We have shown that prenatal ethanol exposure programmes the foetal HPA axis such that HPA tone is increased throughout life, with alterations in HPA regulation under both basal and stress conditions. Ethanol-induced disturbances of the reciprocal interconnections between the pregnant female and the foetus may provide a common pathway for foetal programming by early life events. Data from such investigations may have important implications for the development of therapeutic interventions focused at reversing the long-term adverse effects of prenatal alcohol exposure. In addition to the more typically seen FAS and FASD outcomes, many other adverse pregnancy and birth outcomes have been linked to prenatal alcohol exposure. Although further research is needed, existing studies suggest that drinking during pregnancy may increase the risk of miscarriage, stillbirth, preterm delivery, and SIDS. It remains to be seen whether these effects primarily are attributed to true biological effects, sociodemographic and lifestyle factors that co-occur with pregnancy drinking, or, most likely, a combination and possibly synergistic effect.
Morphologic Abnormalities
Behavior problems also have been reported among offspring prenatally exposed to alcohol but without FAS. In one study, 4-year-old children whose mothers drank one to five drinks per day during pregnancy were less attentive and more active when observed in the home, compared with children of control mothers who drank less (Landesman-Dwyer 1982). At age 7½, the children were less attentive and took a longer time to react to a stimulus on a Continuous Performance Task (Streissguth et al. 1986). In children ages 7 (Streissguth et al. 1989b) and 14 (Streissguth et al. 1994), researchers demonstrated the effects of prenatal exposure to alcohol on both attention and memory. These effects were linear (i.e., the extent of the effect was directly correlated with the amount of alcohol exposure), implying that no “safe” threshold of alcohol exposure exists. Children with FAS are small for their age (Streissguth et al. 1991)—indeed, such smallness is one of the criteria for diagnosis, although growth deficits also are found among children who were exposed to alcohol during pregnancy but do not fulfill the full criteria for FAS.
2.2. Hypothalamic-Pituitary-Adrenal (HPA) Axis
Oestrogen regulation of HPA activity appears to occur at sites upstream from the PVN, as few PVN CRH neurones contain oestrogen receptor mRNA (112). Importantly, the stimulatory effects of oestrogen occur only against a background of low progesterone levels (112). Both oestrogen and progesterone appear to have antagonistic effects on glucocorticoid feedback, acting primarily at GR (108, 113). Conversely, males typically have lower ACTH and corticosterone responses under both basal and stress conditions, as well as lower CRH and CRH mRNA levels in the PVN than females, mediated, at least in part, by the inhibitory effects of testosterone (106). Consistent with the data in females, testosterone effects on HPA regulation occur upstream from the PVN (107), at the level of the amygdala and bed nucleus of the stria terminalis (114), as there is little overlap in androgen receptor and CRH mRNA in the PVN (113).
Limitations of research on FAS
In this study, “heavy drinkers” were defined as people who consumed eight or more drinks per day as often as three times per week. This research was funded by the Australian Commonwealth Department of Health and Aged Care (GO2647). The funder had no role in the study design, data collection, data analysis, data interpretation or preparation of the manuscript. If you drank alcohol before you knew you were pregnant or before you knew that alcohol could harm your baby, stop drinking now.
PAE induces HPA alterations at multiple levels of the axis
- This multiplicity of problems complicates the pregnancy of an alcoholic woman, because her fetus is exposed not only to the teratogenic effects of alcohol, but also to the negative effects of the other factors that coexist in her life.
- Sustained attention deficits become evident among FAS/FAE patients only on tasks that also require active processing of information.
- There is also a body of evidence indicating a role for the maternal HPA axis in mediating ethanol’s effects on PAE offspring.
- In addition to the more typically seen FAS and FASD outcomes, many other adverse pregnancy and birth outcomes have been linked to prenatal alcohol exposure.
- In another study, FAS/FAE children with normal range IQ scores were given 8 trials to learn to press 5 computer keys in a particular 10-item sequence (Carmichael Olson et al. 1998).
