Expanded carrier screening for recessively inherited disorders: economic burden and factors in decision-making when one individual in a couple is identified as a carrier

Abstract

Purpose

When undergoing expanded carrier screening (ECS), couples are often screened sequentially to reduce need for a second individual’s test. It is unknown how often partners of individuals found to be carriers complete the recommended testing with a sequential approach and what factors contribute to decision-making regarding partner testing. Additionally, the economic burden placed on individuals by ECS testing and its effect on partner testing has not been evaluated.

Methods

In part 1, all individuals at a university-affiliated reproductive endocrinology and infertility practice identified to be carriers of a recessively inherited mutation using the Counsyl/Foresight ECS were included. Conditions were categorized by severity according to a previously described classification system. In part 2, all individuals who underwent ECS with a single test provider between September 1, 2013 and February 1, 2020 were contacted via email to complete a confidential and anonymized online survey.

Results

In part 1, a total of 2061 patients were screened. 36.9% were carriers of one or more recessively inherited disorders. Twenty-seven percent of positively screened individuals did not have their partner screened. Carriers of a moderate condition had a trend towards a reduced odds for having their partner screened compared to a profound condition (OR 0.36, 95% CI 0.12–1.05, p = 0.06). Number of conditions was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72–1.25, p = 0.72). In part 2, the cost of ECS was not covered by insurance for 54.5% (103/189) and most paid over $300 out-of-pocket for testing (47.6%). The most common reason for not completing partner testing was that the results would not alter their course when seeking conception (33.3%). 73.5% of patients knew that the largest benefit of ECS comes from knowing a partner’s results as well as their own.

Conclusions

Not all carriers of recessively inherited disorders choose to undergo partner screening. Patients found to be carrier of more debilitating genetic disorders may be more likely to screen their reproductive partners. For many, ECS testing is not covered by insurance, and this test may impose a significant economic burden. For some patients, the results of ECS would not change what they would do when seeking conception. Providers should evaluate whether a patient’s ECS result would change their treatment course prior to testing.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10815-021-02084-6.

Introduction

Over one thousand single-gene disorders have been identified in the general population [1]. Although individually rare, single-gene disorders collectively have a significant clinical impact. Together, Mendelian disorders affect an estimated 1 in 300 pregnancies and account for 20% of infant deaths [2, 3].

Historically, carrier screening was only offered to certain high-risk ethnic groups or patients with a personal or family history of a genetic disorder with the goal of reducing the risk of having a child affected by the disease [4]. One of the earliest applications of carrier screening was testing for carrier status of Tay-Sachs disease, a universally fatal neurodegenerative disorder, in Ashkenazi Jewish and French Quebecois populations. Over the past 30 years, the incidence of Tay-Sachs disease in the USA and Canada has been reduced by over 90% due to the implementation of pre-conception carrier screening programs focusing on these high-risk groups [4].

In recent years, expanded carrier screening (ECS) has been increasingly adopted. As this technology has evolved, testing has become more comprehensive, less expensive, and more widely available [5]. With the inclusion of hundreds of additional disorders in widely available screening panels, over 30% of individuals are identified as carriers of at least one recessively inherited or X-linked disease using ECS [6]. The vast majority of these individuals are unaware that they are carriers and have no family history of the disease [7]. Pre-conception determination of a couple or individuals reproductive risk enhances reproductive autonomy and facilitates the ability to make informed decisions in the pursuit of pregnancy [8].

Many fertility clinics, as well as general OB-GYNs, now routinely offer ECS to all patients regardless of ethnicity or family history, and the American College of Obstetrics and Gynecology (ACOG) has recently determined the universal use of ECS to be an acceptable alternative to traditional screening methods [8]. This change in guidelines was based on the acknowledgement of several limitations that exist in traditional carrier screening that can be overcome with the use of ECS. Traditional carrier screening is ethnicity-based, and our increasingly multiethnic society often makes it difficult to assign a single ethnicity to an individual [9]. It is also dependent on an individual’s self-reporting, which can be vary significantly even within a single family; ethnicity is a complex concept which takes into account cultural, religious, and social considerations [10]. ECS offers a pan-ethnic screening approach that addresses these issues by adopting a more inclusive approach to genetic screening.

