For a couple at risk for having a child with a genetic disorder there are a number of reproductive options: (1) choosing to remain childless, (2) having children and accepting the risk, (3) choosing to have prenatal diagnosis to determine if the fetus is affected, (4) having artificial insemination or oocyte donation to avoid passing on the mutant gene, (5) undergoing preimplantation genetic diagnosis (PGD), or (6) adoption. In order to have all these options available to them, a couple must receive counseling regarding their specific risks before becoming pregnant; thus, the term preconception counseling.

A preconception counseling session should include a detailed family history and construction of a pedigree. Medical records should be obtained, if necessary, to confirm a diagnosis. Complete medical histories of both members of the couple should be ascertained. Should a significant factor be found, the information provided should include the risk of occurrence in their offspring, the natural history of the disorder, and the testing available to them. Counseling should always be done in a nondirective fashion.

Preconception counseling is the responsibility of all obstetrician-gynecologists, but it is also their responsibility to remain current on diagnostic tests available to determine carrier status or for prenatal diagnosis. Because genetics is a rapidly changing field, each practitioner should have a good working relationship with the local genetics center, and refer couples for consultation, when the situation requires more in-depth knowledge of the disorder, there is an undiagnosed disorder, or when more specialized testing is necessary.

The purpose of this chapter will be to discuss those circumstances in which preconception genetic counseling is appropriate. Table 6-1 briefly outlines the family history, medical history, and social history factors that may require a preconception counseling session. Although it is possible to elicit these findings by careful history taking, a more cost-effective approach is to use a questionnaire such as the one offered by the American College of Obstetricians and Gynecologists (ACOG). In addition to a questionnaire, it is important to ask a general question such as: “Is there any child that died unexpectedly, any person who has a learning disability or is ‘slow,’ or is there any disease that seems to run in the family?” It is common for a couple to check “no” for family members with mental retardation, even when further evaluation reveals several members with moderate to severe intellectual disability. In these families, such individuals are not labeled as mentally retarded, but as “slow” or “learning disabled.” This type of question also will illicit the history of the family member who died in early childhood as a result of a metabolic disease.

A history of a previous stillbirth should prompt a review of the pregnancy records, as well as the autopsy report, if one was performed. The patient’s recollection most often does not provide adequate or complete information on which to base counseling. For example, a stillborn with an encephalocele could represent an isolated neural tube defect (NTD) with a 2% to 3% risk of recurrence, or a component of a number of genetic syndromes, some of which have a 25% risk of recurrence. The patient with an isolated NTD will benefit from preconceptional folate supplementation, but the risk of recurrence will not be modified by folate, if the disorder is a genetic syndrome with autosomal recessive inheritance.

Recurrent miscarriages always should raise suspicion of a possible genetic or chromosomal etiology (see Chapter 14). However, two points must be emphasized. First, a translocation or other chromosome rearrangement will be found as the etiology of recurrent miscarriage in approximately 3% to 6% of cases.¹ Second, the history of a normal child interposed in a history of multiple losses should not be taken as a reason to rule out a chromosomal etiology. An individual who carries a balanced translocation would be expected to have three possible gametes: (1) those with the unbalanced form of the translocation, (2) those with the balanced form of the translocation, and (3) those that did not receive the translocation at all. The latter two types of gametes would be expected to result in normal offspring.

The first priority is to obtain the autopsy report. In this circumstance, the combination of findings were a skin-covered encephalocele, polydactyly, and large polycystic kidneys. The autopsy is consistent with Meckel-Gruber syndrome, an autosomal recessive disorder. You would counsel the patient that the risk of recurrence is 25% for any subsequent pregnancy. When a specific diagnosis is made of a mendelian disorder, the next step should be consultation with a geneticist to determine if a specific gene mutation has been found for the disorder. If there is a known mutation, then the patient has the option of PGD, or prenatal diagnosis by chorionic villus sampling (CVS). If a specific mutation has not been identified, a second trimester ultrasound may be diagnostic, if known structural malformations are present. Although the features of Meckel-Gruber may be variable, at least one of the triad of abnormalities should be present in a subsequent affected pregnancy. Should ultrasound be the only option available, prenatal evaluation in a subsequent pregnancy always should be done by sonologists with extensive experience in detecting fetal structural malformations.

Finally, although folate supplementation (1 mg) is recommended for all women planning a pregnancy, this patient would not be a candidate for the 4 mg dose recommended for women who have had a pregnancy complicated by an NTD. Folate supplementation will not decrease the risk of an NTD that is part of a mendelian syndrome.

The most common way to ascertain a couple at risk for a genetic disorder is by the previous birth of an affected child. For some disorders, the history will be obtained when taking a pregnancy history that reveals a child born with a birth defect. But for later onset diseases, further information may be ascertained only if the history taking includes questions such as: “What is the child’s health now?,” “Has the child had any significant health problems?,” “Is the child on any special diets or medications?” Many of the degenerative neurologic diseases may not present clinically until age 2 years or later, and may not be seen as a birth defect by the family. A child placed on appropriate dietary management at birth for a metabolic disorder, such as phenylketonuria (PKU), and doing well at age 4 may not be considered by the couple to have a genetic disease. For most of these disorders, the inheritance pattern is autosomal recessive, with a 25% recurrence risk. More importantly, prenatal diagnosis is possible in the majority of these conditions. Even in cases in which an effective treatment exists, many couples will choose prenatal testing for reassurance, if the fetus is unaffected, and for planning if the fetus is affected. It is the obstetrician’s responsibility to inform the couple of all of the options available to them.

One of the major difficulties facing the practicing obstetrician/gynecologists is the rapidity with which discoveries are occurring in the field of genetics, and the major impact new information can have for counseling patients at risk. One of the best examples is that of a couple with a previous child having achondroplasia. This common form of dwarfism is inherited in an autosomal dominant fashion; therefore, an individual with achondroplasia has a 50% chance of having a child with the same disorder. Because the gene is 100% penetrant, an individual has the disease if the gene is present. Parents of normal height, who have a child with achondroplasia, should be expected to have essentially a zero chance of a second child because the first child must represent a new mutation in a sperm or egg. In addition, our counseling to the couple would have, in the past, included information that the disorder could not be detected prenatally by ultrasound until the third trimester. As more couples who had been counseled regarding this low risk had a second child with achondroplasia, it became clear that another mechanism must be found to explain what appeared to be a 5% risk of recurrence in these couples. With the advent of molecular studies, mutational analysis confirmed that a second affected child within a family had the exact mutation seen in the previously affected sibling. The mechanism to explain this finding is germ cell mosaicism (Figure 6-1). Depending on where in the lineage of the egg or sperm the mutation occurred, the number of gametes with the mutation could range from a single gamete to 100% of the gametes. Because of multiple DNA replications that occur in the formation of sperm, almost all cases of new dominant mutations are paternal in origin.

The discovery that the mutation causing achondroplasia is in the gene for fibroblast growth factor 3 allows the very precise diagnosis of achondroplasia as early as the first trimester with CVS or by cell free fetal DNA in the maternal circulation (see Chapters 8 and 9).² Preimplantation diagnosis is an option as well.