Sex selection

INTRODUCTION — Couples may desire to select the sex of their progeny for a number of 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".)

REASONS FOR SEX SELECTION — The major reasons for sex selection are:

●Personal preference for a child (or children) of a specific sex

●To achieve a "balanced" family with children of both sexes

●To avoid a sex-linked genetic disease

●To avoid diseases with unequal sex incidence

Personal preference — Personal preference for a child of a specific sex may involve only the first-born child or all offspring and can be based on one or more factors. Social and economic conditions may foster preferences for children of a specific sex, such as 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 [1]. Cultural stereotypes also play a role. The preference may be related to the strong desire of one parent or the other to have a child of similar sex with whom they hope to share similar interests. Sometimes one parent or the other strongly desires a child of the opposite sex because of a previous difficult relationship with the parent, siblings, or others of the same sex. Sometimes parents believe a child of one sex versus the other is easier to raise.

A 1993 survey of United States clinics reported that over 80 percent of couples seeking sex selection desired a male child [2]. However, subsequent studies in 2007 found that nulliparous women did not significantly prefer one sex over the other [3], and sex preferences varied among ethnic groups [4]. Interestingly, in a 2006 Gallup global study, only parents in Spain and Iceland had a preference for female offspring [5].

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 opposite sex to "balance" the family [6]. In a web-based questionnaire assessing preferences for sex of children, 50 percent of the over 1100 respondents expressed a desire for a family with an equal number of boys and girls, while 7 percent wanted more boys than girls, 6 percent wanted more girls than boys, 5 percent wanted only boys, 4 percent wanted only girls, and 27 percent expressed no preference [7].

The couple's effort to balance sexes sometimes leads to a larger family size than they would have otherwise desired. Therefore, the ability to preselect sex could help couples control both the size and sex make-up of their families. However, it has been suggested that sex allocation in mammals may result from an adaptive process involving the suitability of a mother to conceive an offspring of a particular sex; therefore, attempting to create a balanced family may be harmful [8].

X-linked disease — There are over 350 X-linked diseases, many of which can be severely debilitating or fatal. 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 fetuses for embryo transfer can prevent situations in which couples struggle with the decision to terminate a pregnancy with a possibly unaffected male. Although the female will be unaffected, 50 percent of female offspring will be carriers of the genetic abnormality.

Unequal sex incidence — Some non-Mendelian disorders are distributed with unequal sex incidence. Diseases with a higher male incidence include autism spectrum disorder (ASD), pyloric stenosis, Hirschsprung disease, and otosclerosis. Diseases with a higher female incidence include breast cancer, systemic lupus erythematosus, and Graves' disease. 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 [9]. 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 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 [10,11] and parental age [12].

Preferred techniques — The preimplantation techniques for sex selection best supported by evidence are (1) preimplantation genetic testing (PGT) to select embryos of the desired sex, followed by transfer of only those embryos, and (2) preconception sperm separation by flow cytometry (where available), followed by use of sperm with the desired sex for in vitro fertilization with or without intracytoplasmic sperm injection or in vivo fertilization via intrauterine insemination.

Preimplantation genetic testing — PGT for sex can be performed on one or more cell(s) removed from a preimplantation embryo. Typically, five to seven trophectoderm cells are biopsied from blastocyst stage embryos. The sex can be determined by using one of several standard techniques for genetic analysis, which will also identify aneuploidy. 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 embryos the next day without the need for freezing. (See "Preimplantation genetic testing".)

PGT is expensive, typically ranging from USD $2500 to $5000, and is only offered in conjunction with in vitro fertilization. Pregnancy rates after the procedure are good, and no adverse effects on offspring have been reported; however, extensive long-term data are lacking.

Preconception sperm separation by flow cytometry (where available) — MicroSort is a patented process of flow cytometry that purports to be able to sort X- and Y-bearing sperm based upon the amount of genetic material the spermatozoa carries [13]. 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 often precludes its use for intrauterine insemination [14].

