Sex selection

INTRODUCTION — 

Patients may desire to select the sex of their progeny for multiple reasons. This topic will discuss those reasons as well as preimplantation and postimplantation approaches for sex selection. Information on related topics can be found elsewhere:

●(See "Preimplantation genetic testing".)

●(See "In vitro fertilization: Overview of clinical issues and questions".)

●(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

BACKGROUND

Epidemiology — Prevalence of sex selection varies by region. Some countries, such as Chile and Australia, restrict preimplantation genetic testing (PGT) use for nonmedical purposes. Other countries, like Saudi Arabia and Lebanon, commonly use PGT solely for the purpose of sex selection. Extensive use of PGT in the People's Republic of China and India has resulted in imbalances in population-level sex ratios; these countries have now banned sex selection practices. With varying constructs of legality around the globe, many in vitro fertilization (IVF) patients seeking PGT testing travel to the United States [1].

Biology of sex determination — The sex of a child depends upon whether fertilization of the haploid ovum occurs with a haploid spermatozoon containing an X or a Y chromosome. Although this process is affected by a variety of factors, the probability of delivering a male in any pregnancy is approximately 51 percent; this probability remains constant and is independent of the sex of previous siblings [2,3] and parental age [4].

REASONS FOR SEX SELECTION

Personal preference — Personal preference for a child of a specific sex may involve only the first-born child or all offspring. Contributing factors can include:

●Social and economic conditions – Social and/or economic considerations include a desire for children who will carry on the family name, support older adult parents, keep property within the family, perform specific religious rituals, or have greater potential for contributing to the family's economic status [5].

●Cultural beliefs – Cultural beliefs surrounding parenting approaches for different sexes may drive an individual to desire a child of specific sex [6].

●Impact of interests or prior relationships – The preference may be related to the strong desire to have a child of the same, or different, sex, based on desire to share interests or based on prior relationships.

●Sex of prior children – An observational study of US patients undergoing frozen embryo transfer (FET) reported that patients were more likely to select the sex when conceiving a second child compared with a first child (62 versus 32 percent, respectively) [7]. The same study reported that patients selected an embryo of the sex other than that of the first child 81 percent of the time (203 of 248 FET) [7].  

Family balance — Family balancing refers to selecting for the sex that comprises less than 50 percent of the children in a family. Couples with one or more children of one sex may strongly prefer to have a child of the other sex to "balance" the family [8]. A patient's effort to balance sexes could lead to a larger family size than they would have otherwise desired. Therefore, the ability to preselect sex could help individuals control both the size and sex make-up of their families.

Avoid X-linked disease — There are over 530 X-linked diseases, many of which can be severely debilitating or fatal [9]. They occur in approximately 1 in 1000 births. In most cases, these disorders are carried by unaffected females and expressed in males. Preimplantation or prenatal genetic testing may be possible if an identifiable mutation or known marker exists for the disease.

However, in families without an identifiable mutation or other marker, identifying affected offspring through preimplantation or prenatal testing is not possible; therefore, the only way to be certain of giving birth to an unaffected child is to continue only those pregnancies with female progeny. For these couples, preimplantation selection of only female blastocysts for embryo transfer can prevent situations in which couples struggle with the decision to terminate a pregnancy with a possibly affected male. Although the female will be unaffected, 50 percent of female offspring will be carriers of the genetic abnormality.

Avoid disease with unequal sex incidence — Some non-Mendelian disorders are distributed with unequal sex incidence. Diseases with a higher male incidence include autism spectrum disorder (ASD) [10], pyloric stenosis [11], and Hirschsprung disease [12]. Diseases with a higher female incidence include breast cancer [13], systemic lupus erythematosus [14], and Graves' disease [15]. If no genetic marker is available, a couple may opt for sex selection in order to reduce the risk of having a child with a specific disorder [16]. For example, with ASD, if a couple has more than one affected male child, their chances of having another affected male child with their next pregnancy is 25 percent, so this couple may opt for sex selection of a female to decrease this risk.

APPROACHES TO PREIMPLANTATION SEX SELECTION — 

The techniques for sex selection are presented in the preferred order of use based on available supporting evidence.

Preimplantation genetic testing (PGT) — Preimplantation genetic testing (PGT), typically with aneuploidy testing (PGT-A), is commonly used to aid embryo selection during IVF cycles [17]. A byproduct of this approach is availability of information on embryo sex prior to transfer. While use of IVF purely to allow PGT for sex selection is discouraged, the practice does occur. One study of over 300,000 US IVF cycles reported increasing PGT use from 17 to 34 percent between 2014 and 2016; cycles that used PGT were associated with higher male:female sex ratios compared with non-PGT cycles (ie, PGT use for any indication was more likely to result in birth of a male offspring) [18]. (See "Preimplantation genetic testing".)

