Abstract
How many human embryos die between fertilisation and birth under natural conditions? It is widely accepted that natural human embryo mortality is high, particularly during the first weeks after fertilisation, with total prenatal losses of 70% and higher frequently claimed. However, the first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period, and establishing the fate of embryos before this is challenging. Calculations are additionally hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are used to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in TheLancet is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig's data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data concluded that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, natural human embryo mortality is lower than often claimed and widely accepted. Estimates for total prenatal mortality of 70% or higher are exaggerated and not supported by the available data.
Highlights
Human embryo mortality is a matter of considerable interest to reproductive biologists and fertility doctors, and to philosophers1,2, theologians3 and lawyers4
Observed human fecundability is low compared to other animals21, but at approximately 20–30%9,38 it is still higher than implied by such a high embryo mortality rate
Some scientists and legal judgements define pregnancy as beginning with implantation, one week after fertilisation. This definition is of particular utility in the context of in vitro fertilisation (IVF) treatment where evidence of implantation is the earliest sign that a transferred embryo has developed normally and that fertility treatment has, up to that point, been successful
Summary
Any reports and responses or comments on the article can be found at the end of the article. Version 2 has a new figure and glossary to assist readers and help them to follow the timings of key reproductive events. Sections of text in the Introduction and Discussion have been re-ordered. In text dates have been provided to aid with understanding of the chronology of studies. A brief commentary on a study into implantation by Brosens et al (2014) has been included. Methods for the Roberts & Lowe simulation study, the calculation of bootstrap confidence intervals, and the calculation of estimated loss from implantation to birth have been clarified. Comments have been included to note value in Roberts & Lowe’s analysis, to affirm the significance of Leridon’s critique, and to better contextualise the subjects from Hertig’s study.
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