The success rates in terms of pregnancies of the desired sex achieved are 93 percent for females and 82 percent for males. Studies in humans have not reported mutagenic effects from the MicroSort process. The first human infant born from this process was in 1995; over 1200 children were born subsequently. In 1998, follow-up of 29 children exposed to this sorting process found them to be normal and healthy [14]. Although flow cytometry appears to be safe, more long-term data are needed to confirm efficacy as safety concerns have been raised [15,16] based upon reports of increased embryo loss [17,18], chromosomal abnormalities caused by UV light [19], and mutagenicity from bisbenzimide in animal studies [20].

After a long US Food and Drug Administration (FDA) review period following the initial clinical trial of the process, MicroSort failed to obtain FDA approval for clinical use in 2011. The MicroSort process has not been available in the United States as of March 2012 but is available in several other countries. No flow cytometry-based sperm sorting technology is available in the United States.

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, and we recommend not attempting either of them to improve the chances of conceiving a child of either sex. 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 [21]. 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 [22]. 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 [22-27], 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 [26].

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 – Despite promising initial reports, sperm separation techniques other than flow cytometry have been shown to be unreliable when fluorescence in situ hybridization (FISH) was used to determine the Y- and X-bearing sperm concentrations of separated fractions [28-33]. The proportions of X- and Y-bearing sperm in the fractions were approximately 50-50 and not significantly different from untreated sperm [28-33]. Unfortunately, these techniques are still marketed to patients as options.

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 [2,34-37].

•Sephadex column – Sperm are fractionated through a column of Sephadex-G 50 and Locke solution, which seems to improve overall spermatozoa motility in the final fractions [38,39]. In one study, some samples had only a 6 percent change in the proportion of X and Y spermatozoa, while other samples showed increases of as much as 37 percent [40].

•Modified swim up – Swim-up techniques are based on the principle of motility; therefore, the top layer of the supernatant will disproportionately be populated by faster-moving Y-bearing sperm, while the slower X-bearing sperm will disproportionately remain at the bottom portion. The upper layer of supernatant is removed and centrifuged, and the resulting pellet is used for insemination. In one study, the proportion of males born from singleton pregnancies was approximately 90 percent in the group treated by a modified method of swim-up sperm preparation prior to insemination [41].

•Albumin gradient – Spermatozoa are separated by filtering semen through columns of albumin solutions of differing concentrations. It has been hypothesized that the male sperm can be isolated because they reach the bottom more quickly due to their assumed ability to move more quickly [2,40,42-46]. Some studies claim isolates containing 43 to 76 percent male sperm can be achieved with this method [2,40]. However, confirmatory studies with reliable molecular techniques have not been able to replicate even a small enhancement in concentration of male sperm.

•Percoll – Sperm are filtered through a gradient of multiple layers of Percoll at different concentrations. X- and Y-bearing sperm are separated with low-speed centrifugation based upon their size and weight. Because X-bearing sperm are larger and denser than Y-bearing sperm, they tend to migrate through the gradient more quickly and can be isolated from the Y-bearing sperm. Y-bearing sperm concentrations of 77 to 85 percent have been reported [47,48].

When studies used FISH analysis to confirm sex concentrations after Percoll separation were performed, only a slight enhancement of X-bearing sperm was noted [49]. Apparently, Percoll interferes with the stain that was used to identify sex in the sperm, leading to the artificially elevated counts of X-bearing sperm in previous studies. Therefore, although a small increase in X-bearing sperm may be noted, it is not enough to alter sex ratios when used in clinical practice.

POSTIMPLANTATION SEX DETERMINATION — Sex can be determined after implantation and then followed by pregnancy termination if the fetus is not the desired sex.

CVS or amniocentesis for karyotype — Traditionally, identification of fetal sex has been 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".)

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 both sexes 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 [50].

Cell-free DNA — Fetal sex can be determined by analysis for Y chromosome sequences in cell-free DNA in maternal blood. These sequences are usually associated with a male fetus and are cleared after delivery. In order to ensure an adequate fetal fraction, the test is usually performed at ≥10 weeks of gestation.

In a systematic review of 60 studies using this technique for evaluating fetal sex, sensitivity and specificity were 98.9 and 99.6 percent, respectively, but sometimes no result was reported [51]. 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 "Prenatal screening for common aneuploidies using cell-free DNA".)