●Approach – Embryos undergo genetic testing with one of several standard techniques for genetic analysis and only the embryos of the desired sex are transferred. Because the analysis usually takes several days to perform, the most common practice is to freeze the embryos and then transfer one or more thawed embryos into the uterus in the next cycle; however, some clinics have overnight capability for genetic testing and can transfer fresh embryos the next day without the need for freezing.

●Limitations – Limitations of this approach include that PGT is expensive, typically ranging from USD $2500 to $5000, and is only offered in conjunction with IVF. Pregnancy rates after the procedure are good, and no adverse effects on offspring have been reported; however, extensive long-term data are lacking.

●Error rate – Embryonic mosaicism (XX/XY) could result in misdiagnosis. One study reported zero sex determination errors when array comparative genome hybridization (aCGH) testing was used to evaluate cycle day-5 biopsy samples (0 in 695, Wilson 95% CI 0-0.53 percent) [19]. Birth data confirmed the finding.

One possible method of determining the rate of sex misdiagnosis is to calculate estimates based on the specificity and sensitivity of PGT-A. Rates would apply to all chromosomes, but extrapolating these data is possible. A study using next generation sequencing testing for 24-chromosome aneuploidy screening reported chromosome-level specificity of 100 percent (95% CI 94.59 to 100 percent) and sensitivity of 100 percent (95% CI 97.39-100 percent) [20].

Additional discussions of PGT, including test types and techniques, are presented separately. (See "Preimplantation genetic testing".)

Preconception sperm separation by flow cytometry (where available) — Flow cytometry (commercial name MicroSort) is a less preferred technique that purports to be able to sort X- and Y-bearing sperm based upon the amount of genetic material the spermatozoa carries [21]. It involves coating the sperm with a fluorescent dye (bisbenzimide). Ultraviolet (UV) beams are then used to excite the fluorochrome. Sperm containing more genetic material, the X-bearing sperm, will have increased fluorescent intensity detected, allowing the sperm to be separated into X- and Y-bearing sperm. However, a large number of sperm are lost in the sorting process due to lack of orientation, undetermined fluorescence, or undesired sex, which together often precludes its use for intrauterine insemination [22]. Flow cytometry techniques for sperm sorting are available outside of the US.

Although flow cytometry appears to be safe, more long-term data are needed to confirm efficacy as safety concerns have been raised [23,24] based upon reports of increased embryo loss [25,26], chromosomal abnormalities caused by UV light exposure [27], and mutagenicity from bisbenzimide in animal studies [28].

Ineffective interventions — A number of publications in the lay press have purported to help parents determine the sex of their child. Timed intercourse and diet are the two most common methods, but neither is effective. Sperm separation techniques other than flow cytometry are offered by some practices but are not reliable.

●Preconception sex selection diet – The preconception sex selection diet is based on the theory that a couple can improve their chances of having a female infant by increasing dietary intake of both calcium and magnesium; to improve chances of having a male offspring, dietary intake of sodium and potassium should be increased [29]. These claims have not been verified.

●Factors relating to sexual intercourse – The Shettles method of sex selection involves timing, sexual position, depth of penile penetration, and female orgasm [30]. Timing intercourse with respect to the first signs of ovulation is based upon the belief that Y-bearing sperm move faster but do not live as long as X-bearing sperm. Studies that have attempted to correlate the sex of offspring with timed intercourse have reported conflicting results [30-35], but the study with the most scientifically rigorous design found that the timing of intercourse in relation to ovulation did not influence the sex of the fetus [34].

Shettles also proposed that deep penile penetration, rear-entry position, and female orgasm increased the chances that a Y-bearing sperm would reach and fertilize the egg before X-bearing sperm. This hypothesis has never been supported by data.

●Sperm separation techniques other than flow cytometry  

•Methods – Sperm separation techniques with inadequate reliability include fractionation through a column of Sephadex-G 50 and Locke solution [36-38], the modified swim-up test [39], filtering semen through columns of albumin solutions of different concentrations [38,40], and sperm filtered through a gradient of multiple layers of Percoll at different concentrations [41-43].

•Test rationale – Like flow cytometry, these techniques rely on differences between X- and Y-bearing human spermatozoa; however, the technical process for sperm sorting is different and based primarily on the enhanced swimming ability and a lower net negative charge of Y-bearing sperm [40,44-47].