Some clinics prefer to screen couples in tandem, while others offer sequential screening in order to reduce the need for a reproductive partner to undergo testing if an individual is not found to be a carrier. It is unknown how often partners of positively screened individuals complete the recommended testing with a sequential approach and what factors may influence that decision during pre-conception ECS. In addition, although the argument has been made that ECS is cost-effective for the overall healthcare system given the high cost of caring for an affected child, the average economic burden placed on the patients themselves has yet to be assessed [11, 12]. The objective of this study is to determine the frequency at which positively screened individuals choose to screen their reproductive partners and what factors may contribute to that decision. A secondary objective is to assess the economic burden placed on patients who undergo screening with ECS.

Materials and methods

Patient selection

All patients underwent expanded carrier screening (Foresight^TM Carrier Screen) through Myriad, formerly Counsyl (South San Francisco, CA), a molecular diagnostics laboratory. The number of conditions screened for by the panel has evolved over time: 102 in 2013, 105 in 2015, and since November 2016 it has covered over 175 recessively inherited conditions of varying severity and onset by full-exon sequencing with panel-wide deletion calling. The diseases included on the testing panel were selected based on clinical severity and actionability, disease prevalence, ability to maximize sensitivity, specificity, and negative predictive value (NPV) [11].

ECS was routinely offered as an option to all patients undergoing fertility evaluation. For patients attempting conception with an opposite-sex partner, sequential testing was performed, wherein one individual was screened first with a plan to screen a partner if the patient was found to be a carrier of a recessively inherited disorder. The decision of which reproductive partner to screen first was made at the discretion of the provider and varied from couple to couple. Factors that were considered when determining which partner to screen first included patient preference, insurance coverage for ECS, ethnic background, and other risk factors. If the initially screened individual was not found to be a carrier, the choice of whether or not to screen their reproductive partner was left up to the couple after provider counseling. Test orders required physician authorization. Carrier screening was voluntary, and consent for research was included within the general consent form, with the option to request exclusion. Post-test genetic counseling was made available at no additional cost to all individuals tested.

This study consisted of two parts using two different patient cohorts. Both parts of the study were independently reviewed and approved by the University of California, Los Angeles (UCLA) Institutional Review Board.

Part 1: Rate of partner testing for positively screened individuals and impact of condition severity on partner testing

All patients at a university-affiliated reproductive endocrinology and infertility practice who underwent screening by the Foresight^TM Carrier Screen between September 1, 2013 and April 1, 2019 were included. All positively screened individuals were encouraged by their providers to undergo genetic counseling, and partner testing was strongly recommended, where applicable. Patients using donor gametes were excluded.

The total number of conditions for which a patient screened positive was tabulated. Conditions were categorized according to a previously described and validated classification system which stratifies 15 autosomal-recessive diseases into 3 categories (profound, severe, or moderate) based on variables such as shortened life span, intellectual disability, impaired mobility, and treatment availability (Supplemental Table 1) [13]. If an individual screened positive for more than one condition, the category corresponding to the more severe condition was used for classification purposes. If the condition for which a patient was identified as a carrier was not included in the classification system previously described, the patient was not included in a disease severity analysis.

Logistic regression was performed and odds ratio (OR) calculated with 95% confidence interval (CI) to determine the impact of number of positive conditions and disease severity on rate of partner testing.

Part 2: Patient survey of all subjects undergoing ECS

All individuals screened with Foresight^TM Carrier Screen between September 1, 2013 and February 1, 2020 who provided an email address on their test requisition form were included. Patients were contacted via email to complete a confidential, anonymized online survey comprising 16 questions. Survey questions were developed by the investigators to assess patients’ experience, economic burden, and motivations behind decision-making after results were obtained. Patient experience with ECS was evaluated using questions asking about adequacy of provider counseling, understanding of risks and benefits of ECS, and willingness to undergo ECS testing if presented with the option again. Economic burden was evaluated by questions regarding insurance coverage for ECS, co-pay, and out-of-pocket costs. Motivations behind decision-making after obtaining ECS results were evaluated with questions about primary and secondary reasons for testing or not testing a partner (where applicable). All survey questions were in multiple-choice format with an optional free text response. The survey included question branching to skip or display certain questions based on each individual’s response. Free text responses were reviewed by the investigators.

A total of 1638 patients were invited by email to participate. After invitations were sent, 52 emails were undeliverable, likely due to incorrect email addresses on file or email accounts that were no longer in use. This effectively reduced the cohort to 1586 patients. To complete the survey, respondents were directed to the University of California, Los Angeles (UCLA) RedCap survey site which included an explanation of the research project and asked for consent to participate. A single reminder was sent 14 days after the initial invitation by email. No reimbursement was provided for subject participation. Descriptive statistics were then performed. All data analysis was performed using STATA version 14.2 (College Station, TX).

