Prenatal maternal stress: A knowledge-translated review of associated mechanisms, sources, and outcomes

Extant policies and regulations inadequately address the unique and complex needs, vulnerabilities, and risks at the intersection of maternal and child health (Leiss & Kotch, 2010). Stress experienced by a pregnant mother, or prenatal maternal stress (PNMS), has attracted especial scrutiny within the field. Modern evidence emphatically concurs that the long-term disease, developmental, and other trajectories of gestating fetuses are significantly programmed by the intrauterine environment, and are highly vulnerable to disturbances provoked and/or produced by PNMS, via functional perturbations of maternal (and fetal) neuroendocrine-immune network(s). PNMS is a catchall encompassing distinct operationalizations of stress, including self-reports by pregnant women; prenatal mental illness(es); prenatal maternal disease, nutrition, and assorted physiological factors and complications; prenatal maternal use of both licit and illicit substances; and maternal exposures to any number of environmental toxicants and/or teratogenic agents. The ubiquity of vectors for PNMS makes for daunting consideration, as does the essential precariousness of fetal programming; yet peril coexists with opportunity (Johnson, Riley, Granger, & Riis, 2013), and an evidence-informed understanding is a first, necessary step to ensuring the health of future generations.


Introduction

The juncture of pregnancy and stress is a critical, strategic locus for public policy and intervention, and medical paradigms have promoted its salience and clinical exigency by emphasizing early-life engagement and preventative health management. The following sections adumbrate and enumerate the sources, outcomes, qualities, and considerations unique to prenatal maternal stress (PNMS), and in the spirit of prevention, this paper attempts to satisfy two basic criteria: 1) dissemination of the most robust empirical evidence to-date (ENDNOTE1), and 2) adaptation of the latter for compatibility with the practical needs and contextual realities of affected populations and a broader readership (ENDNOTE2).
    Stress and PNMS, at root, are identical: “[…] an event or events that are interpreted as threatening to an individual and which elicit physiological and behavioral responses” (McEwen, 2000, p. 173). In some ways distinct from a traditional conception and understanding of stress a working definition of PNMS might have the following conditions and clarifications:
    a) an ‘event’ may constitute anything from a mother’s mental status to acute exposure to an environmental toxicant;
    b) said ‘event(s)’ act upon both a primary (i.e., mother) and a downstream target (i.e., fetus), often with permanent, tangible consequences to the latter but not the former;
    c) that ‘interpretation’ need not occur consciously, as deliberated phenomenon, to entail deleterious consequences;
    and d) what constitutes ‘threatening’, to a fetus, pertains to relative adverse impact(s) on developmental outcomes, either short- or long-term.

The Study of PNMS
Preliminary Considerations: Animal vs. Human Models and Methodologies
While there are frequently limits and caveats to the validity of the extrapolation and generalization of findings from animal models to humans, animal models have, nevertheless, enormously contributed to and informed our understanding of PNMS (Beydoun & Saftlas, 2008; Charil et al., 2010). The study of animal tissue is comparatively free of the economic, bureaucratic, experimental, and ethical restrictions and parameters unique to the study of human tissues—not least that of human offspring. For example, whereas researchers may measure cytokine and cortisol levels with equally relative ease in animals and humans (see Johnson et al., 2013), changes at the neurostructural level are, for the above-listed reasons, far more easily ascertained and examined in animals (Beydoun & Saftlas, 2008). Knowledge of placental functions, for example, has mainly derived from the latter (Charil et al. 2010; see Harris & Seckl, 2011). The strongest human-animal parallels can be drawn from nonhuman primate models (see Schneider, Roughton, Koehler, & Lubach, 1999; Schneider & Moore, 2000; Schneider, Moore, Kraemer, Roberts, & DeJesus, 2002; Suomi & Higley, 1991), wherein systems such as the endocrinological are especially similar (Schneider, Coe, & Lubach, 1992).
    Animal models are amenable to more rigorous scientific protocols than human models. They tend to suffer less experimental bias, and to benefit from greater methodological liberty with, as well as control over, experimental design, condition(s), and/or possible confounding variables. As such, animal models produce higher-quality evidence more conducive and appropriate to causal inferences. Human research on PNMS, indeed, has been described as disproportionately correlational/associational (Charil, Laplante, Vaillancourt, & King, 2010; Harris & Seckl, 2011) and observational (Beydoun & Saftlas, 2008; Charil et al., 2010). Beydoun and Saftlas (2008) found that 100% of the animal studies they examined had been conducted under controlled conditions, whereas only a paltry 6% of the human studies met a similar standard.
Further Considerations
    The intent of this paper is not to fear-monger, nor to encourage either trigger-happy alarmism or parental hypervigilance. Rather, one could make a defensible case that perceptions of risk during pregnancy themselves produce circular, counterproductive effects, for example by increasing maternal anxiety (Lennon, 2016). And so, as ostensibly compelling the subject matter, and as pressing the need for action, vying or aspiring to extirpate stress—omnipresent as the latter is—may be wrongheaded or impossibly lofty respectively. The reader is instead enjoined, particularly when appraising evidence in terms of personal, client/patient, or other practical relevance, to consider a conscientious, parsimonious, prudent, but flexible perspective: neither overly punctilious, nor prone to conclusive leaps, nor inclined to flout findings as nullities absent careful reflection. As noted, human studies are resistant to causal inferences by design, and in fact many adverse offspring outcomes studied alongside PNMS manifest relatively commonly to begin with, like preterm birth, which occurs in 18% of all pregnancies (Kozer et al., 2003). Similarly, “not all small babies [low birth weight] develop mental health or behavioural problems” (Schlotz & Phillips, 2009, p. 906). For health practitioners thinking about clients/patients, factors of maternal risk perception should be cautiously negotiated in terms of potential impact on maternal decision-making (Lennon, 2016).