Taken together, these findings suggest reduced sensitivity of central CRH pathways to testosterone in PAE males. By contrast, testosterone appears to have greater effects on central AVP pathways in PAE and/or PF compared to control males. Both PAE and PF males showed higher AVP mRNA levels in the posterior BNST following high testosterone replacement compared to either intact or low testosterone replacement conditions, respectively, and PAE males had higher AVP mRNA levels under intact conditions in the MeA compared to controls.
Of relevance to this review, PAE decreases the concentrations of 5-HT or its metabolites during foetal life and in weanling rats (175, 176), and results in long-lasting 5-HT deficits in mice, possibly through selective apoptosis (177). Foetal ethanol exposure also increases the number of binding sites for the 5-HT transporter in some areas of the developing rat brain, but decreases transporter binding site numbers in other areas (178). Importantly, prenatal administration of buspirone, or ipsapirone, partial 5-HT1A agonists, in conjunction with ethanol, ameliorates some of these ethanol-induced changes (179). On the other hand, postnatal ethanol exposure increases hypothalamic 5-HT content in adult rats of both sexes, with females showing greater overall concentrations than males (180), whereas exposure during both pre- and postnatal life does not differentially alter hypothalamic 5-HT concentrations (181).
Moreover, positive correlations between basal oestradiol and corticosterone were found in PAE and PF but not control females. In addition, both PAE and PF females had higher basal and stress oestradiol levels in pro-oestrous compared to other phases of the cycle, as well as higher stress oestradiol levels than control females during pro-oestrous. PAE and PF females also showed downregulation of GnRH mRNA compared to control females in dioestrous, when oestradiol levels are low. However, PAE females showed greater variation in LH levels than PF and control females across the cycle, and in pro-oestrous, showed a significant LH increase following stress (158). Together, these data support the possibility that ethanol-induced changes in HPA activity may reflect differential regulation by ovarian steroids in PAE compared to control females, with increased HPA sensitivity to oestradiol.
For example, there is evidence that improving nutrition during pregnancy 341, 342 and early childhood 343 can positively influence the severity of deficits following PAE. Thus, care is required when applying PAE thresholds in clinical practice at an individual level due to the wide range of determinants of PAE impacts. Diagnosis of FASD is a complex process that is best undertaken using a holistic interprofessional approach 344. Maternal alcohol use during pregnancy contributes to a range of effects in exposed children, including hyperactivity and attention problems, learning and memory deficits, and problems with social and emotional development.
- Prenatal alcohol exposure is a leading preventable cause of birth defects and neurodevelopmental disorders in the United States.
- Each of these risk factors for poor pregnancy outcome must be considered in evaluating the effects of prenatal alcohol use, because it is unclear whether alcohol effects occur independently or in interaction with risk factors such as an impoverished social environment.
- Similarly, Mattson and colleagues (1996, 1998) found that FAS/FAE children tested on the CVLT have more difficulty in memorizing new information than in retaining and retrieving what they have previously learned.
- The family of kisspeptin neuropeptides is derived from the 145-amino-acid precursor peptide coded for by the KISS-1 gene; post-translational processing results in C-terminal peptide fragments (kisppeptin-54, −14, −13, and −10) that activate the G-protein coupled receptor 54 (GPR54) (160–162).
- Importantly, weanling pups exposed to corticosterone prenatally showed no increase in basal or stress ACTH levels or in hypothalamic CRH mRNA levels compared to controls.
