The thickness of growth marks in primary teeth may help identify children at risk for mental health disorders

The thickness of growth marks in primary (or “baby”) teeth may help identify children at risk for depression and other mental health disorders later in life, according to a groundbreaking investigation led by researchers at Massachusetts General Hospital (MGH) and published in JAMA Network Open.

The results of this study could one day lead to the development of a much-needed tool for identifying children who have been exposed to early-life adversity, which is a risk factor for psychological problems, allowing them to be monitored and guided towards preventive treatments, if necessary.

The origin of this study traces back several years, when senior author Erin C. Dunn, ScD, MPH, learned about work in the field of anthropology that could help solve a longstanding problem in her own research. Dunn is a social and psychiatric epidemiologist and an investigator in MGH’s Psychiatric and Neurodevelopmental Genetics Unit. She studies the effects of childhood adversity, which research suggests is responsible for up to one-third of all mental health disorders.

Dunn is particularly interested in the timing of these adverse events and in uncovering whether there are sensitive periods during child development when exposure to adversity is particularly harmful. Yet Dunn notes that she and other scientists lack effective tools for measuring exposure to childhood adversity.

Asking people (or their parents) about painful experiences in their early years is one method, but that’s vulnerable to poor recall or reluctance to share difficult memories. “That’s a hindrance for this field,” says Dunn.

However, Dunn was intrigued to learn that anthropologists have long studied the teeth of people from past eras to learn about their lives. “Teeth create a permanent record of different kinds of life experiences,” she says. Exposure to sources of physical stress, such as poor nutrition or disease, can affect the formation of dental enamel and result in pronounced growth lines within teeth, called stress lines, which are similar to the rings in a tree that mark its age.

Just as the thickness of tree growth rings can vary based on the climate surrounding the tree as it forms, tooth growth lines can also vary based on the environment and experiences a child has in utero and shortly thereafter, the time when teeth are forming. Thicker stress lines are thought to indicate more stressful life conditions.

Dunn developed a hypothesis that the width of one variety in particular, called the neonatal line (NNL), might serve as an indicator of whether an infant’s mother experienced high levels of psychological stress during pregnancy (when teeth are already forming) and in the early period following birth.

To test this hypothesis, Dunn and two co-lead authors – postdoctoral research fellow Rebecca V. Mountain, Ph.D., and data analyst Yiwen Zhu, MS, who were both in the Psychiatric and Neurodevelopmental Genetics Unit at the time of the study – led a team that analyzed 70 primary teeth collected from 70 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom.

In ALSPAC (which is also called Children of the 90s), parents donated primary teeth (specifically, the pointed teeth on each side of the front of the mouth known as canines) that naturally fell out of the mouths of children aged five to seven. The width of the NNL was measured using microscopes.

Mothers completed questionnaires during and shortly after pregnancy that asked about four factors that are known to affect child development: stressful events in the prenatal period, maternal history of psychological problems, neighborhood quality (whether the poverty level was high or it was unsafe, for instance), and level of social support.

Several clear patterns emerged. Children whose mothers had lifetime histories of severe depression or other psychiatric problems, as well as mothers who experienced depression or anxiety at 32 weeks of pregnancy, were more likely than other kids to have thicker NNLs. Meanwhile, children of mothers who received significant social support shortly after pregnancy tended to have thinner NNLs.

These trends remained intact after the researchers controlled for other factors that are known to influence NNL width, including iron supplementation during pregnancy, gestational age (the time between conception and birth) and maternal obesity.

No one is certain what causes the NNL to form, says Dunn, but it’s possible that a mother experiencing anxiety or depression may produce more cortisol, the “stress hormone,” which interferes with the cells that create enamel. Systemic inflammation is another candidate, says Dunn, who hopes to study how the NNL forms.

And if the findings of this research can be replicated in a larger study, she believes that the NNL and other tooth growth marks could be used in the future to identify children who have been exposed to early life adversity. “Then we can connect those kids to interventions,” says Dunn, “so we can prevent the onset of mental health disorders, and do that as early on in the lifespan as we possibly can.”

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Exposure to early-life adversity is one of the biggest risk factors for both mental and physical health problems across the lifespan. Early-life adversity encompasses experiences of threat or deprivation that deviate from a child’s expectable physical and psychosocial environment and require some form of adaptation (1).