•Lack of demonstrated efficacy – Despite promising initial reports, these separation techniques have been shown to be unreliable when evaluated with fluorescence in situ hybridization (FISH) [39,48-53]. The proportions of X- and Y-bearing sperm in the fractions were approximately 50-50 and not significantly different from untreated sperm [48-53].

●Proprietary gender selection techniques – Various gender selection services are available direct-to-consumers (sample names GenSelect, Smart Stork). The methods used and outcomes data are not available for independent verification.

POSTIMPLANTATION SEX DETERMINATION — 

Sex can be determined after implantation and followed by pregnancy termination if the fetus is not the desired sex.

Noninvasive tests

Ultrasound examination — Ultrasound examination can be used to visualize the fetal genitalia, usually in the second trimester. Sonography is noninvasive, relatively inexpensive, and widely available. The external genitalia of female and male embryos appear similar on ultrasound examination until 11 to 12 weeks of gestation, but 100 percent accuracy of sex prediction has been reported at ≥13 weeks of gestation [54].

Cell-free fetal DNA — Cell-free fetal DNA tests, often referred to as noninvasive prenatal testing (NIPT), were designed to screen for aneuploidy, including of the sex chromosomes. Fetal sex can be determined by analysis of Y chromosome sequences in cell-free DNA in maternal blood. The test is usually performed at ≥10 weeks of gestation, although accuracy as early as seven weeks of gestation has been reported [55]. A bivariate meta-analysis including 60 studies reported test sensitivity and specificity of 98.9 and 99.6 percent, respectively, for singleton pregnancies [56]. An abnormal aneuploidy result requires invasive testing, such as amniocentesis, for confirmation [57]. False and inconclusive test results can occur for various reasons, including that the cells themselves arise from placental cells (not fetal cells), low fetal levels of cell-free DNA, vanishing twin, or maternal chromosome abnormalities. Detailed discussion of prenatal testing with cell-free DNA is available separately. (See "Prenatal screening for common fetal aneuploidies: Cell-free DNA test".)

Invasive tests

Chorionic villus sampling (CVS) or amniocentesis for karyotype — Fetal sex can be determined by karyotype analysis of fetal chromosomes obtained by chorionic villus sampling (CVS) at 10 to 14 weeks of gestation or amniocentesis at ≥15 weeks of gestation. Both are invasive and expensive procedures with procedure-related risks. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)

Direct-to-consumer kits — Proprietary first-trimester sex identification kits are marketed directly to the public, including through online vendors. The patient uses the enclosed kit equipment to send a few drops of blood to a proprietary laboratory. The techniques used by these companies and data regarding accuracy have not been disclosed [58], and the companies state that test results should not be used for medical decision-making.

The US Food and Drug Administration, which regulates the manufacturers of genetic tests, and the United States Centers for Disease Control and Prevention, which promotes health and quality of life, have warned the public that some of these tests lack scientific validity, and others provide medical results that are meaningful only in the context of a full medical evaluation [59]. They suggest that genetic tests should be performed in a specialized laboratory and the results should be interpreted by a doctor or trained genetics counselor because of the complexities involved in both the testing and the interpretation of the results.

ETHICS AND HARMS OF SEX SELECTION — 

Preconception and preimplantation sex selection for medical reasons has broad approval, whereas sex selection for nonmedical reasons is more controversial [17].

Common ethical arguments

●Supporting reproductive autonomy – Proponents of sex selection believe that, historically, individuals have been given many choices in reproductive matters both legally and ethically. Therefore, individuals should be able to exercise their reproductive choices unless substantial harm to other individuals or to society in general occurs. Furthermore, if preimplantation sex selection is made available, postimplantation sex determination followed by pregnancy termination, which is common in many countries, can be avoided [60]. However, detractors believe that sex selection perpetuates unfounded assumptions about the sexes with the result of constraining the autonomy of both the parent(s) and child [6].  

●Opposing concerns

•Sex ratio imbalances – In some cultures, entrenched preference for male offspring has resulted in profound sex selection and resultant skewing of national sex ratios [61-65]. In most of the world, the sex ratio at birth (ie, proportion of male to female births) is approximately 105 males to 100 females, which is considered the normal ratio [66-68]. However, in some areas of China, the ratio is 117 males to 100 females, and in one rural district of India, the ratio is 187 males to 100 females. A 2020 United Nations Population Fund study estimated that the number of "missing" women globally more than doubled between 1970 and 2020, from 61 million to 142.6 million [69]. "Missing" women reflects both missing female births and excess female deaths attributable to sex selection.

