders should prompt a discussion of fragile X carrier screening. Also, as per the ACOG and the ACMG, individuals with a family history of birth defects, mental retardation, or recurrent miscarriage should also be offered chromosome analysis to exclude carrier status for a chromosome rearrangement (translocation).
Availability of ECS panels (multiple genetic carrier screening tests) is another carrier screening option that patients may consider. These panels are generally not based on ethnicity or family history and may be offered to any interested individual with complete informed consent. However, ECS panels may also be offered based upon personal and/or family 109history (Wienke, Brown, Farmer, & Strange, 2014). For example, some of these panels include DNA-based carrier screening for recessive genetic disorders seen with more frequency in the Ashkenazi Jewish population (Canavan disease, CF, familial dysautonomia, and Tay-Sachs). Also, recommendations for more comprehensive screening have been made for individuals of Ashkenazi Jewish descent to include a host of other conditions, which include Bloom syndrome, familial hyperinsulinism, Fanconi anemia, Gaucher disease, and Niemann-Pick disease, as well as other diseases (ACOG Committee on Genetics, 2017). Health care providers caring for these high-risk individuals in this racial/ethnic group may want to refer for genetic counseling to ensure appropriate genetic screening is considered. ECS panels may also be appropriate for consanguineous couples (first cousins), by testing for a larger group of recessive conditions. However, the efficacy of ESC panels has yet to be determined. In one study, the carrier frequency of more than 100 genetic mutations for 16 recessive disorders was nearly 1:3.3 for one disorder and one in 24 for two disorders among Ashkenazi Jews (Scott et al., 2010). Outcome-based studies that focus on identification of carrier couples (not just carriers) are needed to establish the efficacy of these panels, not only from a cost perspective, but also from patient and provider perspectives. Some organizations provide targeted carrier screening programs at reduced cost or on college campuses (e.g., Jewish heritage or sickle cell carrier screening). The potential impact of identifying couples who are both carriers for these recessive genetic diseases is one more example of the importance of the genetic risk assessment in preconception and prenatal care.
During pregnancy, other factors may prompt a need for referral for genetic counseling, screening, or prenatal diagnosis. Maternal age is an indication for in-depth discussion and genetic counseling regarding associated risks and options for screening or prenatal diagnosis. This discussion may be valuable for families planning future pregnancies, as maternal age–related risks may prompt them to have children closer together after 35 years of age, or take birth control more seriously after they have completed their family. The complexity of maternal age screening and prenatal diagnostic testing options and personal nature of choices regarding these tests warrants formal genetic counseling. However, a summary of current options for standard screening available in any pregnancy including those with advanced maternal age follows. Prenatal screening tests “show only whether a woman is at low or high risk for having an infant with a 110particular disorder” (ACOG, 2015b, para. 2), but may be used to guide decisions regarding prenatal diagnosis. Examples of current tests are described in the following.
First-trimester screening is the earliest test currently offered to screen for Down syndrome (trisomy 21), trisomy 18, and trisomy 13. It is also effective in recognizing or suspecting certain major fetal anomalies (e.g., anencephaly) well in advance of the formal detailed ultrasound at 18 to 20 weeks. This means that a woman whose fetus has major anomalies is now often alerted to their presence at the end of the first trimester, allowing much earlier patient–provider shared decision making regarding possible pregnancy termination or expectant care for these lethal anomalies. A summary of first trimester and other prenatal screening measures are presented in Table 9.3.
Another more recent prenatal screening option is the use of cell-free DNA (cfDNA) screening for aneuploidy, also referred to as noninvasive prenatal screening (NIPS). cfDNA screening can detect women at increased risk for Down syndrome, trisomies 13 and 18, and, if desired, determine fetal sex (Thompson, 2015). This screening test involves the use of cfDNA from pregnant women taken via from the mother’s blood at or after 10 weeks gestation and is not a routine test nor currently recommended as a first screening test in low-risk or multiple pregnancies (ACMG, 2016; ACOG, 2015b; Thompson, 2015). According to the ACMG (2016), the NIPS is the “most sensitive screening option for traditionally screened aneuploidies involving chromosomes 13, 18, and 21” (para. 4). The cfDNA is currently used to detect aneuploidy (trisomies 21, 18, and 13) and does not detect other chromosome abnormalities or fetal anomalies (e.g., spina bifida and other neural tube or abdominal wall defects), and conventional screening methods discussed previously remain the most appropriate choice for prenatal screening for these conditions in low-risk populations. However, cfDNA may be the most appropriate screen for women at increased risk for fetal aneuploidy, especially when used in conjunction with conventional screening methods (Allen, Stoll, & Bernhardt, 2016). As part of informed consent, patients should have precounseling prior to undergoing cfDNA or any screening test to ensure that they understand that a negative result does not ensure an unaffected pregnancy and any positive test warrants further evaluation to exclude a false positive (ACOG, 2015a; Allen et al., 2016). It is important that referral to a trained genetics professional be made to all patients with a positive cfDNA/NIPS or first-trimester screening result so that further counseling and diagnostic testing can be offered (ACMG, 2016).
