Question 1

Is there a certain period of the pregnancy that is higher risk for the fetus when exposed to substances, and others that are lower? I feel like I've heard such conflicting information regarding this.

Edward Riley · Accepted Answer

There is a lot of confusion over this question and it relates to the timing of how the embryo and fetus develop. The first trimester is the time when most major organs develop. So the effects of prenatal alcohol on major organs can occur during this period.   For example, the facial characteristics of FAS are due to exposure to alcohol during a limited period in the first trimester.  If an embryo is not exposed to alcohol during this critical time, it will not develop FAS, because the facial features critical to the diagnosis of FAS will have developed in the absence of alcohol.  Similarly, major cardiac defects seen in FAS may also be due to exposure during this time.

The problems from exposure after the first trimester, are because many organs, most importantly the brain, continue to develop throughout gestation. Thus, while the basic structures of the brain may develop during the first trimester, the brain continues to grow and develop and it is during these periods that the fine-tuning of brain function occurs.  For example, brain cells have to be produced, they have to move or migrate to the right areas, they need to link together in networks by differentiating and forming connections, these connections need to be refined and strengthened, and they need additional cells to help support them and allow for efficient communication. While these processes usually occur in a similar order, when they occur depends on what part of the brain is developing. For example, myelination, the covering of the axons of the neuron to allow rapid transmission of information begins in the third trimester, so if the fetus was exposed to alcohol then, myelination might be affected.  The cerebellum, which is heavily involved in coordinating movement, but also important cognitive functions, undergoes extensive changes during the second trimester, so exposure to alcohol during that period, might impact its development and function, although it is sensitive throughout gestation.

The embryo and fetus are at risk from alcohol throughout gestation, but the specific impact or effect will be dependent upon the time of exposure.  Since a major issue of prenatal alcohol exposure is its impact on cognition and behavior and since the brain develops throughout gestation, it is best to avoid alcohol during pregnancy.

Question 2

How much alcohol intake during pregnancy is associated with FASD? And are there any levels of alcohol intake during pregnancy that are not harmful?

Edward Riley · Accepted Answer

Boy if I could answer this question, I might be in line for a Nobel Prize. Like most things, there are a host of variables that determine the outcomes. As we are seeing with covid, some people get the virus and are asymptomatic, others have a few symptoms, and others wind up in the ICU where some recover, some have long-lasting consequences, and others unfortunately die.

A host of variables influence the effects resulting from alcohol exposure and discovering risk/resilience factors is an important area of study.  When the exposure occurs will impact the outcome, as will the dose and duration of exposure (e.g. was it a binge exposure?).  The genetics of the mom and fetus also need to be considered, as do social/environmental/demographic factors, such as nutrition, access to health care, and other drug use such as tobacco. A recent study showed a major synergistic effect between cannabinoids and alcohol. In both mice and zebrafish, combined exposure to low doses of alcohol with several different cannabinoids caused an increased incidence of birth defects.  All of these risk/resiliency factors will differ between individuals and what may produce a major impact on one embryo or fetus, may only have subtle or no effects on another. The best course to avoid any possible concern is to avoid alcohol if one is pregnant or planning a pregnancy. That way you are sure that there is no chance of an FASD.

I do want to add a comment on very light drinking during pregnancy, since people always ask "How much is it safe to drink while I am pregnant. There a several scientific papers and many lay articles that indicate no serious impact of light drinking (e.g. such as 3-4 drinks spread over a week). However, light drinking may still be associated with small for gestational age infants or a preterm delivery. The authors of the scientific papers often state specifically that their data does not indicate a safe level of exposure. Perhaps light drinking may not have a noticeable impact under certain conditions (e.g. the right genes, good nutrition, no other drug use), but be harmful to some individuals that have particular risk factors.  There is a lack of research in this area and we need to know more about the variables that might influence outcomes. The adage about “Absence of evidence is not evidence of absence” may hold here.  Again, the best individual choice to avoid any possible concern is to avoid alcohol if one is pregnant or planning a pregnancy.

https://www.cdc.gov/ncbddd/fasd/alcohol-use.html
https://www.health.gov.au/health-topics/alcohol/alcohol-throughout-life/alcohol-during-pregnancy-and-breastfeeding
Study on light drinking: https://bmjopen.bmj.com/content/7/7/e015410.long
Comments on that study: https://www.nofas.org/nofas-statement-on-media-coverage-of-bmj-study-on-light-drinking/

Question 3

Question 4

What part of the brain does alcohol affect in order for fetal alcohol syndrome to develop?

Edward Riley · Accepted Answer

Perhaps another way of putting this question is what parts of the brain appear to be particularly sensitive to the effects of prenatal alcohol exposure.  As I mentioned in one of my other answers, the effects you see are going to be dependent upon a host of variables, including the timing of exposure and the dose.  One of the features that diagnosticians look at in assessing FASD is the overall size of the brain, and in some diagnostic systems microcephaly (small head) is one of the diagnostic criteria for FAS.   But some areas of the brain appear to be more sensitive to alcohol than others.  One of my early MRI studies found that the corpus callosum, the major fiber tract that connects the two hemispheres of the brain was smaller in many cases of FAS, or even absent in a few.  Another brain area that seemed to be particularly impacted was the basal ganglia and in particular the caudate, and this does help explain some of the cognitive control and learning issues in FASD.  The frontal lobes are also impacted. The frontal lobes are involved in multiple cognitive and behavioral traits, but especially executive function, such as planning, and judgment.  The cerebellum also can be especially sensitive to alcohol. The cerebellum is involved in both motor control and cognition.  Perhaps as important as these structural changes are changes in communication between various brain areas.  One has to remember that there are networks in the brain connecting various areas, and these areas have to communicate efficiently with each other. Studies of functional connectivity in FASD indicate less efficiency in these networks, which in turn may impact cognitive and behavioral functioning.  But remember, findings are showing that many parts of the brain and how they function and communicate, can be affected following prenatal alcohol exposure.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207054/#R28

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389933/

Question 5

What specialist usually makes the FAS diagnosis?

