Reproductive decisions after fetal genetic counselling

A broad range of testing modalities for fetal genetic disease has been established. These include carrier screening for single-gene mutations, first-trimester and second-trimester screening for chromosome abnormalities and open neural-tube defects, prenatal diagnosis by means of chorionic villus sampling and amniocentesis, and preimplantation genetic diagnosis. Reproductive decisions before and after fetal genetic counselling represent the culmination of a dynamic interaction between prospective parents, obstetrician and genetic counsellor. The decision to undergo genetic testing before and after genetic counselling is influenced by a host of interrelated factors, including patient–partner and family relationships, patient–physician communication, societal mores, religious beliefs, and the media. Because of the complexity of personal and societal factors involved, it is not surprising that genetic counselling concerning reproductive decision-making must be individualised. A limited number of principles, guidelines and standards apply when counselling about testing for fetal genetic disease. These principles are that genetic counselling should be non-directive and unbiased and that parental decisions should be supported regardless of the reproductive choice. A critical responsibility of the obstetrician and genetic counsellor is to provide accurate and objective information about the implications, advantages, disadvantages and consequences of any genetic testing applied to prospective parents and their fetuses. These principles and responsibilities will be tested as newer technologies, such as array comparative genome hybridisation, non-invasive prenatal diagnosis and sequencing of the entire genome are introduced into the field of reproductive genetics and become routine practice.

Introduction

During the past half-century, the number of genetic testing modalities presented to prospective parents has significantly increased. Before the 1970s, reproductive risk assessments were primarily based on family history, patterns of inheritance of known Mendelian diseases, and the prevalence of genetic, developmental disorders, or both, in newborn populations. With the introduction of prenatal genetic diagnoses, first by mid-trimester amniocentesis in the 1970s followed by first-trimester chorionic villus sampling in the 1980s, women were segregated into high-risk and low-risk pregnancies, primarily by preconceived ‘cost’ versus ‘benefit’ comparisons.

The high-risk category included advanced maternal age because of aneuploidy, a previous chromosomally abnormal conception, and known carriers either of a single gene mutation or of a chromosome rearrangement. Population screening for open neural-tube defects, first- and second-trimester screenings for aneuploidy, carrier screening for cystic fibrosis, and spinal muscle atrophy exemplify the use of categorisation of pregnancies by reproductive risks. These categorisations reflected established worldwide standards by healthcare providers concerning the application of genetic screening, genetic diagnostic testing, or both, as well as through legislation or health policies issued by states and countries essentially regulating prenatal testing programmes, pregnancy termination, or both.

Reproductive decisions after fetal genetic counselling, however, are essentially premised on the ‘rational-choice model,’ which views prospective parents as autonomous, sensible and individualistic decision-makers when it comes to prenatal testing. A central principle of genetic counselling that is universally accepted by the health profession is that genetic counselling of reproductive decisions should be non-directive and unbiased in support of parents’ ‘rational choices’. A considerable disconnect, however, occurs between this fundamental principle of genetic counselling and the actual practice of obstetrics in the care of pregnant women and their partners. Although reproductive decisions after fetal genetic counselling are presumed to be primarily a personal choice, these decisions are directly and indirectly affected by a myriad of personal and social factors. These factors include individual beliefs and experiences, interpersonal and family relationships, clinician–patient relationships, cultural, societal mores, or both, and, possibly, even evolutionary-influenced decision-making. In this chapter, we aim to provide an objective critique of reproductive decisions after genetic counselling, and emphasise factors contributing to the understanding by prospective parents of the potential implications of screening and diagnostic test results.

Decision-making, primary and secondary influences

Genetic testing, preconceptually and prenatally, is ever evolving. Reproductive decisions after genetic counselling must be viewed within the cultural context of the second decade of the 21st century. The dynamics of individualism and society are rapidly changing, with an increase in personal choice, access to information and external influences. The individual can now access media, the internet, social media and unlimited sources of information. Within society, fewer marriages are taking place, we have an increase in the number of older couples, and a greater acceptance of disability.

Criticisms of decision-making after genetic counselling, however, have not abated; namely, that prospective parents are not autonomous decision-makers, are not necessarily fully informed by their healthcare providers concerning reproductive choices and options, and are misinformed about the lives of individuals born with developmental disabilities (e.g. Down’s syndrome).

It has been generally accepted that decision-making by prospective parents is based on rational assessment of risk, benefit and choices, specifically: (1) the risk of a fetal abnormality compared with the loss of a normal pregnancy after invasive testing; (2) the benefit of gaining reassurance of a healthy fetus; and, (3) the options available if the fetus is identified as affected by a genetic, developmental disorder, or both. Although the birth of a healthy child is a goal shared by healthcare providers and society, their influence significantly alters, and possibly limits, patient autonomy. In general, either through guidelines established by national committees appointed by legislatures, professional societies dedicated to the treatment of pregnant women, or both, healthcare providers are held to a standard that carries professional and legal consequences. Under these guidelines or national programmes, obstetricians, midwives and related healthcare providers are obligated to make available all of the current genetic testing modalities appropriate to individual prospective parents.