These early-life adversities can thus be both physical and psychosocial in nature-spanning experiences of food deprivation resulting from poverty to witnessing or experiencing violence or having a parent with mental illness. These adversities are estimated to affect nearly half of all youths in the United States (2).

Although not all children who experience early-life adversity will go on to have mental health problems (3), exposure to adversity has been associated with about a twofold increase in risk for depression, anxiety, or substance use disorders (4,5). In fact, researchers estimate that if the association between adversity and mental health risk was causal, approximately one third of all mental disorders could be attributable to childhood adversity (5–7).

Emerging evidence suggests that there may be certain stages in development, or sensitive periods, when the brain is highly plastic and thus when adversity may have even more enduring effects (8,9). Studies finding support for sensitive periods suggest that exposure to early adversity during prenatal life (10) and from birth to 5 years of age (11,12), may be especially important in shaping long-term risk for psychiatric disorders.

These sensitive periods are often conceptualized as high-risk periods-or windows of vulnerability-when adverse life experiences, such as exposure to stressors, are most harmful in increasing disease risk. However, sensitive periods can also be viewed as high-reward periods-or windows of opportunity-when enriching life experiences, including exposure to health-promoting interventions, are even more beneficial in preventing disease and promoting long-term health. Of note, relatively few studies on the time-dependent effects of adversity have been performed, and the evidence both for (11–13) and against (14–16) the existence of sensitive periods is mixed.

Given the well-established association between early-life adversity and a variety of psychiatric disorders, there is an urgent need to both 1) refine our understanding of whether and when in development these sensitive periods occur and 2) identify children who experience early-life adversity-particularly during possible developmental sensitive periods-to guide targeted prevention efforts.

Yet, the lack of tools to reliably and validly measure both the presence and timing of early-life adversity remains one of the biggest obstacles in the field. Current gold standard measures of childhood adversity rely on either retrospective or prospective self-reports, which are susceptible to major biases in recall or self-disclosure (17).

In fact, a recent meta-analysis of 16 studies found that retrospective and prospective measures of childhood maltreatment, one of the most common types of childhood adversity, showed poor agreement, with more than half of individuals with prospective observations of maltreatment not reporting it retrospectively and, similarly, more than half of individuals with retrospective reports lacking concordant prospective measures (18).

Moreover, asking a child to directly report his or her own adversity exposure may raise ethical and other concerns and pose a risk of harm to the child (19). Official reports, such as health and social services records, provide an alternative strategy, but these can also dramatically underestimate the prevalence of certain adversities (20,21).

Although promising biomarkers of early-life adversity and subsequent risk for mental health problems–such as altered DNA methylation patterns (22–24) and changes in amygdala connectivity (25,26)–are beginning to emerge through epigenetic and neuroimaging studies, respectively (27), these measures are currently too costly, time-consuming to implement, and/or lacking in reproducibility. Thus, there is a need for objective measures that are noninvasive, inexpensive, and able to provide more accurate information about the presence and timing of childhood adversity.

If such a measure existed, its public health implications would be profound. For the first time, clinicians would be able to confidently identify children-on a population-wide scale-who experienced childhood adversity during sensitive periods in development and are therefore at future risk for developing a psychiatric (or other) disorder. Such early, accurate risk identification could unlock the full potential of primary prevention programs, altering the course of children’s development before psychopathology symptoms ever even onset.

In this article, we propose that teeth could potentially serve as a promising and actionable new tool capable of achieving these goals. To support this claim, we first summarize empirical work from dentistry, anthropology, and archaeology on human tooth development and show how these fields have collectively studied human and animal teeth for decades, using teeth as time capsules that preserve a permanent, time-resolved record of life experiences in the physical environment.

This body of literature discusses teeth not as they relate to oral health but rather as fossil records in which the history of an individual’s early environmental exposures is permanently imprinted. Importantly, many of the studies cited here were conducted in samples considered large by the standards of their disciplines.

This includes those studies investigating human archaeological populations and nonhuman primate samples where there are a limited number of available specimens. Although these sample sizes are small in comparison with most psychiatric studies, we argue that insights from this collection of studies nevertheless provide initial suggestive evidence of the untapped opportunities for the field of mental health research and, potentially, clinical practice to prevent brain disease and promote brain health.