Basic Overview of PNMS Biomechanics
The significance of PNMS is primarily attributable to fetal programming (Moisiadis & Matthews, 2014b), which is also known as prenatal (Evans, Bellingham, & Robinson, 2016) or early programming (Leiss & Kotch, 2010), imprinting (Beydoun & Saftlas, 2008), developmental plasticity (Schlotz & Phillips, 2009) or the ‘developmental origins of health and disease (DOHaD)’ model (Karlsson, 2011). The fetal programming model speaks to the sensitive attunement of fetal development to the intrauterine environment, and fetal vulnerability (O’Connor, 2011) to suboptimal conditions (Schlotz & Phillips, 2009) and resultant exposures to, for example, maternal stress hormones (Harris & Seckl, 2011) called glucocorticoids (Moisiadis & Matthews, 2014b). Glucocorticoids are critical to normal development (O’Connor, 2011; Moisiadis & Matthews, 2014a), serving as “developmental switch[es]” or “trigger[s]” (Moisiadis & Matthews, 2014a, p. 391) and calibrating the future basal stress-reactivity of the fetus to a significant extent (Johnson et al., 2013). Although they are problematic only under aberrational circumstances (McEwen, 2000), exposure in any case has long-term consequences (O’Connor, 2011; Beydoun & Saftlas, 2008) able to stretch across generations (Harris & Seckl, 2011; Moisiadis & Matthews, 2014a). Fetal plasticity—programmability—is a double-edged sword (Johnson et al., 2013). According to Harris and Seckl (2011):

“During programming, environmental adversity is transmitted to the foetus and acts on specific tissues during sensitive periods in their development to change developmental trajectories and thus their organisation and function. Since different cells and tissues are sensitive to various factors at different times, the effects of adversity on an animal's biology will be tissue, time and challenge specific.” (p. 280)

    PNMS-related modulation mainly operates through the hypothalamic-pituitary-adrenal (HPA)-axis (Moisiadis & Matthews, 2014b; Murphy et al., 2015), and so by intricate feedback loop (Moisiadis & Matthews, 2014a). The HPA-axis is known to be highly plastic (Evans et al., 2016) and sensitive to glucocorticoids (Harris & Seckl, 2011; Moisiadis & Matthews, 2014a; Moisiadis & Matthews, 2014b) during gestation, and it is developed and responsive by the 2nd trimester (Moisiadis & Matthews, 2014b). Stressors stimulate the HPA-axis by inducing activity in its network, and this activity mainly—but not exclusively (Charil et al., 2010)—culminates in the production of the glucocorticoid known as cortisol (Michaud, Matheson, Kelly, & Anisman, 2007; Moisiadis & Matthews, 2014a). Stressors also engage the immune system, specifically by increasing the production and circulation of pro-inflammatory cytokines in the body (Steptoe, Hamer, & Chida, 2007; Marques, O'Connor, Roth, Susser, & Bjorke-Mosen, 2013). Cytokines regulate communication between the brain and the immune system (Johnson et al., 2013), and have received increasing attention for their purported role in a number of pathophysiologies through the lifespan (Johnson et al., 2013). In the case of immunological dysfunction, the body is unable to cease producing them despite an absence of stressor(s) (Johnson et al., 2013), and chronic stimulation of the HPA-axis, by its paradoxical suppression of the production of cortisol (Maccari & Morley-Fletcher, 2007), forces a similarly persistent and protracted inflammatory response (Johnson et al., 2013). Altogether, these systems (HPA and immune), inextricably bound, are known as the neuroendocrine-immune (NEI) network (Johnson, Riley, Granger, & Riis, 2013) of the human body.
    The fetus derives nutrients/agents conducive to its natural development from within the intrauterine environment, and the proteins and enzymes responsible for delivering said actually expose the fetus to risks (Moisiadis & Matthews, 2014b). These risks, as with all fetal exposures are mediated by the blood-brain barrier (BBB) and the placenta (Charil et al., 2010; Harris & Seckl, 2011). Both structures begin to mature around week 7 (Wong, Wais, & Crawford, 2015), but by week 4 the placenta has already begun interfacing with the mother’s blood (Wong et al., 2015), and it peaks in susceptibility to foreign or deviational exposures between weeks 10 and 38 (Wong et al., 2015). Incidentally, this is precisely the interval of time within which the proliferation of neurons—a process known as neurogenesis—reaches its fetal baseline, at 25 weeks (Wong et al., 2015).
    The BBB is responsible for ensuring neuronal health (Wong et al., 2015), making the presence (and function) of the placenta de facto vital to the healthy development of the fetal brain (Charil et al., 2010); the BBB is markedly permeable (Marques et al., 2013), and the placenta thus behaves like its defensive vanguard (Charil et al., 2010). The placenta, however, is vulnerable to penetration by glucocorticoids (Charil et al., 2010), and its processes of gene transcription in utero are in perpetual flux—vulnerable themselves (Monk, Spicer, & Champagne, 2012). One placental enzyme, HSD2, protects the fetus from both stress-produced cortisol and much higher basal maternal cortisol levels (Harris & Seckl, 2011). Levels of HSD2 are reduced or limited by the presence of pro-inflammatory cytokines (Harris & Seckl, 2011), and even still the enzyme only imperfectly fends against cortisol (O’Connor, 2011).
    Pregnancy itself is accompanied by increased baseline maternal cortisol levels (Seth, Lewis, & Galbally, 2016), and while there occurs, simultaneously, an inhibition of a) maternal HPA-axis sensitivity (Murphy et al., 2015) and b) maternal reactivity to external stressors (Seth et al., 2016), as adaptive response, whether such adaptive balance is struck hinges on constitutional factors unique to the pregnant woman. The presence of maternal depressive symptoms, for example, may significantly curtail it or negate it outright (Murphy et al., 2015), or otherwise signify absence of the capacity to engage it altogether (Seth et al., 2016). Pregnancy-related amplification of cortisol production also begets maternal susceptibility to hypercortisolaemia—the pathological overproduction of cortisol—which in turn, circularly, encourages the manifestation of depressive symptomatology (Seth et al., 2016).
    In sum, both exposure to chronic (Johnson et al., 2013) and acute PNMS—large and sudden stressors, such as environmental catastrophes, are particularly influential (Charil et al., 2010), with maternal sensitivity purportedly highest earlier in pregnancy (Glynn, Wadhwa, Dunkel-Schetter, Chicz-DeMet, & Sandman, 2001)—are liable to impact; they do so by way of dynamic, fine-tuned, but imperfect interaction with and among maternal-fetal tissues, NEI networks, and other embedded processes, and they resultantly encourage the development of numerous adverse outcomes and pathologies in offspring (Michaud, Matheson, Kelly, & Anisman, 2008; Harris & Seckl, 2011). Perhaps most notably, disruptions and insults to routine maturation of the fetal HPA-axis, if significant, are able to alter the expression of certain genes (Moisiadis & Matthews, 2014b).