Direct-to-consumer marketing — In 2005, commercial companies began marketing first trimester sex identification kits directly to the public. Women who purchase these kits use the enclosed equipment to send a few drops of their blood to the laboratory. The techniques used by the company and data regarding accuracy have not been disclosed [52], and the company states that test results should not to be used for medical decision making.

The procedure used for this diagnosis is crucial for ensuring accuracy. This was illustrated in a National Institute of Child Health and Human Development study that collected 20 mL of peripheral blood from 20 pregnant women between 10 and 20 weeks of gestation and sent aliquots to five laboratories for sex identification [53]. The sensitivity of the assay for detection of male DNA when the fetus was male varied from 31 to 97 percent among centers.

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 [54]. 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.

Those who oppose the use of sex selection believe it could reinforce sex biases or lead to sex ratio imbalances. This is especially relevant in countries where males are highly prized and sex ratio imbalances already exist. For example, in the United States and most areas of the world, the sex ratio (ie, proportion of male to female births) is approximately 105 males to 100 females, which is considered the normal ratio [55-57]. 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. In these cultures, personal preference for male offspring is so profound that sex selection has resulted in skewing of national sex ratios [58-62].

Another important issue is the potential psychological harm done to children, regardless of whether they are the desired or undesired sex [63]. Parents may be disappointed when the child of a selected sex does not behave in the expected sex-specific ways. 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 [64].

Proponents of sex selection believe that, historically, couples 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 [65].

At least two major societies have issued statements about the ethics of sex selection:

●American Society for Reproductive Medicine – The American Society for Reproductive Medicine (ASRM) is the governing body for fertility specialists in the United States. In 1994, the Ethics Committee of the ASRM first stated its approval for the use of reproductive technologies to decrease the chance of having a child with a genetic disease [66]. They have subsequently issued reports discussing the varied ethical, medical, and legal issues involved with using preimplantation genetic testing (PGT) for sex selection for nonmedical purposes [67-70].

The following excerpt from the 2015 consensus statement from the Ethics Committee of ASRM summarizes their recommendations [70]:

"In conclusion, assisted reproductive technology (ART) practitioners who currently offer or decline to offer sex selection for nonmedical purposes do so against a varied ethical and legal backdrop. Recognizing reasoned differences of opinion, the ASRM Ethics Committee has not reached consensus on whether it is ethical for providers to offer ART for sex selection for nonmedical purposes. 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, 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 is so controversial, clinics are encouraged to draft and make available written policies setting forth whether and under what circumstances nonmedical sex selection will be available. When nonmedical sex selection is offered in clinical practice, clinic employees with objection to the technique must be permitted to absent themselves from its provision."

Although the ASRM has published these recommendations, in a 2008 survey of in vitro fertilization clinics in the United States, 74 percent of participating clinics provided PGT for at least one indication, and 42 percent of the providers acknowledged access to, and provision of, PGT services for sex selection [70].

●European Society of Human Reproduction – The European Society of Human Reproduction task force on ethics and law is divided about the issue of sex selection for nonmedical reasons in the setting of assisted reproduction as stated in their 2013 document [71]. They recommended broader delineation of accepted medical reasons for the practice beyond avoiding a serious sex-linked disorder and asked for clarification of the clinician's legal position when confronted with parental requests for sex selection at embryo transfer after medically indicated preimplantation genetic diagnosis or routine preimplantation screening.

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

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

●Techniques for sex selection may be employed before conception, before implantation, or after implantation. Preimplantation genetic testing (PGT) to select embryos of the desired sex, followed by transfer of only those embryos, is a safe and highly effective technique. Preconception sperm separation by flow cytometry (where available), followed by use of sperm with the desired sex for in vitro fertilization with or without intracytoplasmic sperm injection or in vivo fertilization via intrauterine insemination, is safe, but not as effective as PGT. (See 'Preferred techniques' above.)

●Postimplantation approaches to sex selection include ultrasound examination to image fetal genitalia, chorionic villus sampling or amniocentesis to obtain cells for fetal karyotype, and analysis of free fetal DNA in maternal serum. 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.)

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

●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. (See 'Ethics and harms of sex selection' above.)