•Potential psychological impact – Another important issue is the potential psychological harm done to children, regardless of whether they are the desired or undesired sex [70]. Parents may be disappointed when the child of a selected sex does not behave in the expected sex-specific ways.

•Ethics of embryo creation – There is also ethical concern about the creation and destruction of excess embryos for the sole purpose of selecting an embryo of a particular sex [71].

Specific regional guidance — At least two major societies have issued statements about the ethics of sex selection:

●American Society for Reproductive Medicine (ASRM) – The ASRM, the governing body for reproductive medicine specialists in the United States, has provided guidance since 1994. Initial approval for sex selection was based on use of reproductive technologies to decrease the chance of having a child with a genetic disease [72].

The following excerpt from the 2022 consensus statement from the Ethics Committee of ASRM summarizes their recommendations [17]:

"In conclusion, ART [assisted reproductive technology] practitioners who currently offer or decline to offer sex selection for nonmedical purposes do so against a varied ethical backdrop. Arguments regarding patient autonomy and reproductive liberty have been offered in support of the practice. Risks and burdens of the procedure, gender bias, sex stereotyping and nonacceptance of offspring, efforts to guard against coercion, the potential appearance of sanctioning sex selection, and issues of justice all raise concerns about the practice. Practitioners must take care to ensure that parents are fully informed about the risks and burdens of the procedure and that they are not being coerced to undergo it. Because the practice remains ethically controversial, clinics are encouraged to draft and make available written policies setting forth whether and under what circumstances nonmedical sex selection will be available."

●European Society of Human Reproduction – While the 2013 European Society of Human Reproduction task force on ethics and law was divided about the issue of sex selection for nonmedical reasons in the setting of assisted reproduction [73]. Preimplantation genetic testing with aneuploidy testing (PGT-A) for sex selection is not allowed in European countries except in select cases of sex-linked diseases [74].

●Australia – As of 2018, Australia did not allow use of assisted reproductive technology for nonmedical sex selection [75].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility".)

SUMMARY AND RECOMMENDATIONS

●Reasons for sex selection – The major reasons for sex selection are personal preference for a child (or children) of a specific sex, a desire to achieve a "balanced" family with female and male children, and a wish to avoid sex-linked genetic diseases or diseases more prevalent in a particular sex. (See 'Reasons for sex selection' above.)

●Timing of sex selection – Techniques for sex selection may be employed before conception, before implantation, or after implantation.

•Preimplantation genetic testing (PGT) – Preimplantation genetic testing (PGT), typically with aneuploidy testing (PGT-A), to select embryos of the desired sex, followed by transfer of only those embryos, is a safe and highly effective technique. However, use of in vitro fertilization (IVF) purely to allow PGT for sex selection is discouraged. (See 'Preimplantation genetic testing (PGT)' above.)

•Preconception sperm separation – Preconception sperm separation by flow cytometry, followed by use of sperm with the desired sex for IVF with or without intracytoplasmic sperm injection or in vivo fertilization via intrauterine insemination, is safe, but not as effective as PGT and is only available in certain countries. (See 'Preconception sperm separation by flow cytometry (where available)' above.)

•Postimplantation options – Postimplantation approaches to sex selection include analysis of free fetal DNA in maternal serum, ultrasound examination of the fetal genitalia, and invasive chorionic villus sampling (CVS) or amniocentesis to obtain cells for fetal karyotype. If the test reveals that the fetus is not the desired sex, the pregnancy is terminated. Cell-free DNA is considered a screening, not a diagnostic, test because the Y chromosome sequences result from apoptosis of placental not fetal cells and rarely may be maternal. (See 'Postimplantation sex determination' above.)

●Ineffective approaches for sex selection – Timed intercourse, diet, and specific methods of performing sexual intercourse are not effective approaches to improve the chances of conceiving a child of a particular sex. Sperm separation techniques other than flow cytometry are also ineffective. (See 'Ineffective interventions' above.)

●Ethics and potential harms – Proponents of sex selection believe that couples should be able to exercise their reproductive choices unless substantial harm to other individuals or to society occurs. If preimplantation sex selection is made available, then postimplantation sex determination followed by pregnancy termination, which is common in many countries, can be avoided. However, entrenched preference for male offspring in some cultures has resulted in profound sex selection and resultant skewing of national sex ratios. (See 'Ethics and harms of sex selection' above.)