Building from this literature, we then integrate these insights with knowledge about the etiology of psychiatric disorders and the role of early-life adversity in shaping mental health risk to present a working conceptual model that links past psychosocial stress exposure to markers of tooth development and, ultimately, risk for neuropsychiatric disease.

We end with a research agenda and discussion of future directions for rigorously testing this conceptual model and with a call to action for interdisciplinary research to meet the urgent need for new transdiagnostic biomarkers of adverse early-life experiences and psychiatric outcomes.

Although the evidence to support this conceptual model is in its nascent stages, the time is right to begin empirically testing this model, given increasing investment in the formation of large birth cohort studies that have already collected teeth, the availability of techniques to characterize between-person variability in teeth-related features (28), and the growing recognition of the potential for biomarkers to guide prevention and intervention planning.

THE PROPERTIES OF TEETH AS RECORDS OF EARLY-LIFE EXPERIENCE

Human teeth possess at least five properties that make them promising potential biomarkers of exposure to early-life adversity and therefore helpful tools to guide prevention efforts in psychiatry.

Teeth Develop During Known Sensitive Periods in Development
Most humans have two sets of teeth: a set of 20 primary (deciduous, “baby,” or “milk”) teeth that are shed and replaced by 32 permanent teeth (29). Each tooth is made of enamel (the hard outermost layer of the tooth crown), dentin (the underlying layer extending into the tooth root), and pulp (the innermost core of the tooth containing blood vessels, nerve cells, and dentin-forming cells called odontoblasts) (Figure 1A).

Primary teeth begin to mineralize at approximately the fourth fetal month, begin to erupt at approximately 6 months of age, and are completely formed by 2 to 3 years of age (30) (Supplemental Table S1). In contrast, the formation of permanent second molars extends from 3 years up until 14 to 16 years of age, while the permanent third molars, or wisdom teeth, complete their formation at around 18 to 25 years of age (31). These time frames coincide with known sensitive periods for brain development (32,33) and programming of stress response circuitry (34,35).

Teeth Leave a Permanent Record of Their Incremental Formation, Much Like the Rings in a Tree

The process of tooth formation is well documented (Figure 1B). In the final stage of tooth formation, odontoblasts (dentin-producing cells) and ameloblasts (enamel-producing cells) secrete proteins that incrementally mineralize the dentin and enamel, producing growth marks that remain visible in the completed tooth crown.

These growth marks act as permanent records of the formation process, much like the rings in a tree marking its age. Cross-striations record roughly daily growth (Figure 1C). Longer period growth lines (36), called striae of Retzius (37), correspond to roughly weekly growth in humans. These growth marks are preserved in teeth across mammal species (38–41). Exposure to adversity may affect this growth process, resulting in abnormal growth marks or stress lines, as discussed below.

Because each tooth develops in a specific time window during ontogeny (Supplemental Table S1), these growth marks permanently record different phases of development. In other words, each tooth may tell its own story about human growth and development. Depending on whether the tooth root is present, the growth marks in a primary central incisor record daily and weekly development from prenatal life up to 2 years postnatally, whereas a permanent second molar records development up to 14 to 16 years (30,42,43).

Thus, one remarkable consequence of this natural variation across teeth is that a continuous record of growth from prenatal life up to midadolescence can be pieced together between these different types of primary and permanent teeth. In cases where the tooth root is unavailable, as is the case for most shed primary teeth, this timeline is truncated (as noted in Supplemental Table S1).

Human Teeth Preserve Biological Memories of the Existence and Timing of Past Physical Stressors

Exposure to physical stressors during tooth formation, such as poor nutrition, disease, and ingested toxicants like heavy metals, can affect dentin and enamel cell function (44,45), resulting in alterations that are visible as structural defects or recorded as changes in chemical composition within the tooth crown (44,46,47).

Among the most commonly studied developmental defects are enamel hypoplasias, which appear on the surface of erupted teeth as pits, grooves, or complete absence of enamel. The prevalence and predictors of enamel hypoplasias in both living human participants (48,49) and archaeological populations (50) are well described in archaeology, anthropology, and dentistry.