Outcomes of PNMS

General Outcomes
Physiological (Obstetric, Neonatal, and Postnatal). Various sources of PNMS have been differentially implicated in an increased risk in offspring of congenital defects (ENDNOTE3) (Feldkamp, Botto, & Carey, 2015; Hill, Wlodarczyk, Palacios, & Finnell, 2010; Jin et al., 2013; Lassi, Imam, Dean, & Bhutta, 2014; Myles, Newall, Ward, & Large, 2013; A. D Ngo, Taylor, Roberts, & Nguyen, 2006; Anh Duc Ngo, Taylor, & Roberts, 2010; Selmer et al., 2016; Seto, Einarson, & Koren, 1997; Sibiude et al., 2014), damaged and disrupted lung function (Wright, 2010) including asthma (Lee et al., 2016; Leon Hsu et al., 2015; Flanigan, Sheikh, & Nwaru, 2016), preterm birth (Beydoun & Saftlas, 2008; Bertin et al., 2015; Burdorf et al., 2011; Faucher, Hastings-Tolsma, Song, Willoughby, & Bader, 2016; Garn, Nagulesapillai, Metcalfe, Tough, & Kramer, 2015; Mendez et al., 2014; Rose, Pana, & Premji, 2016; van Melick, van Beukering, Mol, Frings-Dresen, & Hulshof, 2014; Luke et al., 1995; Beydoun & Saftlas, 2008), low birth weight or growth restriction (ENDNOTE4) (Beydoun & Saftlas, 2008; Abusalah et al., 2012; Burdorf et al., 2011; Myles et al., 2013; Rhee et al., 2015; Seto et al., 1997; Grote, Bridge, Gavin, Melville, Iyengar, & Katon, 2010), spontaneous miscarriage/abortion (Pineles, Park, & Samet, 2014; Chen & Hu, 2011; Chen & Cheng, 2015; Boivin, 1997), postnatal obesity (Tate, Wood, Liao, & Dunton, 2015), delayed motor development (Beydoun & Saftlas, 2008), disrupted immune development (Marques et al., 2013; Johnson et al., 2013) including allergies (Flanigan et al., 2016), and disrupted and delayed sexual maturation and function (Beydoun & Saftlas, 2008; Evans et al., 2016).
Psychopathological, Neurostructural, and Developmental. PNMS has been conjectured to influence the pathogenesis of schizophrenia (Khandaker, Zimbron, Lewis, & Jones, 2013; King, St-Hilaire, & Heidkamp, 2010; D. K. Kinney et al., 2010; Meli, Öttl, Paladini, & Cataldi, 2012; Moore & Susser, 2011), autism spectrum disorder (Bauer & Kriebel, 2013; Claassen, Naudé, Pretorius, & Bosman, 2008; D. Kinney, Munir, Crowley, & Miller, 2008; Wong et al., 2015; Schlotz & Phillips, 2009), obsessive-compulsive disorder (Vasconcelos et al., 2007), borderline personality disorder (Schwarze et al., 2013), antisocial personality disorder (Schlotz & Phillips, 2009), schizoid personality disorder (Schlotz & Phillips, 2009), and mood disorders (Schlotz & Phillips, 2009).
    Human studies in the meta-analysis by Beydoun and Saftlas (2008) “[…] found associations of PNMS with broadly defined (e.g. neonatal and infant behaviour, childhood mental disorders, temperament and problem behaviours, developmental disorders, intellectual and language functioning) and specific (e.g. externalizing and anxiety problems, lack of independence, altered social behaviour, atypical or mixed handedness, ADHD symptoms, impulsivity, gender role and sexual orientation) psychiatric entities” (p. 444).
    PNMS has also been found to adversely affect the developing hippocampus and amygdalae (Harris & Seckl, 2011), to decrease corpus callosum and overall cerebral cortex volumes (Harris & Seckl, 2011), and to interfere with the brainstem (Geva & Feldman, 2008), which undergoes dramatic changes late in the 3rd trimester and is hugely important to self-regulation (i.e., stress-reactivity; Geva & Feldman, 2008). PNMS has also been observed to delay psychomotor function (Kingston, Tough, & Whitfield, 2012), and to exert a small, but significant, detrimental effect on postnatal cognitive abilities (Charil et al., 2015). PNMS during the 1st trimester and high maternal cortisol levels in the 3rd trimester saw an effect similar to the aforementioned (Kingston, Tough, & Whitfield, 2012). LeWinn et al. (2009) found higher prenatal maternal cortisol levels to be associated to significant reductions in the IQ scores of exposed children (LeWinn et al., 2009).

