Ethical concerns surrounding sex prediction using non-invasive prenatal screening from pediatric endocrinologists’ perspective

Abstract

Non-invasive prenatal screening (NIPS) with predicted fetal sex chromosomes included in the results has become increasingly available for pregnant individuals. Predicted fetal sex chromosome results from NIPS are interpreted so as to equate sex chromosomes with sex and gender. As pediatric endocrinologists, we worry about how this use of NIPS harmfully reinforces sex and gender binaries and sets potentially inaccurate assumptions about what the identified chromosomes mean. We use a hypothetical case based on our clinical experience in which NIPS report of fetal sex does not conform to expectations at birth to highlight ethical concerns surrounding this practice. Use of NIPS for fetal sex chromosome prediction has the potential to perpetuate stigma and bring psychological harm upon parents and their future children, particularly those who are intersex, transgender, and gender diverse. The medical community should adopt an approach to use of NIPS for fetal sex chromosome prediction that recognizes the spectrums of sex and gender to avoid reproducing stigma towards sex and gender diverse individuals and associated harms.

Non-invasive prenatal screening (NIPS), also known as cell free DNA (cfDNA) testing, has become widely available and is increasingly used to predict fetal sex chromosomes as early as 7 weeks of gestation (Devaney, Palomaki, Scott, & Bianchi, 2011). In fact, the American College of Obstetricians and Gynecologists recommends that all pregnant individuals be offered NIPS (Rose et al., 2020). NIPS detects cfDNA from the placenta and was specifically developed to detect trisomies 13, 18, and 21– not the X and Y (sex) chromosome complement (Gregg et al., 2016). Sex chromosome detection by NIPS is based on screening for sex chromosome aneuploidy (SCA). If this screening is negative, testing is typically reported as consistent with female or male depending on the presence or absence of Y chromosome material (Sofer et al., 2020). The positive predictive value for SCA ranges from 23% to 52% depending on the study (Sofer et al., 2020; Tekesin, 2021; Zhao et al., 2021) with a detection rate of 93% (Gil, Quezada, Revello, Akolekar, & Nicolaides, 2015). Sensitivity for NIPS report of fetal sex chromosomes is high (98.9% in a recent meta-analysis) (Mackie, Hemming, Allen, Morris, & Kilby, 2017). Ethical concern has been raised regarding how this technology may facilitate sex selection (Bowman-Smart, Savulescu, Gyngell, Mand, & Delatycki, 2020), a worry that similarly arose when ultrasound technology made it possible to visualize the external genitalia of the fetus in the second trimester (Elejalde, de Elejalde, & Heitman, 1985). As pediatric endocrinologists, we agree with the concerns regarding sex selection, which is a clear display of cisnormative expectations of sex (see Table 1 for terminology relevant to sex and gender diversity). However, we worry more universally about how use of NIPS harmfully reinforces sex and gender binaries and sets potentially inaccurate assumptions about what the identified chromosomes mean.

Table 1.

Definitions of terms related to sex and gender diversity

Term	Definition
Sex	A term used to label a person based on the type of internal and external genitalia, genes/chromosomes, and/or dominant reproductive hormones with which that person was born
Gender	The social and cultural expression of being male, female, neither, both, or other, which can be divided into the dimensions of the body, identity, and social gender (see https://www.genderspectrum.org/articles/understanding-gender)
Gender identity	A person’s sense of self a relates to their gender
Sex and gender diversity	A phrase used to recognize the spectrum of human variation in sexual development (internal and external genitalia), sexual orientation, and gender identity
Intersex	Refers to an individual with any combination of internal and external genitalia, genes/chromosome, and dominant reproductive hormones that do not align with the bodies of those typically assigned a male or female sex
DSD	An acronym that was first defined as “disorders of sexual development,” but is now preferably defined as “differences of sexual development”; intersex and DSD are used interchangeable in our paper but individuals in the intersex/DSD community differ as to which terminology they prefer
Transgender	Refers to having a gender identity that is distinct from assigned sex at birth—ex. a transgender male is a person assigned female sex at birth who has a male gender identity
Cisgender	Refers to having a gender identity and assigned sex at birth that are concordant – for instance, an individual assigned male at birth who identifies with a male gender is cisgender
Cisnormative	Refers to assuming that all individuals are cisgender
Heteronormative	Refers to assuming that all individuals are heterosexual (i.e. engage in opposite sex relations, as opposed to engaging in same sex relations) and believing that normal human relations are dictated by differences between males and females and their gender roles (based on the definition from the American Psychology Association: https://dictionary.apa.org/heteronormativity)
LGBTQI	An acronym that stands for “Lesbian Gay Bisexual Transgender Queer and Intersex”

