Estimating limits for natural human embryo mortality

Abstract

Natural human embryonic mortality is generally considered to be high. Values of 70% and higher are widely cited. However, it is difficult to determine accurately owing to an absence of direct data quantifying embryo loss between fertilisation and implantation. The best available data for quantifying pregnancy loss come from three published prospective studies (Wilcox, Zinaman and Wang) with daily cycle by cycle monitoring of human chorionic gonadotrophin (hCG) in women attempting to conceive. Declining conception rates cycle by cycle in these studies indicate that a proportion of the study participants were sub-fertile. Hence, estimates of fecundability and pre-implantation embryo mortality obtained from the whole study cohort will inevitably be biased. This new re-analysis of aggregate data from these studies confirms the impression that discrete fertile and sub-fertile sub-cohorts were present. The proportion of sub-fertile women in the three studies was estimated as 28.1% (Wilcox), 22.8% (Zinaman) and 6.0% (Wang). The probability of conceiving an hCG pregnancy (indicating embryo implantation) was, respectively, 43.2%, 38.1% and 46.2% among normally fertile women, and 7.6%, 2.5% and 4.7% among sub-fertile women. Pre-implantation loss is impossible to calculate directly from available data although plausible limits can be estimated. Based on this new analysis and a model for evaluating reproductive success and failure it is proposed that a plausible range for normal human embryo and fetal mortality from fertilisation to birth is 40-60%.

Keywords: early pregnancy loss; embryo mortality; fecundability; human chorionic gonadotrophin.

Figure 1.. Graphical representation of data and best fit models for Wilcox (A, D, G), Zinaman (B, E, H) and Wang (C, F, I) studies.

Each panel shows the data value from the study for each point (○ = women starting cycle; + = hCG pregnancies; × = clinical pregnancies). The line indicates the best fit models as defined in Table 1. Parameter estimates and [95% confidence intervals] from these models are also shown.

Figure 2.. Parameter estimates for fertile and sub-fertile sub-cohorts and associated fecundability values.

Values are shown for Wilcox (□), Zinaman (▲) and Wang ( ) studies. Panel A shows the proportions in the starting cohorts modelled as fertile or sub-fertile ( %fert ₍₁₎ & %subf ₍₁₎). Panel B shows the hCG ( FEC _HCG) and clinical ( FEC _CLIN) fecundabilities and the probability of hCG pregnancies progressing to clinical pregnancies ( π _CLIN). Values are derived from modelled parameter estimates ( Table 1) and error bars indicate 95% confidence intervals.