Sources of PNMS

Prenatal Maternal Mental Illness
While the limits of animal-to-human analogy are purported to be the least limited with respect to mental health outcomes (Beydoun & Saftlas, 2008), findings should nonetheless be interpreted with caution (Satyanarayana, Lukose, & Srinivasan, 2011). For one, crucial determinants and confounds are often neglected across the entire empirical corpus, including (but not limited to) the severity of maternal disorder/dysfunction (Stein et al., 2014); the frequent co-morbidity of disorders (Stein et al., 2014); the use, past and/or intra-study, of medications (Stein et al., 2014; El Marroun et al., 2014); significant mediators such as income disparities (e.g., associating prenatal maternal depression with low birth weight; Grote et al., 2010; Stein et al., 2014); and the verification of the presence of mental illness by reliable, clinical means (e.g., diagnostic and/or semi-structured interviews, as opposed to self-reporting; Seth et al., 2016). Studies also frequently suffer significant methodological heterogeneity even when aggregated within the parameters of same meta-analysis or review (see Seth et al., 2016; Stein et al., 2014). Yet prenatal maternal depression and anxiety have been indexed to a significant extent by relative cortisol levels, according to Monk et al. (2012), suggesting a strong need to continue analyzing PNMS as mental illness and in relation to offspring outcomes in spite of the difficulty inherent to doing so.
Psychopharmacological Treatments. The debate surrounding prenatal psychotropic medication use, untreated prenatal mental illness, and their comparative impacts on offspring conflict is crippled by conflict, (Thompson, Levitt, & Stanwood, 2009; El Marroun, White, Verhulst, & Tiemeier, 2014), insufficient evidence from randomized control studies (Previti, Pawlby, Chowdhury, Aguglia, & Pariante, 2014), and an overarching lack of theoretical consilience. So many contrasting and contested findings, for one, have proven centrally resistant to conclusive inferences for practical application (El Marroun et al., 2014).
    That said, relative risks should always be weighed (Thompson, Levitt, & Stanwood, 2009), and treatment decisions—for example, to maintain or discontinue medication use prior to or intra-pregnancy—should be made on an individual basis (Altshuler et al., 1996; Suri, Lin, Cohen, & Altshuler, 2014) with the appropriate professionals. The findings included here—by no means exhaustive—and/or any omission(s) thereof should neither constitute direct or indirect medical recommendations nor substitute for medical advice.
Antidepressants. For congenital defects, the absolute risks from fetal exposure to prenatal psychotropic medication use, as a whole, are low (Altschuler et al., 1996). Recent evidence for antidepressants, specifically, did not classify them as major teratogens (Yonkers, Blackwell, Glover, & Forray, 2014), except with respect to cardiac defects (Grigoriadis et al., 2013). The most up-to-date CANMAT guidelines did not classify antidepressants as first-line treatment recommendation for pregnant women (MacQueen et al., 2016).
    In terms of birth defects, paroxetine has been the most consistently implicated selective-serotonin reuptake inhibitor (SSRI). First-trimester use in particular has been related to increased risk of any birth defects (Bérard et al., 2016), but especially cardiac malformations (Bar-Oz et al., 2007; Bérard et al., 2016; Myles, Newall, Ward, & Large, 2013; Wurst, Poole, Ephross, & Olshan, 2010; Yonkers et al., 2014). Myles et al. (2013) found first-trimester use of fluoxetine, another SSRI, to be associated with significantly increased risk of major birth defects, but did not find significant risk of any congenital defects with prenatal use of either citalopram or sertraline. The meta-analyses by Satyanarayana et al. (2011) and Ross et al. (2013) suggested relationships unique to antidepressants, but not untreated maternal depression, and low birth weight and preterm birth. to complicate matters further, another meta-analysis found exposure to prenatal maternal antidepressant use and untreated depression, side-by-side, to both be significantly related to various, but short-term neonatal symptomatology (Suri et al., 2014).
    For postnatal psychological outcomes, the second- and/or third-trimester use of SSRIs, independent of maternal depression, was associated with increased risk of developing an autism spectrum disorder (Boukhris, Sheehy, Mottron, & Bérard, 2016). Johnco et al. (2016) found children with diagnosed anxiety disorders to be more likely to have had mothers who used antidepressants during pregnancy. Conversely, on the matter of developmental outcomes, Stein et al. (2014) reported antidepressant use during pregnancy to be associated with improvements in offspring.
    On cognitive performance indicators, Previti et al. (2014) discussed a) considerable empirical conflict about IQ score outcomes; b) an absence of differences in scores on certain cognitive indices of offspring exposed to either antidepressants or none; c) some transient, short-term delays in both mental and motor development in the antidepressant cohort(s); and d) that depression per se can be related to adverse outcomes, which was separately corroborated by the analyses of Stein et al. (2014). On a longer-term scale, Suri et al. (2014) found significantly different motor function and language acquisition in antidepressant cohorts, but no cognitive differences.
    Consider that, with respect to SSRIs, dose-response and duration factors have lacked significant relationships to outcomes (Nulman et al., 2012), which is to suggest that questions of ‘how much’ or ‘how often’ may not be relevant.
Antipsychotics. Thompson et al. (2009), relaying findings from animal models only, claimed severe neurodevelopmental risks inherent to fetal exposure to prenatal maternal antipsychotic use.
Mood stabilizers. Valproate, also known as valproic acid, is commonly used in the treatment of bipolar disorder(s). Exposure to prenatal maternal use has been linked to high teratogenicity and neurotoxicity as well as increased risk of developing an autism spectrum disorder (Thompson, 2009). Teratogenicity, in particular, was further supported by Tanoshima et al. (2015) and their meta-analytic findings. Lithium carbonate, the most commonly used mood stabilizer, was found to have a high likelihood of producing diaphragm-specific birth defects (Hosseini, Mousavi, & Rashidi, 2010), and its use in the 1st trimester was found to increase the relative risk of overall congenital malformations (Altshuler et al., 1996).
Anxiolytics/benzodiazepines. First-trimester use of benzodiazepines was found to increase the relative risk of any congenital malformations (Altshuler et al., 1996), and other evidence uncovered increased risk of preterm birth, low birth weight, and 4.9-times greater odds of a select group of congenital malformations (Hill et al., 2010). As for postnatal outcomes, according to El Marroun et al. (2014): “the use of benzodiazepines during pregnancy
report no associations with behavior or cognition, while other studies report an association between prenatal benzodiazepine exposure and motor functioning and lower scores on mental development.” (p. 984)
Adverse Obstetric and Neonatal Outcomes. The most robust evidence supporting a connection from prenatal maternal mental illness to adverse obstetric and neonatal outcomes exists in the cases of anxiety and preterm birth (Rose, Pana, & Premji, 2016); schizophrenia (see Stein et al. (2014) for a full review); depression and low birth weight (Stein et al., 2014; Seth et al., 2016; Grote et al., 2011) and preterm birth (Grote et al., 2011); and past and/or present anorexia nervosa and low birth weight (Stein et al., 2014). Prenatal maternal substance abuse, meanwhile, has been associated with a risk of adverse offspring outcomes exceeding both prenatal maternal mood disorder and psychotic disorder (Stein et al., 2014).
Behavioural, Emotional/Temperamental, and Neurodevelopmental Outcomes. (ENDNOTE5) There is a compelling case to be made tying exposure to untreated prenatal maternal depression and the subsequent development of externalizing problems and behaviours (i.e., disruptive; e.g., ADHD, ODD, CD; Suri et al., 2014; Stein et al., 2014), including, although less robustly, antisocial personality disorder (Stein et al., 2014). High maternal cortisol levels at 30-32 weeks gestation, arising from untreated maternal depression, was linked to increased reported negative reactivity in infants by their mothers, as well as found to negatively predict cognitive ability of offspring (Satyanar, Lukose, & Srinivasan (2011). Exposure to prenatal maternal depression has been associated with delays in intellectual development (Seth et al., 2016). Some minor baseline decreases have also been observed in cognitive functioning, but long-term effects are inconsistent (Stein et al., 2014). For example, the IQs of children exposed in utero to either SNRIs, SSRIs, or untreated maternal depression were not found to significantly differ (Nulman et al., 2012).