As pediatric endocrinologists who take care of individuals with intersex variations, transgender individuals, and gender diverse individuals, practices that endorse normativity of binary sex and cisgender identities are worrisome. While it is true that most individuals will be 46,XX with typical female genitalia or 46,XY with typical male genitalia, this is not always the case (Baetens, Verdin, De Baere, & Cools, 2019; Linden, Bender, & Robinson, 1995). One in 400 newborns have neither a 46,XX or 46,XY karyotype (Linden et al., 1995). Individuals born with intersex variations (or DSD) represent 18 out of every 100,000 births (Hughes, 2008). Those born with “any variation in their physical reproductive or sexual characteristics” are noted to represent “as many as 17 in 1,000 people” (National Academies of Sciences Engineering and Medicine, 2020). Transgender individuals represent anywhere from 0.1–2% of individuals (Goodman et al., 2019), and an estimated 1.4 million adults in the United States identify as transgender (National Academies of Sciences Engineering and Medicine, 2020).

A hypothetical case based on our clinical experience in which report of fetal sex by NIPS does not conform to expectations at birth highlights the concerns we have about how use of NIPS for fetal sex prediction can pathologize gender and sex diversity and reproduce stigma.

Case: A pregnant woman underwent NIPS. Her results reported chromosomes consistent with female sex. The woman and her partner eagerly awaited the birth of a baby girl as the pregnancy progressed. Prenatal ultrasounds and other routine prenatal testing were reportedly unremarkable, although there was no clear indication of visualization of the genitalia on ultrasound reports. At birth, the infant was noted to have fused labioscrotal folds without palpable gonads and an enlarged clitorophallus. The medical team was concerned for a potentially life-threatening condition, congenital adrenal hyperplasia (CAH), and consulted endocrinology. CAH results from an enzyme deficiency that can lead to inadequate production of cortisol—a hormone needed for the body to respond to and survive physiologic stress—, and excess androgen hormone production (associated with virilization in XX fetuses). Inability to make sufficient cortisol is life-threatening. A hormonal work-up for CAH ruled out this diagnosis prior to the return of the newborn screening results, which were also negative. Intra-abdominal gonads and a hypoplastic uterus were noted on ultrasound. Genetic testing, in the form of a karyotype and SNP microarray, was sent. A few weeks later initial genetic testing resulted demonstrating a 46,XY karyotype. The parents of the child experienced confusion and distress both at birth and then again upon learning the post-natal karyotype result. At follow-up to learn about the karyotype results, the parents shared that they had received comments from medical staff, family members, and friends that made bonding with their newborn challenging. These comments had made them feel that their child was an “oddity,” and they were worried about social acceptance of the child.

The harms that emerge from use of NIPS to predict the sex of a developing fetus in this case include the following. The parents are distressed by a post-natal sex diagnosis—an intersex variation—that does not match the assumptions they and medical providers made based on the NIPS result. The assumptions include the following: that sex is rigidly binary, that sex and gender are the same, that an infant of female sex would be raised with a female gender, and that sex chromosomes always correlate with genital appearance. In turn, the infant faces stigmatization by medical providers, community members, and their parents when theses assumption are disrupted after the infant’s birth, a troublesome sign for the infant’s future well-being (Rohner, 2004). This type of pathologizing intersex variation is what has historically contributed and continues to contribute to unnecessary genital surgeries on intersex individuals (Davis, 2015; Nokoff et al., 2017).

