Our study scope was quite a normal population, so our findings were appropriate for the general population, and increased the literature on biological molecular mechanisms underlying fetal programming, by highlighting distinct associations between variations in maternal PRL level and neonatal birthweight. This is a prospective cohort research to assess the separate and combined effects of prenatal emotional status as well as plasma PRL levels on normal full-term offspring birthweight outcomes and growth development biomarkers. Prenatal depression may play an important role in difference in weight development of normal birthweight infants and it is further supported by our findings.
Our research showed that sufficient maternal PRL levels would mitigate the adverse impact of prenatal depression on infant birthweight. We proved that, given prenatal depression, neonatal birthweight was reduced by a 0.285 unit if the mothers had low PRL levels. And simultaneously we found that infants of depressed mothers who had lower PRL levels had the most risk to have low weight at birth. In animal models of chronic unpredictable mild stress (CMS), which is one of the best validated animal model of depression, the stress-none reactive group had an increased level of PRL in plasma and an increase in PRL binding to PRL receptors in the choroid plexus . This result indicated that PRL had a resilience to stress thereby protecting rodent models against hazard of depression. Zhang H et al. indicated mothers exposed to maternal prenatal depressive symptoms decreased maternal serum PRL . There is an evidence suggesting that a one standard deviation increase in birthweight was linked to an 18% reduction in the risk of psychosis-like symptoms . Wiles et al. observed that for each additional standard deviation in fetal growth is related to a 14% decrease in the child's risk of behavioral problems. Some studies indicate that birthweight is associated with the frequency and severity of depression as well as negative emotional reactions (fear, distress, sadness, anger) in childhood [38, 39]. An analysis of Scandinavian registry data indicated a relationship between birthweight and adult psychiatric disorders, but there was no indication that the effect was specific to birthweight below 2,500 g . Therefore, our results suggest that even maternal depression, if the level of maternal prolactin is sufficient, it could mitigate the adverse effects of depression on offspring physical development.
In addition, ROC curve analysis suggested that combined effect of maternal plasma PRL、PGH and fetal IGF1 had a good predictive effect on the occurrence of neonatal weight more than 50% at birth. Besides, maternal plasma PRL also played an important role in newborn birthweight. PRL have positive effects on adipose tissue mass accumulation during pregnancy . Animal studies demonstrated that injections of ectopic pituitary transplants or exogenous prolactin could result in growing in body weight in both female and male animals. The high PRL level during pregnancy is associated with impaired leptin-induced activation and causes the attenuation of suppression of food intake . PRL promotes lipogenic effects during pregnancy, which is beneficial for the extra energy supply to fetus. Therefore, these beneficial metabolic effects of PRL on white adipose tissues those are supposed to be adaptive in pregnancy, to enhance nutrition for the offspring. During pregnancy, PRL plays roles in the regulation of β-cell mass expansion and insulin resistance in order to transfer nutrients, particularly glucose, to the fetus promoting a passive glucose transport across the placenta. PRL mediates insulin synthesis and release, induces β-cell replication, further enhances STAT5 tyrosine phosphorylation, as well as increases glucose transporter 2 (GLUT2) expression thus facilitating glucose entry into the β-cells. PRL could improve hepatic insulin sensitivity at normal concentrations during pregnancy and higher PRL levels tend to increase serum insulin concentrations and β-cell function.
Biological plausibility was further supported by our findings of growth development biomarkers. Prior mechanistic researches suggested that partial genetic mutations (< 1%), primarily coding with proteins that involved in the GH–IGF-I axis, has affected in infants physical development at birth. PGH resembles pituitary GH, which has a lipolytic and somatotrophic action. Other studies have shown that PGH is a potent lipolytic hormone and insulin antagonist, which stimulates production of IGF1 in pregnancy. The emergence of PGH was the predominant determinant of insulin resistance during pregnancy, through transplacental nutrient delivery promoted IGF1, which promoted fatal liver glycogen storage, fat deposition and fetal growth. PGH and IGF1 may lead to a placenta that is more efficient in nutrient transfer to the fetus, thereby contributing to fetal growth. In animal experiment, models of tissue specific IGF1 knockout manifested the role of circulating IGF1 in regulation of growth. GH deficiency/insensitivity and IGF1 deficiency play an important role in intrauterine linear and cranial growth. The primary clinical features of a homozygous deficient IGF1 include perinatal growth restriction, severe microcephaly as well as severe global developmental delay.
We found that PRL, PGH and IGF1 were all correlated with birthweight, and the relationship between birthweight and PGH was higher than other two hormones. However, prenatal depression was not significantly associated with PGH concentration. We explored the effect of PRL mediated maternal depression on PGH and IGF1 by linear regression analysis. We found analysis stratified based on maternal depressed status, newborns with PRL concentrations had a positive correlation with plasma IGF1, but no association was found in the control group. Therefore, we believe that prenatal depression may affect IGF1 through prolactin and further affect fetal physical development. Prenatal depression could impair maternal PRL concentration, and then would be likely to impede the mobilization of maternal nutrient reserves as well as reduce fetal IGF1 levels, thereby reducing uteroplacental blood flow, nutrient transport and limiting fetal growth. Therefore, according to our results, it can be thought that maternal PRL shortage is an important mechanism of prenatal depression lessening offspring growth and development. However, their precise roles in fetal programming remain largely unknown. It is unclear how maternal PRL mediate fetal IGF1 related to neonatal birthweight in different aspects of maternal emotional status.
The major impact of maternal PRL on glucose homeostasis during pregnancy is advantageous for increasing glucose transfer to the fetus. Therefore, maternal PRL of the pituitary gland and IGF1 of fetuses acted synergistically on integrating the metabolic response to pregnancy with the demands of fetal and neonatal development. In short the changes in PRL concentrations have strong impact on fetal growth as well as long-term metabolic consequences. We found that reduced prolactin concentrations in depressed mothers were an adverse factor for lower birthweight in newborns. This association appears to be related to IGF1. Our data suggest that low PRL levels in maternal depression can have harmful influences on neonatal birthweight, and that sufficient PRL levels can counteract the harmful influences of maternal prenatal depression on offspring.
Although this study has many advantages, such as prospective design, neonatal physical development expressed by Z-scores of age and sex and maternal and fetal hormone testing, due to some limitations, the interpretation of the results should be made with caution. First, these data were based on single-center hospital samples assessed at last trimester, and self-reported depression degrees were comparatively low, limiting the applicability of our findings to high-risk groups as well as different gestational periods. We focused on the third trimester of pregnancy, because it is a time of fast fetal physical growth and brain development, and the rapid changes make fetus particularly vulnerable to environmental effects. Second, we can‘t pinpoint whether the observation of association was specific to the last trimester or was the consequence of continued exposure during pregnancy. Our findings suggest that exposure to prenatal depression in the late trimester of pregnancy versus the earlier trimester of pregnancy has a stronger and more specific effect on offspring outcomes, but we cannot confirm this hypothesis without performing assessments at multiple time points during pregnancy. Our volunteers were women with healthy, singleton pregnancies, so findings may not be generalize to women with higher-risk pregnancies. Finally, since we did not assess the relevant genetic information, we cannot exclude the possibility that shared genes influence maternal depression and infant outcomes, and the study was observational, so we cannot conclude a causal relationship. Therefore, the conclusions drawn from our research must be considered preliminary and require replicating with larger sample and different cohorts.