Prenatal Maternal Illness, Nutrition, and Health Complications
Infections. Maternal infections experienced during the prenatal period, particularly early during gestation, have been implicated as risk factors in the development of schizophrenia (Khandaker et al., 2013).
Fever. The meta-analysis conducted by Shi, Zhang, Mi, Song, Ma, and Zhang (2014) implicated maternal fever experienced during the 1st trimester in an increased preponderance of congenital heart defects in offspring.
Diabetes. Prenatal maternal diabetes has been associated with the development of metabolic disorders in offspring (Philipps et al., 2011).
Blood Pressure. Prenatal maternal hypertension, but only when manifesting as the pregnancy-specific condition preeclampsia, was cited by Brown and Gavoric (2015) as disrupting placental development and increasing maternal inflammation. On its treatment, the latter authors reported, according to extant evidence:

“[…] methyldopa, labetalol, beta blockers (other than atenolol), slow release nifedipine, and a diuretic in pre-existing hypertension are considered as appropriate treatment. If a woman’s blood pressure is well controlled on an agent pre-pregnancy she may continue it during pregnancy, with the exception of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. If restarting drug therapy in women with chronic hypertension, methyldopa is recommended as first line therapy. For emergency treatment in preeclampsia, IV hydralazine, labetalol and oral nifedipine can be used. The ACOG Practice Bulletins also recommend that methyldopa and labetalol are appropriate first-line agents and beta-blockers and angiotensin-converting enzyme inhibitors are not recommended.” (p. 4)

Epilepsy. Pregnant women with epilepsy were found at increased risk of experiencing spontaneous miscarriage, antepartum and post-partum haemorrhage, delivery by caesarean section, and hypertensive disorders, and in their offspring, growth restriction and preterm birth (Viale et al., 2015). Prenatal exposure to the treatment of maternal epilepsy (i.e., anticonvulsant medications) has also been linked to adverse outcomes (Altshuler et al., 1996; Hill et al., 2010; Viale et al., 2015); per the results of their meta-analysis, Hill et al. (2010) make an explicit recommendation to minimize of the number of anticonvulsants used during pregnancy.
Cancer. Prenatal maternal malignancy and distinct treatments thereof, and respective effects on fetal outcomes, vary considerably; see Nulman and Edell (2011) for specific descriptions.
Nutrition. International WHO data revealed a globally significant inconsistency between dietary recommendations and actual prenatal maternal dietary practices (Blumfield, Hure, Macdonald-Wicks, Smith, & Collins, 2012). For example, pregnant women reporting to be strict vegetarians—a common dietary practice—were found to be more likely to report higher levels of anxiety (Vaz et al., 2013).
    Prenatal maternal undernutrition, on a more general level, has long been theorized to contribute to the risk in offspring of metabolic and cardiac problems (‘Barker’s hypothesis’; Karlsson, 2011). It can lead to more ready adipose tissue storage in offspring (Besson, Lagisz, Senior, Hector, & Nakagawa, 2016), and specific disruptions to the HPA-axis (Besson et al., 2016) as well as offspring reproductive functions and respective hormonal distributions (Evans et al., 2016) have been noted in rodent models. Interestingly, rodent models assessed by Besson et al. (2016) did not find any associations with offspring coping styles and either prenatal maternal undernutrition or overnutrition. Prenatal maternal overnutrition has, however, been linked to intrauterine growth restriction (Evans et al., 2016) and to higher risks of certain health complications in offspring later in life (Besson et al., 2016). Prenatal maternal malnutrition, lastly, interferes with the supply of nutrients to the fetus (Marques et al., 2013); it is chiefly consequential vis-à-vis pregnancy and outcomes when involving deficiencies in iodine, B-vitamins, Vitamin D, and/or Vitamin A (Marques et al., 2013).

Thyroid Autoimmunity. Pregnant women with non-clinically pathological thyroid autoimmunity were found to be at greater risk of spontaneous miscarriage (Chen & Hu, 2011).
Inflammatory Bowel Disease (IBD). Cornish et al. (2016) reported greater prevalence rates (2.0 increased odds, on average) of preterm birth, low birth weight, and congenital abnormalities in the offspring of women with IBD. Pregnant women treated with thiopurines and/or antitumor necrosis factor (anti-TMF) drugs for IBD were not found to experience significantly different rates of adverse pregnancy outcomes except in the case of preterm birth (Mozaffari, Abdolghaffari, Nikfar, & Abdollahi, 2015).
Hepatitis B. Antiviral therapies for hepatitis B were shown to successfully reduce mother-to-child transmission without resulting in significantly higher rates of adverse outcomes (Brown et al., 2016).
HIV. The analyses by Sibiude et al. (2014) revealed associations between birth defects and cognitive impacts in offspring and exposure to prenatal maternal antiretroviral therapies, but the latter authors contended that, overall, the benefits of treatment significantly outweigh the risks. Cotrimoxazole has been emphasized as a priority treatment for affected pregnant women by Ford et al. (2014) but on the basis of tentative, limited evidence.