Results

Part 1: Rate of partner testing for positively screened individuals and impact of condition severity on partner testing

A total of 2061 patients underwent ECS over the study period. Seven hundred sixty (36.9%) were found to be carriers of one or more recessively inherited disorders. Of these, 577 (75.9%) had opposite-sex partners listed in the medical record. Among those with a positive screen, the average number of mutations was identified was 1.34 ± 0.62 (mean ± SD). One hundred and fifty-six (27%) positively screened individuals with opposite-sex reproductive partners did not have their partner undergo screening, whereas 421 (73%) opted for partner screening. Of carriers that completed partner testing, two (0.48%) were found to have a shared mutation. Of those, one couple decided to pursue IVF with PGT-M. The second couple completed partner testing after pregnancy had already been achieved and decided not to undergo prenatal diagnosis.

Of the 203 patients that were carriers of one or more of the 15 conditions included in the disease severity classification system [13], 38 (18.7%) were carriers of a profound condition, 94 (46.3%) were carriers of a severe condition, and 71 (34.9%) screened positive for a condition of moderate severity (Table 1). When compared to those who were carriers for a profound condition, those who were carriers for a moderate condition had a trend towards a reduced odds for having their partner screened (OR 0.36, 95% CI 0.12–1.05, p = 0.06). However, those with a severe mutation did not demonstrate a reduction in odds for having their partner screened when compared with those who had a profound mutation (OR 0.60, 95% CI 0.21–1.74, p = 0.35) (Table 1). Number of conditions a patient screened positive for was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72–1.25, p = 0.72) (Table 1).

Table 1.

Likelihood of partner testing when compared to profound disorders

Disease severity classification	Odds ratio (OR)	95% confidence interval (CI)	p value
Profound (n = 38)	–	–	–
Severe (n = 94)	0.60	0.21–1.74	0.35
Moderate (n = 71)	0.36	0.12–1.05	0.06

Part 2: Patient survey of all subjects undergoing ECS

Out of 1586 patients invited to complete a survey on patient experience, economic impact, and decision-making after ECS, 189 subjects completed the survey for a response rate of 11.9%. ECS was not covered by insurance for 54.5% (103/189) of patients and most paid over $300 out-of-pocket for testing (47.6%) (Table 2). ECS was covered by insurance for 34.4% (65/189) of patients, and 11.1% (21/189) did not know if insurance covered their testing. Among those who had insurance coverage, 38.5% had no co-pay and 4.6% had a co-pay of over $300 (Table 3).

Table 2.

Out-of-pocket costs of ECS in patients without insurance coverage

Cost	% of patients without insurance coverage n = 103
Less than $50	3.9% (4)
$50–$100	8.7% (9)
$100–$200	8.7% (9)
$200–$300	23.3% (24)
Over $300	47.6% (49)
Not sure	7.8% (8)

Table 3.

Co-pay for ECS in patients with insurance coverage

Co-pay amount	% of patients with insurance coverage n = 65
None	38.5% (25)
Less than $50	23.1% (15)
$50–$100	13.8% (9)
$100–$200	12.3% (8)
$200–$300	0 (0)
Over $300	4.6% (3)
Not sure	7.7% (5)

Nearly half (49.2%, 93/189) of patients were found to be carriers of at least one disorder. Among carriers, 14% (13/93) were unpartnered. Of positively screened individuals with reproductive partners, 81.3% (65/80) did complete partner testing. The most common reason positively screened individuals had their partners screened was that if their partner was found to be a carrier of the same disorder, they would want to pursue IVF with PGT-M (49.2%), while 21.5% said they would get a amniocentesis during pregnancy, 15.4% wanted to know but it would not change what they did, and 13.8% cited other reasons (Table 4).

Table 4.