As noted, PAE animals are typically hyper-responsiveness to stressors (6, 66, 68, 71–73, 83–85), and show increased HPA drive (49, 69, 75, 87, 89) and deficits in HPA feedback regulation (50, 91, 214). Furthermore, our data (214) suggest an alteration in MR-mediated corticosterone signalling, and perhaps an altered MR/GR balance, which is proposed to underlie neurobiological alterations in depression (191). Finally, PAE animals exhibit altered neurotransmitter regulation of HPA activity, particularly in the serotonergic system (55, 182, 215, 216), suggesting altered serotonergic influences on HPA activity similar to those seen in depression. We examined the effects of gonadectomy in unmasking the extent to which prenatal ethanol influences both HPG and HPA activity and regulation (150). In terms of HPA function, we found that, under intact conditions, PAE males showed significantly higher ACTH levels than controls following 30 min of restraint stress, suggesting increased responsiveness to stress at the level of the pituitary.
The results have also highlighted key research gaps that can be targeted to improve understanding of the potential associations between PAE and diagnostic outcomes. Importantly, a collaborative international approach, driven by a goal of continuous quality improvement is required to advance assessment and diagnostic practices for FASD, with the united goal of improving quality of life for individuals with FASD and their families. On the Personality Inventory for Children (PIC), the two domains identified by parents of school-age FAS/FAE children as most problematic were cognitive function and delinquency; the latter is not a prominent domain in most forms of mental retardation (Roebuck et al. 1999). These children were more likely to exhibit antisocial behaviors, lack consideration for the rights and feelings of others, and resist limits and requests by authority figures. This finding is consistent with the reports, cited above, of high levels of aggression in the classroom as well as a report by Streissguth and colleagues (1996) that adults with FAS are more likely to get into trouble with the law and to exhibit sexually inappropriate behavior.
Taken together, these data suggest that altered interactions between the serotonergic and HPA systems may play a role in mediating the HPA hyper-responsivity reported in PAE animals following stress. In addition, these data may have important implications for understanding the increased incidence of secondary disabilities, and in particular, the increased rate of depression, reported in children with FASD (25, 26, 48). Ethanol-consuming animals typically reduce their food intake, and therefore their nutrient intake, below the levels that they would consume if given the same diet without ethanol. Therefore, it is common practice to include a control group that is ‘yoked’ or ‘pair-fed’ (PF) to the alcohol group. Each PF animal receives a control diet, typically with a carbohydrate such as maltose-dextrin isocalorically substituted for alcohol, in the amount (g/kg body weight) consumed by its ‘yoked’ alcohol partner on the same day of gestation.
Physicians must accurately obtain the medical history of the mother and provide safe antenatal care and education for FAS once maternal alcohol consumption is confirmed. If the prevalence of FAS is decreased, it will be possible to reduce the financial burden on society and unrealized human suffering 12. Symptoms of fetal alcohol syndrome may include any mix of issues with how the body develops; thinking, learning and behavior; and functioning and coping in daily life. Finally, the inflammatory effects of PAE may synergize with the effects of other concurrent life experiences. For example, one study used a combined rodent model of PAE (ad libitum liquid ethanol diet with gestational day 1–34%, 2–66%, 3 to 21–100% ethanol diet) with a naturalistic model of early-life adversity that deprived rat mothers of sufficient bedding from P8-12 73.
All women who consumed an average of three or more drinks per week during their first trimester, plus a random sample of one-third of the women who drank alcohol less often, were selected as study subjects. In general, alcohol use during pregnancy was light to moderate among the women participating in the study, although subjects who represented the entire spectrum of use were included in the sample. Whilst there have been previous systematic reviews on isolated diagnostic features (e.g. executive function, motor skills, birth weight) 11,12,13, none have provided a comprehensive summary to inform evidence-based decisions regarding diagnostic criteria. We systematically reviewed and synthesised the existing evidence examining the association of PAE with diagnostic outcomes to provide an evidence base for the improvement of diagnostic criteria, in the context of revising the Australian Guide for the Diagnosis of FASD 8. Mental disorders are common secondary disabilities among FASD populations (26, 29, 30, 48, 203), and HPA dysregulation is often observed in major depression (204–206). Consistent with these findings, brain areas implicated in depression overlap with areas that mediate the stress response, with prenatal alcohol exposure the HPA axis a key player in both (205, 207–209).