Social Determinants of PNMS
Ethnoracial, Social, and Environmental. Mendez et al. (2014) found that pregnant women living in high segregation areas and/or experiencing high levels of everyday discrimination were more likely to experience preterm. Paradies et al. (2015) linked racism with poorer health and mental health, broadly, while Bécares and Atatoa-Carr (2016) not only corroborated the latter relationship with mental health, but also tied ethnic discrimination/unfair treatment by health professionals to a 66% higher likelihood of postnatal maternal depression.
    Social hostility and isolation have been associated with increased circulation of inflammatory markers in the body (Steptoe et al., 2007). For pregnant mothers, relationship strain with a partner was found to be responsible for three-quarters of the variance of the effect of prenatal stress on cognitive and fearfulness scores in offspring (Satyanarayana et al., 2011). In a comprehensive meta-analysis by Howard, Oram, Galley, Trevillion, and Feder (2013), the experience of intimate partner violence during pregnancy was significantly related to numerous adverse maternal mental health outcomes.
    Fetal exposure to psychosocial adversity experienced prenatally by the mother has been associated with both placental dysfunction and maladaptive epigenetic changes (Monk, Spicer, & Champagne, 2012). Both life stress and cumulative (i.e., lifetime) maternal trauma were significantly associated, in one study cited by Johnson et al. (2013), to changes in neonatal immunological activity and adaptability. Saulnier and Brolin (2015) observed increased rates of metabolic, cardiovascular, and mental health outcomes in the offspring of mothers exposed to famine or war during pregnancy, though these differences were marginal.
Occupational. Lower income and work-related stress has been known to increase the circulation of inflammatory markers (Steptoe et al., 2007). The impacts of long working hours (van Melick et al., 2014) and shift work on risks of preterm birth and low birth weight have ranged from marginal (Bonzini et al., 2011) to, for preterm birth, non-significant (van Melick et al., 2014), but significant methodological limitations were present (van Melick et al., 2014), and contrary evidence exists for long working hours in particular (Luke et al., 1995). Luke et al. (1995) found adverse working conditions, especially those featuring standing, noise, and greater energy demands, to plausibly increase the risk of preterm birth. Maternity leave was found to reduce neonatal mortality rates in low-, middle-, and high-income countries—and with the longer the leave, the better the rates (Nandi et al., 2016). Steptoe et al. (2007) reported that work stress increases the cytokine stress response.

Psychoactive Substances
Alcohol. Exposure to prenatal maternal alcohol use—at any point during gestation—has numerous, well-established consequences, including but not limited to low birth weight (Schneider et al., 2002), birth defects (Lassi et al., 2014), male and female reproductive abnormalities (Evans et al., 2016), fetal alcohol syndrome, damage to the central nervous system, and maladaptive alterations of the fetal HPA axis (Thompson et al., 2009). Fetal alcohol syndrome and the latter alterations to the fetal HPA-axis are intimately entwined (Schneider et al., 2002).
Cannabis. Gunn et al. (2016) found that the use of cannabis while pregnant significantly increased the risks in offspring of lower birth weight and intensive care needs.
Tobacco. Prenatal exposure to both direct maternal tobacco use and significant maternal environmental exposure to its use have been robustly tied to, among other outcomes, congenital cardiac defects (Lassi et al., 2014), low birth weight (Abusalah et al., 2012), fetal growth retardation, hypoxia and interference with sexual differentiation (Thompson et al., 2009), Sudden Infant Death Syndrome (SIDS) and childhood cancers (Kelley, Bond, & Abraham, 2001), increased risk of childhood invasive meningococcal disease (Murray, Britton, & Leonardi-Bee, 2012), and complications related to DNA methylation (Joubert et al., 2016) such as orofacial clefts and asthma (Joubert et al., 2016). As well, in the review by Johnco et al. (2016), anxious children were more likely to have mothers who smoked.
In more counterintuitive findings, maternal tobacco smoking actually increased the risk of offspring becoming overweight (Oken, Levitan, & Gillman, 2008), and Thompson et al. (2009) conjectured transdermal delivery of nicotine—the primary psychoactive ingredient in tobacco—to have even worse implications for pregnant mothers than the inhalation combusted tobacco.
Anesthetic Gases. Boivin’s (1997) meta-analysis found that maternal occupational exposure to anesthetic gases (e.g., nitrous oxide) significantly increased the risk of spontaneous miscarriage.
Analgesics. Bauer and Kriebel (2013) found prenatal maternal paracetamol (i.e., acetaminophen) exposure to be significantly positively correlated with autism spectrum disorder in offspring.
Opioids. A limited meta-analysis conducted by Baldacchino, Arbuckle, Petrie, and McCowan (2014) found in aggregation that in utero exposure to maternal opioid use predicted non-statistically significant, but poorer, outcomes on a range of cognitive, psychomotor, and behavioural indicators.
Psychostimulants. Prenatal exposure to maternal use of cocaine has been linked to numerous adverse long-term neurodevelopmental outcomes, including attention and emotion regulation-related difficulties, with effects worsening and deepening in impact according to extent of use (Thompson et al., 2009). Similar effects have been observed for amphetamines and methamphetamine, although evidence is limited owing to the relative novelty of certain trends of use (Thompson et al., 2009). For caffeine, increased use has been implicated in a higher likelihood, in offspring, of low birth weight, with risk increasing linearly per 100 mg dose (Rhee et al., 2015), and with daily doses greater than or equal to 300 mg also significantly increasing the risk of spontaneous miscarriage (Lassi et al., 2014). Greenwood et al. (2014), likewise, observed an overall average increased risk of 12.5%, per daily 100 mg increment of ingested caffeine, for spontaneous miscarriage, stillbirth, low birth weight, and small for gestational age outcomes. Lastly, prenatal methamphetamine use was found by Liles et al. (2012) to be unrelated to perceived problems in child behaviour (i.e., perceptions of behaviour reported by the mothers).