Primary reason for screening a reproductive partner among positively screened individuals

Primary reason for partner testing	% of positively screened individuals that obtained partner testing n = 65
Would do PGT-M	49.2% (32)
Would get amniocentesis	21.5% (14)
Wanted to know but would not change what we did	15.4% (10)
Other	13.8% (9)

Among positively screened individuals with opposite-sex reproductive partners, 18.8% (15/80) did not have their partners screened. The most common reason this group of positively screened individuals cited for not testing their partners was that the results would not alter what they would do when seeking conception (33.3%), while 20% said it was too expensive and 20% said because their partner was unable to come in due to time conflict (Table 5). Finally, 13.3% did not have a reproductive partner screened because their partner did not want to know the results and 13.3% cited other reasons (Table 5). None of the positively screened patients (0%) cited not knowing partner screening was recommended as the reason for not testing their reproductive partners (Table 5), and 73.5% (139/189) of all patients knew that the largest benefit of ECS comes from knowing a partner’s results as well as their own. Of patients with an opposite-sex reproductive partner, 89.4% felt that they had enough information about the benefits and risks of testing to make a decision about partner screening. If presented with the option again, 82.6% would choose to undergo ECS screening themselves, and of those with partners, 80.5% would have their reproductive partners screened.

Table 5.

Primary reason for not testing a reproductive partner among positively screened individuals

Primary reason for not testing partner	% of positively screened individuals that did not obtain partner testing n = 15
Too expensive	20% (3)
Unable to come in due to time conflict	20% (3)
Partner did not want to know	13.3% (2)
Would not change what we did	33.3% (5)
I did not know it was recommended	0% (0)
Other	13.3% (2)

Over half (50.8%, 96/189) were not found to be carriers of a recessively inherited disorder. Among negatively screened individuals, 93.8% (90/96) had opposite-sex reproductive partners. From this group of negatively screened individuals, 38.9% (35/90) chose to undergo partner screening. The most common reason that the reproductive partners of negatively screened individuals chose to undergo ECS themselves was that it was recommended by their doctor (68.5%, 24/35), while 28.6% (10/35) cited wanting to know for family benefit, and 2.9% (1/35) said it was because it was covered by their insurance.

Discussion

When an individual planning conception is found to be a carrier for a genetic disorder that is inherited in a recessive fashion, the risk to offspring is dependent on the carrier status of a reproductive partner, when present, or gamete donor. Despite this, there were a substantial number of positively screened individuals with opposite-sex reproductive partners who did not complete partner testing (27% and 18.8%, for part 1 and 2, respectively). Disease severity does appear to influence the decision to screen a reproductive partner in heterosexual couples using autologous gametes. Patients found to be carriers of mutations causing moderate disorders had a reduced odds for having their partner screened when compared to carrier of a profound mutation. Carriers of mutations causing severe and profound genetic disorders had similar odds of having a partner screened. The number of conditions a patient screened positive for was not found to be predictive of subsequent partner screening, suggesting that for many individuals, the number of mutations they carry did not influence their decision for partner screening. This is surprising given the more genetic mutations an individual carries, the more likely it is that a reproductive partner may have a shared mutation.

We sought to elucidate the reasons why individuals did not pursue partner testing after ECS using a follow-up patient survey. The most common reason positively screened individuals cited for not testing their partners was that the results would not alter their course when seeking conception (33.3%). Even among those that did complete partner screening, 15.4% cited that it would not change how they proceeded with treatment. These results highlight how adequate pre-test counseling has the potential to save these patients the time, cost, and anxiety of undergoing ECS.

A prior study evaluating 17 women who screened positive during prenatal ECS but did not receive pre-test counseling found significant patient confusion about the meaning of a positive result [14]. In addition, only 9/17 (53%) completed the recommended partner screening [14]. In contrast, our patient survey found that 73.9% of patients understood that the largest benefit of ECS screening comes from knowing both partners ECS results. Partner testing rates were also significantly higher, with 70.9% of positively screened individuals completing partner screening. Furthermore, 81.4% of patients felt that they had enough information about the risks and benefits of partner testing to make an informed decision, suggesting that provider counseling was adequate in explaining the significance of a positive result. These findings emphasize the important role of both pre- and post-test counseling by providers in increasing patient understanding of test significance, as well as compliance with partner testing.

Coverage for ECS from insurance companies can vary significantly between individuals [8]. Many insurance providers still do not consider ECS to be a medical necessity and question its clinical utility, despite the fact that ACOG has recognized ECS to be an acceptable alternative to traditional screening methods [8, 15, 16]. In this patient cohort, 54.5% reported no insurance coverage for ECS. In contrast, most insurance providers do cover preconception or prenatal screening for cystic fibrosis and spinal muscular atrophy, in accordance with ACOG guidelines [8, 15–17]. Some insurers may provide coverage for screening of certain disorders if a patient meets specific criteria, such as a personal or family history of the disease [17]. In our findings, insurance coverage contributed to the decision-making for partners of negatively screened individuals that underwent ECS.

