In vitro fertilization gender predilection: more but less.

In this issue of F&S Reports, Perlman et al. (1) examined birth gender ratios following both cleavage-stage and blastocyst-stage frozen-thawed embryo transfers. Their data was obtained from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System from 2004 to 2013. Fresh transfers, those utilizing preimplantation genetic testing, and donor cycles were excluded; however, multiple deliveries were not. They showed that births following cleavage-stage frozen embryo transfer registered 0.5% more males than females; the blastocyst group had 1.9% more males. The difference between the two groups was statistically significant and remained as such when controlling for body mass index, age, male factor infertility, and race/ethnicity. While a male bias in in vitro fertilization (IVF) cycles has been previously established, this study is noteworthy because it had a large number of transfers, all transfers were from frozen embryos, and day 3 and 5 embryos were compared.

The birth gender ratios of natural conception have been monitored worldwide for decades. In the United States, for every year between 1946 and 2001, more males than females were born at differences varying from 4.6% to 5.9%, higher when only including firstborns (5.0%–6.9%). From the early to later years, this ratio did not increase, removing gender selection as a possible influencer. This led to an annual mean number of excess males of 91,685 (2). Thus, it may not be the practice of IVF that skews birth gender ratios toward male.

What is the biologic basis for more boys being born? Using published gender data reported from preimplantation embryos, chorionic villus and amniocentesis samples, and miscarriages, Orzack et al. (3) produced a comprehensive review of changes in gender ratios throughout pregnancy. It appears that conception has no gender bias; however, the preimplantation genetic testing results show that female embryos are more likely to be karyotypically normal (there may be some autosomal abnormalities that are more frequent in male embryos). Within the first week, males out-survive females. Perlman et al. (1), likewise, support this, showing a decrease in the percentage of female embryos from days 3 to 5. After the first week, however, females quickly develop a higher death rate. Chorionic villus and amniocentesis data show female-biased mortality, flipping gender surplus to male after 15 weeks of gestation. This phenomenon continues until near term, resulting in a birth ratio favoring males.

We are all aware of the evolutionally factors encouraging male birth predominance: more boys than girls die in infancy, childhood, adolescence, and beyond. In fact, for every age category of 5 years, males have a higher death rate; in not one age group do females die at higher frequency. The reasons for this “male disadvantage” change with time. A study using the Netherlands Perinatal Registry revealed that boys are more likely to be born prematurely from labors with and without intact membranes at relative risk ratios of 1.5 and 1.2, respectively (4). When born prematurely, boys of similar gestational ages have higher morbidity and mortality rates. Males have weaker immune systems, making them more prone to childhood infections (5). Increased rates of accidents, deaths by suicide, and homicide haunt boys into adolescence and through adulthood. By age 50, the human population becomes more female, with this difference increasing with age as more men perish from mostly age-associated illness (5). This unfailing pattern is universal throughout the world and has not changed through time. Thus, it is theorized that males need to start in higher numbers to overcome their mental and physical friability to survive at a level still below their female counterparts.

The investigators offer insights into the grounds for their findings, citing references showing male embryos grow faster than females. They deduce that more male than female embryos may be transferred because males have higher morphology scales and are thus deemed more suited for success. However, this reasonable, logical, and generally accepted theory raises some interesting questions. Do female embryos of lesser grade have the same potential for implantation as male embryos of a higher grade? Are nonviable embryos more likely to be girls? If every embryo produced by every patient with IVF were to be transferred, what would the gender ratio be? Is this gender bias actionable, that is, should embryos for transfer be chosen more randomly?

This theory does not explain the most significant finding in this study: while more boys than girls are born via IVF, IVF results in fewer boys than are born in the wild. In vitro fertilization results in more boys but at the same time fewer boys. Worldwide utilization of IVF is expected to increase. This raises a final question to be debated in classrooms and parlors alike: can society prosperously survive with a few less males?