Environmental Toxicants and Teratogenic Agents
Agent Orange (Ngo, Taylor, Roberts, & Nguyen, 2006; Ngo, Taylor, & Roberts, 2010) and lead (Genius, 2009; Genuis & Kelln, 2015; Johnson et al., 2013; Leiss & Kotch, 2010; Virgolini, Bauter, Weston, & Coryslechta, 2006) are two well-known agents whose infamous teratogenicity can be traced at least in part to extensive media coverage, if not to genuinely disturbing consequences to both affected individuals and society. As for other environmental toxicants and agents, most people are poorly acquainted with 1) the sheer variety, and 2) the diversity and magnitude of agent-specific obstetric, neonatal, and postnatal outcomes associated with maternal exposures to them. The facts of both 1) and 2) significantly limit the feasibility, in the present undertaking, of mapping a complete and itemized list of prenatally toxic agents whether by, or according to, a) their most familiar, everyday vehicles; b) the oft-unique parameters, mediators, and specifications necessary to the proper contextualization of harmful--as opposed to harmless--exposure; c) clarified taxonomies/classifications (e.g., familial or molecular; e.g., endocrine disruptors, carcinogens, xenobiotics, etc.); and d) their frequently differing (i.e., agent-specific) impacts.
    Relative prenatal harm from a given environmental toxicant is determined by the intensity (i.e., magnitude; level) and extent (i.e., duration and/or frequency over time) of maternal exposure (Leiss & Kotch, 2010). Often, via a process called bioaccumulation (Genuis & Kelln, 2015), the body neither easily nor naturally motions to excrete, metabolize, or otherwise rid itself of its various toxic exposures, and instead stores them, sometimes indefinitely, in various physiological repositories such as adipose (fat) tissues, cells, and the blood (see, e.g., Genuis, 2009). Additionally, the built-in ‘protections’ afforded the gestating fetus are liable to be inadequately equipped to effectively screen or filter molecules hitherto alien to the original and long-standing evolutionary conditions which made them necessary and shaped them. To illustrate, some persistent organic pollutants (POPs, e.g., organochlorine pesticides [OCPs], polycholorinated biphenyls [PCBs], polybrominated biphenyl ethers [PBDEs] share the capacity to engage in transplacental transfer, meaning that they readily cross the placenta (Tan, Loganath, Chong, & Obbard, 2009).
    Leiss and Kotch (2010) proposed that differential exposures could be attributed to parallel-effects of the “weathering hypothesis” (p. 311): for lead, according to their example, cumulative lifetime exposure manifests in bloodstream levels able to be marshaled and transferred in utero to the fetus, and the fetus, once at reproductive age, may pass both its inherited and subjective cumulative exposure to its own offspring; this process, according to the authors, ultimately leads to an intergenerational perpetuation of birth and outcome disparities. Policy governing the use of lead, in particular, has historically been slowest to benefit more impoverished and marginalized populations (e.g., African-Americans; Leiss & Kotch, 2010). They add, too, that each partner—both maternal and paternal—contributes his or her ‘burden’ of exposure(s) to the reproductive cycle (Leiss & Kotch, 2010).
Sources. Environmental toxins and toxicants of consequence to pregnancy include air pollution (Leiss & Kotch, 2010; Allen et al., 2014; Wong et al., 2015; Bertin et al., 2015; Genuis & Kelln, 2015; Suades-González, Gascon, Guxens, & Sunyer, 2015); urban noise (Leiss & Kotch, 2010); proximity to a hazardous waste site (Leiss & Kotch, 2010); formaldehyde (Chen & Cheng, 2015); heavy metals (Jin et al., 2013; Leiss & Kotch, 2010; Wong et al., 2015; Genuis n Kelln, 2015) such as arsenic (Quansah et al., 2015; Rahman et al., 2015), cadmium (Leiss & Kotch, 2010), methylmercury (Genuis, 2009; Leiss & Kotch, 2010; Karagas et al., 2012) and titanium (Savabieasfahani, Alaani, Tafash, Dastgiri, & Al-Sabbak, 2015); consumer products (Wong et al., 2015); polychlorinated biphenyls (PCBs), perfluorinated compounds (PFCs), and phthalates (Leiss & Kotch, 2010); wood fuel smoke (Abusalah et al., 2012); pesticides (Berkowitz et al., 2004; Van Maele-Fabry, Lantin, Hoet, & Lison, 2010; Romitti, Herring, Dennis, & Wong-Gibbons, 2007; Leiss & Kotch, 2010; Genuis & Kelln, 2015; ); flame retardants (Genuis & Kelln, 2015); plasticizers (Leiss & Kotch, 2010; Genuis & Kelln, 2015); plasticizers (Genuis & Kelln, 2015; Leiss & Kotch, ); acrylamide (Allam et al., 2010); dioxins (Leiss & Kotch, 2010); and endocrine disruptors (Leiss & Kotch, 2010).
Outcomes. Van Maele Fabry et al. (2010) make a defensible argument for increased risks of childhood cancers due to certain exposures; this risk was omitted or neglected by Leiss and Kotch (2010). However, the latter generated a comprehensive review, based on past and contemporaneous evidence, which proved adequately encapsulating and compelling in its presentation of the total and veritable gamut of theorized and ostensible outcomes for offspring exposed to toxic agents in the womb. Said cited outcomes ranged from impaired fetal growth to “[…] preterm birth, reduced gestational age, small for gestational age, reduced birth weight (continuous), low birth weight (categorical), reduced birth length, and/or reduced head circumference” (p. 310), as well as, in the longer-term:

“[…] respiratory allergies and impaired lung function, infections and impaired immune function, impaired motor function, cognition, and reading comprehension, autism [spectrum disorder], ovarian dysfunction, dental defects and carries, behavioral problems (including hyperactivity, delinquency, and violence) and teen pregnancy, altered gender-specific play behavior, abnormal or altered sexual development, elevated childhood blood pressure and abnormal adolescent cardiac function, and childhood obesity” (p. 311)

