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The events of early pregnancy: prying open the black box

The events surrounding natural human conception remain frustratingly elusive. We have no marker or sign that identifies conception in vivo. The earliest point at which a pregnancy can be detected biochemically is when it begins to implant in the uterus. The day of ovulation in the conception cycle is a useful surrogate for the day of conception because conception occurs within 24 hours after release of the ovum1 (reviewed by Winston et al.2). However, ovulation dating requires prospective collection of biological samples during the conception cycle. The best prospective studies of early pregnancy include detection of ovulation and the initial rise of human chorionic gonadotropin (hCG), serial ultrasound measures of fetal growth and documentation of the clinical outcomes of pregnancy. While such studies are demanding, they are unmatched in their ability to peer inside the black box of early pregnancy and reveal the biological processes at work. The paper by Mahendru et al., published in this issue of the Journal3, is an example of such a study. The authors address a question of particular interest: the pace of fetal growth during early pregnancy. Embryonic and fetal growth are not simply evidence of fetal viability and health: they provide an important surrogate for gestational age. In modern obstetric practice, the ultrasound measure of fetal size is the preferred means of determining gestational age. The use of fetal size as a measure of fetal age, however, rests on a crucial assumption: that all variability in size of the fetus is due to time since conception. We must assume that the extensive variability of fetal size so obvious at term is absent during the first trimester of pregnancy. This assumption is almost certainly wrong4, but perhaps it is sufficiently correct for practical purposes? The degree to which first-trimester growth varies is a matter of discussion (reviewed by Pemberton et al.5). The study by Mahendru et al. provides an intriguing look at this question3. The authors recruited 143 women who were trying to conceive. Women tested their urine daily until a surge in luteinizing hormone (LH) was identified, and 8 days later they started daily home pregnancy tests. These pregnancy tests continued until either the next menses commenced or hCG was detected (with the first day of detection defined as ‘implantation’). Ultrasound examinations were then carried out at 6–7, 8–9 and 10–14 weeks from the last menstrual period. Fifty-six women with 10–14-week ultrasound examinations provided complete information on ovulation and implantation. By combining daily hormonal measures around conception with ultrasound measures during the first trimester, the authors were able to assess embryonic and fetal size in relation to exact gestational age as determined by ‘conception’ (date of the LH surge). What Mahendru et al. report is fascinating. According to their data, fetuses were not all the same size at 10–14 weeks of gestation – and a factor associated with fetal size was the estimated time of implantation. The time from conception to implantation has been shown to vary6; what has not been reported previously is that late-implanting fetuses are subsequently smaller on ultrasound. It is plausible that implantation plays a key role in the pace of fetal growth. At implantation, the cells that subsequently form the embryo are still a small and undifferentiated mass within the blastocyst. It is not until attachment to the endometrium that maternal nutrients become plentiful. Assuming that these authors’ observation is confirmed in other studies, implantation could be a more crucial benchmark than is conception for the effective onset of embryonic growth. The authors also suggest that early growth may be relatively constant starting from the time of implantation. Conclusions about constant growth, however, are limited by the small sample size. A study of only 56 fetuses has too little power to rule out variability in the pace of fetal growth. Larger prospective studies will be needed to address this question. Another unanswered question is the extent to which variations in implantation timing might reflect aspects of fetal wellbeing in addition to growth. We know from the present paper as well as from a previous study6 that later implantation is associated with fetal loss. These findings suggest at least the possibility that later implantation might be accompanied by less successful placentation, and thus correlate with pre-eclampsia or preterm delivery. While the study does not have sufficient statistical power to allow consideration of rare events, an analysis of mean gestational age in relation to implantation would be of interest. A further contribution from the study by Mahendru and colleagues might come from consideration of the longitudinal measures of embryonic and fetal growth. The 56 fetuses were measured by ultrasound at more than one time point, allowing the possibility of tracking individual growth velocities and growth variability among fetuses – an aspect not considered in this paper. Those who seek to investigate an association between implantation timing and fetal growth should keep in mind that precise measures of ovulation and especially implantation are not simple. In particular, the day of the first positive pregnancy test in this study was not the ‘day of implantation’ as has been defined previously6. The authors compared their daily measure of hCG to that of Wilcox et al.6, but there is a crucial difference in the sensitivity of the two assays. Home pregnancy tests