Through visual inspection of tooth characteristics–whether using macro-level tools (e.g., hand lenses) or more micro-level tools (e.g., scanning electron microscopes, microcomputed tomography)–this work has revealed that individuals exposed to famine (51), malnutrition (48,52), infectious diseases (52), and injuries (47) have significantly higher risk for enamel hypoplasias as compared with individuals without such physical stress exposures. Similarly, individuals exposed to poor diet, disease (53), and maternal hypertension (54) have also been shown to have teeth that are significantly smaller than those of their unexposed peers.

Perhaps most uniquely, these physiological stressors have also been shown to produce accentuated growth marks known as stress lines (55,56) (Figure 1C). These stress lines permanently record the specific day or week in development when the stressor occurred. One of the most studied stress lines in teeth is the neonatal line marking an individual’s birth (57). Seminal work by Andra et al. (58) and Smith (59) revealed that by using the neonatal line as a kind of temporal benchmark, teeth can be used to capture the developmental timing of a variety of physical environmental exposures, including exposure to heavy metals (60,61), organic chemicals (62), injury and infections (63), and extreme wintertime cold (61).

Human Teeth May Also Preserve Biological Memories of the Existence and Timing of Past Psychosocial Stressors

To our knowledge, no studies have yet examined the extent to which psychosocial-based early-life adversities, such as changes in family or household structure (e.g., divorce, bereavement following family death) and experiences of deprivation or threat (e.g., physical or sexual abuse and neglect, other interpersonal and noninterpersonal traumas), are recorded in human teeth. However, at least three preliminary yet intriguing lines of evidence suggest that teeth may preserve biological memories of past psychosocial stressors, with the timing of these stressors recorded in stress lines.

As noted, the majority of research on stress lines in humans has focused on the neonatal line, which can be seen in the primary teeth of about 90% of children (64). Most commonly, anthropologists and forensic experts use the neonatal line to determine the causes and timing of infant death (65) because the neonatal line is absent in the case of stillbirth (66). A small number of researchers have used the neonatal line as a marker of different types of potential perinatal stress.

From these studies, there is initial evidence showing an association between certain stressful perinatal factors (64,66–70)–including preterm birth, winter birth, and a more complicated or longer duration of delivery–and a wider neonatal line (see Supplemental Table S2).

Of note, models of prenatal stress that include high-risk pregnancies and maternal prenatal exposure to chronic social disadvantage have, in turn, identified an impact of these factors on adverse offspring brain development and risk for psychiatric disorders later in life (71,72). Determining whether these associations represent the effects of psychosocial stress experienced by the mother or physiological stress experienced by the infant will require more routine measurement of the neonatal line in cases where the conditions of delivery are well documented, as is the case for many current birth cohort studies.

As summarized in Supplemental Table S3, a second body of evidence comes from seven studies in nonhuman primates exploring the associations between potential psychosocial stressors and markers of disrupted tooth development. Like humans and other mammals, nonhuman primates have two sets of teeth that develop incrementally and leave behind time-resolved growth marks (38); nonhuman primates are also affected by the same types of social stressors known to affect humans such as disruptions in parent-child bonding (73).

Thus, primate studies provide a strong animal model to complement human studies. As shown in Supplemental Table S3, three studies did not have animal life histories and thus made inferences about stress exposures using evidence such as local rainfall records and knowledge of typical weaning patterns (74–76). Among the four studies in which animal life histories were known, all four documented the emergence of stress lines corresponding to the timing of psychosocial stress exposure such as separation from the mother (77), transfers to new enclosures (78), postsurgery hospital checkups (78), death of a sibling (79), and other disruptions in the caregiving environment (63,79).

In one suggestive study of captive juvenile rhesus macaques, Austin et al. identified stress lines in enamel that corresponded to the timing of individuals’ temporary separations from their mothers and the social group to undergo biobehavioral assessments (63). These biobehavioral assessments included measures of behavioral and physiological stress response to a novel environment (80) and coincided with stress lines that typically appeared within a day of the assessment. These stress lines also correlated with the timing of changes in chemical composition.

Based on these primate findings, there is reason to hypothesize that the time resolution of social stressors may also be captured in human teeth. Empirical research in both humans and animals is needed to investigate this question further and, as we discuss later, to clarify which types of social experiences produce stress lines.