Edward Riley · Accepted Answer

Good question, but I will start by saying that it is going to depend on exactly what you want to diagnose, where you are, and what services are available. Ideally, any fetal alcohol spectrum disorder (FASD) should be diagnosed by a multidisciplinary team, since the range of potential effects from prenatal alcohol exposure is far-reaching.  As your question relates to FAS, I will delve into that first. FAS is diagnosed by distinct facial characteristics, growth retardation, cognitive or behavioral effects, and alcohol exposure.  But it is also a diagnosis of exclusion, meaning that other syndromes and circumstances have to be ruled out.  If available, the diagnosis should be made by a medical geneticist, a dysmorphologist, or a developmental pediatrician.  The problem is that there are not enough of these experts to meet the demand, and these specialists are often located in metropolitan areas, medical schools, or clinics specializing in developmental disabilities or FASD.  An FASD diagnosis can also be made by a general pediatrician, or a family physician if they have had appropriate training and know what to look for.

The multidisciplinary diagnostic team is critical, especially in cases where some or all of the cardinal facial features may be absent. For example, the diagnosis of one of the neurodevelopmental disorders resulting from prenatal alcohol exposure is going to depend on a thorough neurobehavioral evaluation.  This involves someone with cognitive and behavioral test experience, such as a neuro- or developmental psychologist. Others who may be involved in this team effort are speech and language experts, occupational therapists, and social workers. An accurate alcohol exposure history also has to be obtained by someone on the team.

All professionals who might have contact with someone with an FASD should receive training about the physical and behavioral characteristics of this disorder. This would include psychiatrists, psychologists, occupational and language therapists, social workers, nurses, and teachers. If they suspect the condition they can make a referral for an evaluation by an expert.

Another point is that even though there aren’t a large number of experts always available, with the growth of telemedicine, it should be possible shortly, if not already to get an expert consultation regardless of where you are located.

For a detailed discussion of FASD, you might want to see:  https://www.fasdhub.org.au/siteassets/pdfs/australian-guide-to-diagnosis-of-fasd_all-appendices.pdf

For a discussion of how an evaluation might be conducted see: https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/fetal-alcohol-spectrum-disorders-toolkit/Pages/Algorithm-for-Evaluation.aspx

For a discussion of telemedicine in FASD see: https://pubmed.ncbi.nlm.nih.gov/33316074/

Question 6

Are their known genetic contributors to FASD?

Edward Riley · Accepted Answer

Similar to what occurs in many disorders and diseases, one’s genes can influence the outcomes from prenatal alcohol exposure and either increase or decrease a particular effect. Shortly after the identification of FAS, it was found that differing genotypes (one’s genetic makeup) influenced the effects of prenatal alcohol exposure.  Animal studies showed differential sensitivity of various strains or lines to the same dose of alcohol, either as a result of differences in the metabolism of alcohol or their functional sensitivity to it. Most recently, zebrafish have been used extensively to study genetic risk/resiliency to fetal alcohol effects.  For example, a few growth factor and cell death genes have been identified that also appear to impact cranial facial development and preliminary work with humans appears to support these findings.

Another important piece of data implicating genetic factors is that there is a higher percentage (concordance rate) of similar FASD diagnosis among identical twins (share 100% of their genes) exposed prenatally to alcohol than between fraternal twins, who only share 50% of their genes.

Researchers are also examining epigenetic effects resulting from alcohol exposure.  These involve heritable changes in gene expression without underlying changes in the genes. This is currently a major area of study in FASD.

For a detailed discussion of the genetics of FASD see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125635/pdf/nihms831571.pdf

For a review of epigenetic research see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3860549/ and https://obgyn.onlinelibrary.wiley.com/doi/full/10.1002/pd.5731

Question 7

Can ultrasounds of the brain and face during pregnancy identify a developing FASD?

Edward Riley · Accepted Answer

This is an area that is still in its infancy. Obviously, one isn’t going to diagnose a case of FASD without adequately assessing the infant, but progress is being made on trying to determine if some of the facial features or brain changes that are seen in FASD can be detected prenatally. For example, a recent paper out of Italy looked at the association between a marker for drinking (EtG) during pregnancy and physical characteristics of FAS during a second-trimester ultrasound. The fetuses of pregnant women whose marker for alcohol consumption reached a certain threshold had an increased distance between their eyes (interorbital distance) and a greater distance from the front of the brain to the back of the thalami (FTD). See https://pubmed.ncbi.nlm.nih.gov/30811093/

An earlier study also identified brain changes in the fetuses of moderate to heavy alcohol exposure, but some of the changes were not consistent with the above paper. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746738/

There are also a few primate studies that have looked at alcohol-exposed fetuses using magnetic resonance imaging (MRI).  In one study in rhesus monkeys, brain alterations were found at 135 days of gestation in fetuses whose moms had been drinking alcohol prior to and during early pregnancy. When assessed in the third trimester several markers of brain dysfunction or disorder were observed using MRI. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211988/

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