In the present study, a prospective evaluation of AFP, SHBG, hormone levels during pregnancy and placental characteristics, we found that placental weight was positively associated with third trimester AFP, SHBG, testosterone, estradiol and estriol among whites, and with third trimester AFP and estriol among blacks. However, these associations were modest based on the magnitude of the partial correlation coefficients. Results were not supportive of an association between any of the placental characteristics and first trimester maternal AFP, SHBG, and hormone levels. They were also not supportive of an association between third trimester maternal AFP, SHBG, and hormone levels and placental thickness. We followed up on results published in a previous manuscript [20
] and reported that birth weight was positively associated with third trimester SHBG among both whites and blacks and third trimester estriol in blacks; however, in all instances the magnitude of the correlation between these biomarkers and placental weight was greater.
To our knowledge, only two studies have evaluated an association between placental weight and maternal estrogen levels during pregnancy [11
]. The first, a study of multiparous women in three Scandinavian cities who gave birth to either a male or female infant, reported a positive association between estriol levels during pregnancy (at gestational weeks 17, 25, 33 and 37) and placental weight [11
]. The authors also reported that birth weight was a stronger predictor of estriol levels than placental weight [11
]; however, they used the geometric mean corrected area under the curve to estimate the total estriol load during pregnancy rather than an estimate of third trimester estriol levels as used in the current study. The second, a study of 230 white pregnant women who gave birth to either a male or female infant at Beth Israel Hospital in Boston Massachusetts, reported that estriol and SHBG were positively associated with placental weight at the 27th
gestational week [13
]. The findings of the present study, positive associations between third trimester estriol level and placental weight in white and black sons and third trimester SHBG level and placental weight in white sons, are consistent with these results. Further, the magnitude of the associations between placental weight and hormone level in whites is similar between the study in Massachusetts (mean change in placental weight per standard deviation increase in: estradiol 10.1, estriol 42.6 and SHBG 33.1) and our study (mean change in placental weight per standard deviation increase in: estradiol 16.8, estriol 30.2, and SHBG 29.6), suggesting that our results might be more broadly generalized to pregnancies with female fetuses and that placental weight, rather than birth weight, may be a surrogate for in utero hormone level in breast cancer studies.
The relationship between maternal biomarker levels and placental weight is of interest because birth weight and other perinatal characteristics have been associated with TGCT in a number of studies [4
]. However, only one study to date has included placental weight in their evaluation of perinatal characteristics and risk of TGCT [31
]. Akre and colleagues reported a significantly increased risk of seminoma with increasing placental weight in a nested case-control study of men born in Sweden between 1920 and 1978 [31
]. The authors of the study emphasized the role of higher levels of pregnancy estrogens, represented by perinatal characteristic proxies including higher placental weight, as the potential mechanism for increased seminoma TGCT risk [31
]. However, in the context of our results it is difficult to know whether the increased risk of TGCT is due to in utero estrogen level, as the associations between placental weight and the estrogens were not different between whites and blacks, and TGCT occurs more frequently among whites than blacks. Based on our results it could be hypothesized that the increased risk of TGCT in the Swedish study could be due to increased exposure to testosterone in utero, given that increased placental weight was positively associated with third trimester testosterone level in whites but not in blacks.
Our study demonstrates that placental weight was a better surrogate for in utero third trimester biomarker levels than birth weight; suggesting that placental weight could also be, if available, a surrogate measure of in utero AFP, SHBG, and hormone levels in cancer studies where birth weight was used previously. Unlike birth weight, placental weight is not captured on the birth certificate and may not be available to all studies. However, placental weight is often captured in the medical record, thus obtainable, and placental weights are readily available for entire populations, such as in Norway, Sweden and Finland.[34
The present study has several strengths; the major advantages were that the study was conducted prospectively, included mothers of more than one ethnic group, included only mothers pregnant with male fetuses, and included only mothers giving birth to their first child. The evidence suggesting that maternal biomarker levels may be affected by fetal sex and maternal parity make the last two advantages critical to the extrapolation of results to TGCT studies [14
]. In addition, the sample size permitted sufficient statistical power to study the associations separately in populations at lower (blacks) and higher (whites) risk of TGCT [20
Although our results are consistent with those of others [11
], there are limitations to our study. The biomarkers levels were measured on samples stored for approximately 40 years; however, prior studies of freeze-thaw cycles of serum levels in stored samples have shown that steroid hormones are fairly robust [39
]. In addition, the biomarker levels in the present study are equivalent to those reported in other studies examining newly drawn samples [40
]. Finally, because a large number of comparisons were analyzed caution should be exercised in interpreting the results.
Presumably, placental characteristics and birth weight represent the integrated effect of growth over the entire pregnancy, and if AFP, SHBG, and hormone levels during pregnancy play a role in health related outcomes later in life, it is most likely a result of these concentrations over some period of pregnancy. We evaluated biomarker levels during the first trimester, but did not observe substantial associations with placental characteristics or birth weight. Follow-up of this research question with multiple measures of biomarkers over the third trimester would better elucidate the correlation of pregnancy biomarkers and placental size or birth weight. Follow-up of these results in non-first born infants and females is also warranted.
In conclusion, our results suggest that the utility of placental weight as a surrogate measure for third trimester AFP, SHBG, and hormone levels of first born male infants was modest overall. The other characteristics evaluated, placental thickness and birth weight, had limited utility as surrogate measures for third trimester levels.