A third body of evidence suggesting that teeth may preserve biological memories of past psychosocial stressors comes from a very small collection of studies showing that psychosocial stressors may have time-resolved effects on human hair and nails, which are formed from the same ectodermal tissue as tooth enamel (81). Like enamel, hair and nails also grow incrementally and are affected by circadian cycles (36,82,83).

The same physical stressors known to compromise ameloblast functioning–including injury, malnutrition, and physical illness–also disrupt hair and nail growth cycles. In hair, these stressors can trigger an abnormal shift of scalp follicles from the growing (anagen) stage into the dying (telogen) stage, resulting in acute temporary hair loss 2 to 4 months after the inciting event (84). In nails, these disruptions can manifest as linear grooves called Beau’s lines.

Given that nails grow at a known rate, the timing of exposure can be estimated by measuring the distance of the lines from the nail bed (85). Similar to the neonatal line, Beau’s lines appear in the fingernails of 92% of infants at 4 weeks of age and then disappear with growth (86). Notably, acute temporary hair loss (telogen effluvium) has been empirically linked to acute psychological stressors such as car accidents and bereavement (87). The appearance of Beau’s lines has also been anecdotally attributed to similar adverse psychosocial experiences (88).

Teeth Are Spontaneously Shed or Routinely Removed Across the First Two Decades of Life, Making Them Potentially Ideal Tools to Guide Primary Prevention Efforts in Psychiatry

A final useful property of human teeth is that healthy or nondecayed teeth are naturally shed or routinely extracted during the first 2 decades of life. As an alternative to discarding or storing those unused teeth, three possibly easy and inexpensive screening opportunities exist when teeth could instead be used to measure early-life exposure to both physical and psychosocial stressors and thus to identify children at highest risk for a psychiatric disorder. To illustrate this point, we highlight these possibilities below and in Figure 1D in relation to major depressive disorder (MDD), one of the most common and burdensome psychiatric disorders that onsets at different stages of the early-life course (89).

First, most primary teeth begin shedding at around 6 to 8 years of age (30). This time period precedes the onset of puberty, a known high-risk period for the onset of depression, particularly in girls (90). It is therefore reasonable to imagine the possibility that one day pediatricians or dentists could collect children’s shed teeth from parents, send these teeth to specialized labs for analysis, and use the results as an additional MDD risk assessment tool.

A second opportunity exists during early adolescence, when otherwise healthy primary and permanent teeth are surgically extracted for orthodontic reasons (91). Approximately 14% of U.S. children have at least one tooth extracted by 13 years, before the age of onset for most adolescent MDD cases (92,93).

Moreover, approximately one third of preschool children experience a traumatic injury to one or more primary teeth, and approximately one quarter of school-age children experience a traumatic injury to the permanent teeth (94). Although the treatment of traumatic injury varies depending on the nature of the injury and clinician training, some of these cases result in the extraction of the injured tooth, providing yet another opportunity for assessment of brain health and risk for future brain health problems.

A third opportunity exists during late adolescence and early adulthood, when about half of all insured individuals in the United States have their third molars, or wisdom teeth, removed (95). This period spanning 15 to 20 years of age coincides with the developmental stage when approximately 25% of MDD cases onset (96).

Of course, these prevention opportunities could also be realized for other psychiatric disorders as well. These include disorders that onset during the early teen years, including attention-deficit/hyperactivity disorder, and oppositional defiant disorder (93), as well as disorders that onset during young adulthood, including schizophrenia, bipolar disorder, and substance use disorders (93).

THE TEETH CONCEPTUAL MODEL

Based on these prior findings and the previously described potential of teeth to serve as new biomarkers, we introduce the TEETH (Teeth Encoding Experiences and Transforming Health) conceptual model (Figure 2). This model proposes that early-life psychosocial stressors disrupt multiple developmental processes (97), potentially including those involved in tooth formation, and that these developmental disruptions leave behind measurable biological imprints that can then be leveraged to predict risk for later psychiatric disease.

Through this model, we propose that primary and permanent teeth may serve as dual markers of both past psychosocial stress exposure and future mental health risk. Below, we describe and review the evidence supporting each of the three main tenets of our model in the hopes of translating the current literature on tooth formation into testable research hypotheses for the mental health field.