Cost may be a significant barrier to obtaining ECS, and out-of-pocket payments vary widely, regardless of insurance coverage. For patients with insurance coverage, some had no co-pay, while others paid anywhere from less than $50 (23.1%) to over $300 (4.6%) (Table 3). For patients without insurance coverage, a few patients paid less than $50 for testing, while almost half paid over $300 out-of-pocket (Table 2), a significant cost for many individuals. For patients that were found to be carriers who did not screen their reproductive partners, 20% cited cost as the primary reason for not testing their partner, despite knowing that it was recommended by their provider. Notably, only cost of testing per individual was evaluated, and the cost of testing for both partners in a reproductive couple is likely significantly higher. Increased cost transparency and offering discounted partner screening for positively screened individuals may help to increase rates of partner testing.

Prior studies have sought to evaluate patient behavior when both individuals in a reproductive couple screen positive as carriers for the same disorder, referred to as at-risk couples (ARC). A study by Franasiak et al. identified only 8 ARCs (0.21%) out of 3738 couples that underwent screening as part of their fertility care [18]. They estimated that 450 couples would need to be screened in order to find one ARC. In this study, however, all eight couples found to be carriers of the same genetic disease chose to pursue in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M) to prevent having an affected child. Another study evaluating 391 ARCs found that 77% took steps to prevent having an affected pregnancy [19]. Of those, 59% chose to pursue IVF with PGT-M, 20% underwent prenatal diagnosis with amniocentesis or chorionic villus sampling, 7.7% chose to use donor gametes, 5.1% decided to pursue adoption, and 3.8% stopped attempting pregnancy altogether [19]. In a theoretical exercise, 49.2% and 21.5% of positively screened patients in our study indicated that they chose to undergo partner testing with the understanding that they would pursue PGT-M and amniocentesis, respectively, if a partner was found to also be a carrier for the same disorder (Table 4). Of the two ARCs found in our study, one decided to pursue PGT-M. For a small number of individuals, ECS has a dramatic impact on their reproductive decision-making.

Several considerations must be taken into account when interpreting the results of this study. Both patient cohorts included only those presenting for infertility evaluation that had completed pre-conception ECS screening. This is not a random sampling and may not be representative of the general population nor the population undergoing prenatal ECS. It also does not include patients undergoing routine prenatal ECS, and therefore it may be difficult to extrapolate results to that particular population. For the patient survey, results may be affected by response bias and limited by participants’ memory and medical literacy. Patients were asked about options that they would have pursued in hypothetical situations which may not correlate with future actions had those situations actually occurred. In addition, the assessment of economic burden only includes patients that actually completed ECS and may have missed patients who chose not to undergo testing at all due to cost.

Lastly, in part 1 of the study, only 15 recessively inherited or X-linked disorders were included in the utilized disease severity classification system, so patients that screened positive for a disorder that was not in the classification system could not be included. It would be beneficial if this system was expanded to include additional disorders to aid in future studies. Part 1 of the study also only included heterosexual couples not using donor gametes which may limit the generalizability of the results to the general population. The ECS test used also underwent expansion to include additional disorders during the study period and may have missed some individuals that would have screened positive had they undergone screening with the full panel currently offered.

Conclusions

Pre-conception ECS is a valuable tool for increasing patient reproductive autonomy; however, it may not be the right choice for every patient. Pre-test ECS counseling can help assess future actions in the case of a positive result and can help identify individuals for whom ECS has the potential to influence their reproductive choices. Pre- and post-test counseling are essential to patient understanding of test risks and benefits, as well as interpretation of results. ECS is not currently routinely covered by insurance, and cost of ECS, with or without insurance coverage, may pose a significant barrier to partner testing for positively screened individuals.

Author contributions

AS performed data acquisition and interpretation and drafted the manuscript. MQ performed data analysis and interpretation and critically revised the manuscript. LK contributed to data interpretation and critically revised the manuscript.

Data availability

Not applicable.

Code availability

Not applicable.

Declarations

Ethics approval

This retrospective chart review and survey study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of the University of California, Los Angeles (UCLA) approved both portions of this study independently.

Consent to participate

Consent for research was included within the general consent form for expanded carrier screening, with the option to request exclusion. For the patient survey, informed consent was obtained.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.