10 percent.693–695 There is a limited list of known and proven human drug teratogens696 (see Chapter 3). Maternal use of specific teratogenic medications,697 such as isotretinoin, may be missed, unless the physician expressly inquires about them.
Preconception advice to avoid heat exposure in early pregnancy is appropriate. Our observations showed a 2.9 relative risk for having a child with a NTD in mothers who used a hot tub during the first 6 weeks of pregnancy.698 High fever in the very early weeks of pregnancy is a potential teratogen698 and should be avoided and treated promptly. Animal studies show that commonly used drugs enter the fetal brain.699
A report from the Spanish Collaborative Study of Congenital Malformations noted a 2.8‐fold increased risk of Down syndrome in the offspring of women ≥35 years of age and who were taking oral contraceptives when they became pregnant.700
Identification of preconception options
The time to deal with unwanted risks is not during the second trimester of pregnancy, as is so often the case in practice. Preconception counseling will identify specific risks and attendant options, which include the following:
Knowledge of family history
Attention to maternal health (e.g. diabetes control,701, 702 confirm cardiac and vascular normality)
Decision not to have children (includes consideration of vasectomy or tubal ligation)
Adoption
In vitro fertilization
Gamete intrafallopian tube transfer or allied techniques
Artificial insemination by donor
Ovum donation (includes surrogacy)
Intracytoplasmic sperm injection
Carrier detection tests
Noninvasive prenatal screening by fetal DNA in the maternal circulation
Naternal serum α‐fetoprotein screening for NTDs
Prenatal diagnosis (CVS, amniocentesis, cordocentesis, ultrasound, MRI)
Preimplantation genetic testing
Fetal treatment or surgery for selected disorders
Folic acid supplementation in periconceptional period (see Chapter 10)
Noninvasive prenatal testing (aneuploidy; monogenic disorders)
Selective abortion
Genetic counseling as a prelude to prenatal diagnosis
The assumption that noninvasive prenatal testing for common chromosomal abnormalities (see Chapter 7) is a screening and not a diagnostic test, is unfortunately common. Many women receiving a normal report opt to avoid an amniocentesis. The vast majority will be vindicated, but some will complete pregnancy with a child having a disorder that could have been diagnosed in early gestation. Physicians and counselors are advised to remind women of this limitation, given that about half of all chromosomal abnormalities will be missed by the noninvasive screen.703
Prospective parents should understand their specific indication for prenatal tests and the limitations of such studies. Frequently, one or both members of a couple fail to appreciate how focused the prenatal diagnostic study will be. Either or both may have the idea that all causes of intellectual disability or congenital defects will be detected or excluded. It is judicious for the physician to urge that both members of a couple come for the consultation before CVS or amniocentesis. Major advantages that flow from this arrangement include a clearer perception by the partner regarding risks and limitations, a more accurate insight into his family history, and an opportunity to detect an obvious (although unreported or undiagnosed) genetic disorder of importance (e.g. Treacher–Collins syndrome, facioscapulohumeral dystrophy or one of the orofacial–digital syndromes). Women making an appointment for genetic counseling should be informed about the importance of having their partner with them for the consultation, avoiding subsequent misunderstanding about risks, options, and limitations.
Before prenatal genetic studies are performed, a couple should understand the inherent limitations both of the laboratory studies and, when relevant, of ultrasound. For detection of chromosomal disorders, they should be aware of potential maternal cell admixture and mosaicism (see Chapter 11). When faced with potential X‐linked hydrocephalus, microcephaly, or other serious X‐linked disorders, and the realization of less than 100 percent certainty of diagnosis, couples may elect fetal sex determination as the basis for their decision to keep or terminate a pregnancy at risk. For some, neither chromosomal microarrays, biochemical assays, nor DNA analyses will provide results with 100 percent certainty.
The time taken to determine the fetal karyotype or other biochemical parameters should be understood before amniocentesis. The known anxiety of this period can be appreciably aggravated by a long, unexpected wait for a result. The need for a second amniocentesis is rarer nowadays but, in some circumstances, fetal blood sampling remains an additional option that may need discussion. Despite the very unlikely eventuality that no result may be obtained because of failed cell culture or contamination, this issue should be mentioned.
The potential possibility for false‐positive or false‐negative results should be carefully discussed when applicable. Any quandary stemming from the results of prenatal studies is best shared immediately with the couple. The role of the physician in these situations is not to cushion unexpected blows or to protect couples from information that may be difficult to interpret. All information available should be communicated, including the inability to accurately interpret the observations made. This is especially so with the use of the chromosomal microarray (see Chapter 13) and whole‐exome sequencing (see Chapter 14). Cautions are appropriate with special reference to VOUS (see Chapter 14), that require in addition, parental samples to determine inherited or de novo changes.
Other key issues to be considered by the genetic counselor and discussed when appropriate with the consultand follow.
Informed consent
Consent for minor procedures including amniocentesis and CVS has been a requirement for decades and needs no repetition. However, the advent of chromosomal microarrays (see Chapter 13) and whole‐exome sequencing for prenatal diagnosis (see Chapter 14) requires additional explanations and caveats. Informed consent for these two technologies is focused on the potential results, not sampling risks and procedures. The specific issues primarily involve the interpretation of results, their significance, the small possibility of uncertain findings, test limitations, and incidental results.
Chromosomal