Evidence-Based Interventions and Recommendations at a Glance

Mental Health and Addictions:

  • Maternal mental health promotion is the least undertaken (2%) of all mental health prevention and awareness programmes in the world (WHO, 2014), and our approaches to treatment “[…] begin far too late” (Kingston et al., 2012, p. 707). Some maternity-/pregnancy-specific mental health initiatives, however, such as the Integrated Maternal Psychosocial Assessment to Care Trial (IMPACT; Kingston et al., 2014), show promise. Cognitive-behavioural therapy (CBT), as well, has been tabled as viable and putatively superior psychotherapeutic treatment modality for pregnant women (O’Connor, 2011; Kingston et al., 2014; Lever Taylor, Cavanagh, & Strauss, 2016), especially if delivered accessibly (i.e., electronically; Kingston et al., 2014) and on an individual, one-to-one basis (Kingston et al., 2014; Sockol, 2015). Current Canadian guidelines recommend CBT as a first-line treatment for pregnant women (MacQueen et al., 2016). Moreover, CBT, unlike all psychotropic medications, is free of “iatrogenic risk” (O’Connor, 2011, p. 16), and it follows that other evidence-based psychotherapies would share the same benefit.
  • Hoisington, Brenner, Kinney, Postolache, and Lowry (2015), addressing the immune- and inflammation-related mechanisms inherent to mental health, reported access to green spaces to be a valuable means of bolstering said systems (due to exposure to beneficial microorganisms).
  • Massage therapy for pregnant women was reported to reduce cortisol levels and improve neonatal outcomes in studies cited by Previti et al. (2014).
  • According to Rajendiran et al. (2015), sleep, already reportedly affected in pregnant women, can cause oxidative stress and increase immune response if dysfunctional; thus, quality of sleep would seem an important area to address, and in all cases.
  • Smoke-free legislation and designated smoke-free environments have been associated with significant reductions in rates of preterm births and asthma-related hospitalizations in offspring (Been et al., 2014). For maternal smoking cessation, Kelley, Bond, and Abraham (2001) contended that the most effective interventions 1) deemphasized threat perception (i.e., risks of harm to offspring) and the individual counseling context, and 2) had greater emphases on cognitive preparation and follow-up.
  • In one study included by Lassi et al. (2014), prenatal alcohol use was significantly curtailed by the application of ‘preconception counseling’.

Health (Nutrition, Supplementation, and Pharmaceutics):

  • Vis-à-vis offspring outcomes, the strongest evidence to date failed to demonstrate efficacy to multiple micronutrient supplementation over-and-above that of targeted supplementation with iron and folic acid/folate (Devakumar et al., 2016).
  • Avoiding excessive weight gain during pregnancy has demonstrated some value in the mitigation of the risk of gestational diabetes (Brunner et al., 2015). Relatedly, lifestyle changes aiming to reduce weight gain during pregnancy were tentatively found to reduce the risk of it in obese pregnant women (Oteng-Ntim, Varma, Croker, Poston, & Doyle, 2012).
  • Health Canada recommends that pregnant women limit their intake of fish (due to high methylmercury content; Genuis, 2009).
  • Medium- to high-risk pregnancies incurred slight reductions in the risk of preterm birth via prenatal maternal aspirin use (Kozer et al., 2003).
  • In one study included by Huang, Wang, and Hu (2016), probiotics demonstrated efficacy for both healthy and depressed populations in the alleviation of depressive symptomatology (Huang, Wang, & Hu, 2016). Bioimmunomodulatory probiotics, such as Lactobacillus reuteri, have shown stress-protective effects (Hoisington et al., 2015).
  • According to Yang et al. (2014), selenium, a mineral known to be a fundamental mediator of oxidative stress in the brain, may plausibly exert a neuroprotective effect against manganese toxicity/over-exposure when supplemented during pregnancy (Yang et al., 2014).

Endnotes

1 The evidence cited henceforth has been systematically retrieved on condition of emphasis, in whatever capacity, on the period of time following conception and prior to birth. The types of sources retrieved are, by-and-large, limited to reviews, meta-analyses, and systematic reviews. Communicated findings may be based on secondary data (i.e., sources nested within the latter articles) rather than primary findings, and may be subject to possible flaws in interpretation as such. Additionally, methodological caveats, unless absolutely critical to interpretation of results, may be omitted on the basis of desired brevity, concision, and wider comprehensibility. Any interest in particular findings should, ideally, be followed by personal scrutiny of the relevant source(s).
2 A truly comprehensive review of the PNMS literature is necessarily beyond the scope of the present undertaking. Collectively, the subject of PNMS is as multidisciplinary as it is broiling, foreboding, and encompassing, comprising as many unwieldy descriptions of morphological implications and functional outcomes—communicated, occasionally, in onerous, specialist cant—as it does multifarious claims to specialized variables and unique relationships.
3 ‘Birth’ and ‘congenital’, and ‘defects’ and ‘malformations’, are used interchangeably, and per differential usage by the authors themselves, but share identical meaning throughout.
4 According to Harris and Seckl (2011), low birth weight carries a significant disease burden.
5 The study design with the greatest capacity to approximate conclusive determinations of postnatal outcomes, and/or persistence of effect(s), is the long-term follow-up (Steptoe, Hamer, & Chida, 2007).
6 Prenatal maternal psychoactive drug withdrawal, as opposed to active use, may have equally important implications (Thompson et al., 2009)
7 Relevantly, potentiation of the maternal stress response is among the manifold harms of lead (Leiss & Kotch, 2010).

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-Meta-Analysis: Pesticides and Orofacial Clefts
Romitti, Paul A;Herring, Anna M;Dennis, Leslie K;Wong-Gibbons, Donna L
The Cleft Palate - Craniofacial Journal; Jul 2007; 44, 4; ProQuest pg. 358

-O’Connor, T. (2011). stress-and-pregnancy doc~~


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