The goal of those providing care to pregnant women and their partners is to deliver a normal, healthy child, and healthcare providers have increasingly used preconceptual and prenatal genetic testing as a means of providing prospective parents as much reassurance as possible during the course of managing a pregnancy. The relationship between a pregnant woman and her obstetrician or allied healthcare provider cannot be over-emphasised as a factor that influences the decision-making process and the initial choices made concerning genetic testing. Reproductive decisions made after counselling in the case of a fetal genetic disorder has been the subject of a large body of research, emphasising the multi-faceted factors involved in assessment and choice. Prospective parents must first address their views concerning their real and perceived risks of the possible birth and care of a child with a genetic disability compared with the benefit of information of fetal wellbeing through genetic testing and the prospect of selective termination, if affected. Resolution of these questions depends on how individuals make decisions in the face of competing or inconsistent value systems.

The numerous factors that initially influence reproductive decisions before and after genetic counselling, and some of their interactions, are shown Fig. 1 . The importance and effect of each of these factors can only be presumed to vary considerably among different decision makers. Quantifying or assigning value to each factor is understood to be extremely difficult. Research does not present a clear picture of the interaction of factors influencing reproductive decisions made before undertaking preconceptual or prenatal genetic testing. No sufficiently comprehensive model or explanation has categorised the factors influencing reproductive decisions.

In a systematic review of 32 publications of the perceptions of women, their partners and health professionals of Down’s syndrome prenatal testing, the most frequently reported sources of difficulty for decision-making in women were pressure from others, emotions and lack of information; in partners, emotion was the most frequently reported source of difficulty; and in health professionals, it was lack of information, length of consultation, and personal values. The most important sources of reassurance were, in women, personal values, understanding and confidence in the medical system; in partners, personal values, information from external sources, and income; and, in health professionals, peer support and scientific meetings. In most Western cultures, be it in the USA where healthcare is provided on a private, non-governmental basis, or in Canada and many European countries where medical care is provided as a government service, most prospective parents expect and empower their own healthcare provider to provide guidance and direction in making reproductive decisions. As such, they become the dominant, compelling influence in the means and forms of genetic testing.

A decision to terminate a pregnancy after identifying a fetal anomaly illustrates the complexity of the process. Issues thought to affect decision making were related to timing of the diagnosis, the nature of the anomaly, type and severity, level of certainty about the diagnosis and prognosis, and religious and moral convictions of the parents. The effects of diagnosis, demographic factors and gestational age have been evaluated after identifying a perinatal lethal condition. Pregnancies with a central nervous system defect or severe urinary tract defect were more likely to be terminated, whereas pregnancies with unexplained oligohydramnios or a twin pregnancy, in which one twin was affected, were more often continued to term. Demographic factors, gestational age at the time of diagnosis, and referral indications did not influence decision-making in pregnancies diagnosed with a lethal condition. Whether timing of diagnosis (first trimester compared with second trimester) influenced decision-making, however, is controversial.

The rationale in support of parents favouring first-trimester termination included obstetrical safety, less emotional damage and privacy issues (i.e. the pregnancy is not yet physically evident). Yet, after diagnoses of fetal aneuploidy or structural anomalies, reproductive decisions were not affected by gestational age, as long as legal limits for termination were met.

Several studies have shown that the specific chromosome abnormality and its prognosis are major determinants of the parental decision to continue or to terminate a pregnancy. Parental decisions to terminate a pregnancy varied by type of chromosome abnormality, by the presence of fetal ultrasound anomalies, and by the number of previous children. For example, in one Turkish study, 85% of parents terminated the pregnancy if autosomal aneuploidy was present, whereas 60% continued their pregnancy when a sex chromosome abnormality was identified.

In a similar study of Swiss parents, pregnancy termination rates were as follows: Turner syndrome 100%; Klinefelter syndrome 50%; 47,XXX females 70%; 47,XYY 50% and mosaic cases 43%.

Prospective parents have three options for assessing reproductive genetic risk: screening, diagnostic testing or rejection of genetic testing, either completely or selectively. A minimum of nine major testing modalities are available relative to reproductive decisions after genetic counselling; their timing, advantages, risk to fetus and limitations are presented in Table 1 .

Table 1

Testing modalities available in making reproductive decisions after genetic counselling.

Testing modality	Timing and advantages	Risk to fetus	Limitations
Parental carrier screening	Preferably preconceptually	None.	Not all mutations in genes analysed.
First-trimester screening for aneuploidy	10–13 wks; high detection rate.	None.	False–positive rate; false–negative rate.
Second-trimester screening for aneuploidy and open neural-tube defects	From 15 weeks onwards.	None.	High false–positive rate; later in pregnancy.
Chorionic villus sampling	10–13.6 weeks; early diagnosis.	Depends on operator skill.	Confined placental mosaicism.
Amniocentesis	From 15 weeks onward; detects open neural-tube defects.	Depends on operator skill.	Results available late in gestation.
Preimplantation genetic diagnosis	Transfer of only unaffected embryos.	None.	Pregnancy rates less than 30%; accuracy of genetic analyses not established.
Array comparative genome hybridisation	Anytime; higher detection rate of copy-number variations.	None.	May identify copy-number variations of unknown clinical significance.
Ultrasound fetal anatomic survey	18–22 weeks; minimal risk.	None.	Skill of ultrasonographer; anxiety caused by presence of ‘soft’ signs.
Non-invasive prenatal diagnosis	10 weeks onwards.	None.	Limited to aneuploidy; false negative rate; false positive rate.