Tenet 1: Early-Life Adversity May Be Associated With Disrupted Processes Involved in Brain and Tooth Development

Psychosocial stress during an organism’s early development is associated with disruptions in key biological processes, including programming of brain structure and function (98,99), the body’s stress response circuitry (97,100), and the epigenome (22,23). As discussed, there is also preliminary support for the notion that psychosocial stressors can leave a detectable trace in the microstructure and chemical composition of primate teeth (63,77,78). We propose that these stressors may also affect human tooth formation (Figure 2). Nascent evidence suggests parallels between biological processes involved in the development of teeth and the brain, the key organ giving rise to psychiatric disease and modulating stress responses. For instance, receptors for neuropeptides, including serotonin and melatonin, are expressed by ameloblasts and potentially modulate enamel formation (101,102). Other markers specific to glial cells (the most abundant central nervous system cell type) are also expressed in dental pulp (103).

Like enamel, brain structures are also derived in ontogeny from ectodermal tissue (104), supporting observations that developmental defects in enamel are disproportionately common among people with Down syndrome, cerebral palsy, and other brain-related congenital conditions (105,106). Therefore, enamel formation not only appears to track ameloblast function but also may be susceptible to processes affecting early brain development (107,108). Together, these findings led Morishita and Arora to suggest that “it is possible that the timetable of key neurodevelopmental events is imprinted in an individual’s teeth” (109).

As noted previously, the relationship between psychosocial stress and tooth development in humans is largely unexplored. However, one previous study did examine the association among features of primary teeth, socioeconomic status (an indicator of both material and social deprivation), and cortisol reactivity (a commonly used proxy for stress response system dysregulation) (110). This study found an interaction between socioeconomic status and cortisol reactivity, such that the children with the greatest enamel thickness tended to have both low socioeconomic status and low salivary cortisol reactivity. Thus, these initial findings suggest important interrelationships among socioeconomic disadvantage, biological sensitivity to stress, and tooth-based markers of development that require further elucidation.

Tenet 2: Developmental Disruptions During Tooth Formation May Produce Time-Resolved Biological Imprints That Can Be Objectively Captured

Both prenatal and postnatal disruptions in brain development following exposure to adversity are increasingly being identified through neuroimaging markers of structural changes (e.g., cortical thinning) (111,112) and functional changes (e.g., decreased amygdala connectivity) (25,26). Early-life adversity has also been associated with altered stress response functioning, which may manifest in the form of chronically low or high cortisol reactivity (35,113). Similarly, altered epigenetic processes following early-life psychosocial stress appear to become encoded in the epigenome, detectable at birth (24) and beyond (22,23).

We propose that psychosocial stress-induced disruptions in tooth formation may result in macro-level alterations, such as changes in tooth dimensions, as well as micro-level biological signatures, including changes in microstructure and chemical composition as visible in stress lines (Figure 2). Importantly, because teeth form during known developmental periods, all markers of tooth developmental disruptions can be considered time resolved, with the level of temporal specificity varying depending on the measure used and the tooth analyzed. For example, macro-level measures may reveal the existence of exposures within the 3- to 5-year window corresponding to that tooth type’s mineralization. Examination of more micro-level measures, such as stress lines, could more precisely pinpoint the timing of exposures to within a 1-week margin of error (78).

Tenet 3: Disrupted Developmental Processes May Predict Mental Health Risk

Most research on biological markers of psychiatric risk have focused on the brain, indicators of stress reactivity, or epigenetic markers. Our model proposes that teeth may serve as an additional, albeit novel, biomarker linking early-life psychosocial stress exposure to mental health risk (Figure 2). Although this proposition has not yet been widely tested, recent work from at least eight studies on tooth-based markers of environmental toxins (e.g., pollutants, heavy metals) has provided some evidence that these physical exposures can be captured in teeth and used to predict risk for mental disorders such as schizophrenia and psychotic disorders (114,115), autism spectrum disorder (60,116–118), and both internalizing and externalizing symptoms (119,120) (Table 1). Whether tooth-based markers of psychosocial stress can function as indicators of psychiatric risk will be a rich area of future inquiry.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822497/

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More information: Rebecca V. Mountain et al, Association of Maternal Stress and Social Support During Pregnancy With Growth Marks in Children’s Primary Tooth Enamel, JAMA Network Open (2021). DOI: 10.1001/jamanetworkopen.2021.29129