Whereas ultrasound technology previously assigned sex (conflated with gender) based on external genitalia, giving primacy to genitalia in sex prediction (Larkin, 2006), NIPS results for sex prediction are interpreted so as to equate X and Y chromosomes with phenotypic appearance, sex, and gender. Based on NIPS results, the parents in the case expected a girl—language that reflects the idea that female sex equals female gender (Larkin, 2006). Particularly in a societal context that assumes cisnormativity, prenatal sex prediction using NIPS misleadingly reinforces a biological binary whereby XX equals female sex and gender and XY equals male sex and gender. In a survey of 916 parents, 78% reported they would be upset and 75% reported they would be worried if prenatal ultrasound and NIPS showed a discrepant sex result; only 22% were aware of differences in sexual development (DSD, also known as intersex variations) (Sofer et al., 2020).

This case, particularly when considering the above noted statistics on sex and gender diversity, highlights the need to avoid reinforcing the false notion that human individuals are either 46,XY cisgender male or 46,XX cisgender female in interpreting NIPS (or other prenatal genetic testing) results. This imperative is particularly salient considering research findings that expecting parents attach themselves early in pregnancy to a child of a specific gender based on information about sex from prenatal ultrasounds (Barnes, 2013, 2014; Pélage, 2019). Parental expectations based on a cisgender and heterosexual identity for their future child raises concern for psychological harm to infants who become LGBTQI (lesbian, gay, bisexual transgender, queer, and intersex) children and adolescents given the importance of parental acceptance for well-being among LGBTQI individuals (National Academies of Sciences Engineering and Medicine, 2020).

The following reminders about the importance of remembering and accounting for sex and gender diversity in clinical evaluation also arise from this case. Is it well documented that inadequate healthcare provision for LGBTQI individuals arises from heteronormative and cisnormative clinical care standards (National Academies of Sciences Engineering and Medicine, 2020). Examples include reduced rates of breast cancer screening in transgender males due to cisgender care standards (Clarke et al., 2022; Taylor & Bryson, 2016) and inadequate screening for sexual transmitted diseases due to lack of knowledge about non-heteronormative sexual practices (Scheim & Travers, 2017). Current use of NIPS for sex chromosome prediction can fall into this care pattern as exemplified in the case. In general, the potential for non-alignment between sex chromosomes, genitalia, and gender identity should always be considered in clinical evaluation and patient interactions. Awareness among physicians of the possibility of discordance between prenatally predicted sex chromosomes and actual infant sex chromosomes [reviewed elsewhere: (Bianchi et al., 2015; Finney et al., 2020; Smet, Scott, & McLennan, 2020)] is important to guide accurate clinical work-up. Ultrasound assessment of genitalia is important to assess for discordance between results of prenatal sex chromosome screening (NIPS or other prenatal genetic testing) and the appearance of external genitalia (Byers et al., 2019; Smet et al., 2020). Lack of visualization of the genitalia prenatally led to a missed opportunity to prepare the family prenatally for the idea that their infant may have an intersex variation.

This case highlights the need to exercise caution to not impose sociocultural narratives—here binary and cisnormative understandings of sex and gender (Breitkopf, 2020)—on use and/or interpretation of biotechnology. Prenatal genetic testing for sex prediction places undue importance on sex of the fetus; medicine should be circumscribed to focusing on the health of the fetus—the original intention of prenatal screening tests (Gregg et al., 2016). Acknowledging that the practice of using NIPS for sex prediction is likely to continue despite its critics, it is crucial that clinician receive education and patients receive counseling on the limitations of this NIPS —this should include education about the contribution of chromosomes versus other factors to fetal sexual differentiation and about the spectrums of sex and gender (Sofer et al., 2020). Clinicians could also benefit from exposure to the experiences of gender and sex diverse individuals via written, audio, or visual materials to help de-pathologize their views on these individuals. Clinician advocacy to improve the status quo to one that defaults to acknowledging sex and gender diversity is also needed. Ethical medical care is medical care that avoids stigmatizing LGBTQI individuals by recognizing and normalizing human sex and gender diversity starting from the moment of first invoking sex and gender in the context of prenatal genetic testing.

• What is known? Non-invasive prenatal screening is used for sex prediction, which raises ethical concerns about sex selection.

• What is added? Use of non-invasive prenatal screening for sex prediction also raises ethical concerns about how this practice conflates chromosomes with sex and gender and can reproduce longstanding stigmatization of sex and gender diverse individuals.

Data Availability:

Data availability is not applicable to this article as no datasets were generated or analyzed.