By Piper Sneed
Photo Credit: CNN and Adobe Stock
An Introduction to the Significance of Preterm Birth:
Preterm birth, defined as live birth before 37 weeks gestation, is a major determinant of infant and maternal mortality and morbidity. While it is estimated that the incident number of cases of preterm birth has decreased worldwide, from 16.06 million in 1990 to 15.22 million in 2019, preterm birth remains a considerable problem affecting mothers and children around the globe. Complications that arise from preterm birth, such as impaired respiration, difficulty feeding, and a high risk of infection, are the leading cause of death among children under five years old worldwide (Cao et al.). Those that survive have an elevated risk of developing various diseases and disorders, some of which may be lifelong and debilitating. Preterm birth has been associated with an increased risk of neurodevelopmental disorders, coronary artery disease, stroke, type II diabetes mellitus, and obesity in adulthood (Vidal et al.). The burden of preterm birth is distributed unequally, with low income countries, especially those in Africa and Asia, having the highest prevalence. Systematic review and modeling analysis of data from 2014 showed that 80% of preterm births occurred in countries in sub-Saharan Africa and South Asia. Disparities in preterm birth rates are also seen within countries and regions in relation to differences in maternal education, race, ethnicity, and other sociodemographic characteristics. In the United States, for instance, the preterm birth rate in 2016 was 14% among African-American women but only 9% among white women (Walani).
Research on the etiology of preterm birth is an important step in lowering the incidence of cases and improving perinatal care. A wealth of studies have focused on uncovering potential risk factors, and while there have been no definitive results as to specific causes, many significant associations have been made. Evidence suggests that having a history of preterm birth, becoming pregnant within 6 months of one’s last delivery, having multiple gestations, experiencing vaginal bleeding during pregnancy, and acquiring intrauterine or intra-amniotic infections are associated with an elevated risk of preterm birth. Other associations with preterm birth include a low or high pre-pregnancy body mass index (BMI - which is associated with nutritional deficiencies and conditions like hypertension and diabetes respectively), a large volume of amniotic fluid, maternal conditions like thyroid disease or asthma, receiving abdominal surgery or invasive procedures for cervical disorders, and cigarette and tobacco use (Goldenberg et al.). While all of these potential risk factors warrant our attention, the subject of this article will be an association with preterm birth that is often neglected: high levels of psychosocial stress. This article presents studies conducted over the past few decades that focus on the role that stress and related issues like depression and anxiety play in one’s risk for delivering preterm. In doing so, this article makes the case that more needs to be done to address the emotional and psychological needs of pregnant women both for the sake of the mother and her unborn child.
As previously stated, preterm birth (PTB) is defined as live birth before 37 weeks gestation, a definition adopted by all of the studies that will be presented. Additionally, in all of the presented studies, preterm birth is categorized in three broad ways. The first is spontaneous preterm delivery, which is defined as a sudden, early onset of labor. The second is premature rupture of membranes, which is the premature rupture of the amniotic sac. Finally, there is medically indicated preterm delivery, which occurs when a doctor induces labor prematurely in a pregnant individual who is at risk of serious complications. For most studies, only spontaneous preterm birth and premature rupture of membranes were included, as these represent the onset of preterm labor without medical intervention. Criteria for inclusion varied across studies, but common characteristics that barred potential subjects from participating were having multiple gestations, being under a certain age (usually under 18 years old), engaging in drug or alcohol use while pregnant, having active infections like HIV, or having a severe chronic illness.
The way that stress levels were quantified varied from study to study, but in general, stress was measured in terms of a) whether participants are exposed to external events (stressors) that are thought to necessitate an inherent stress response and/or b) participants' subjective perception of whether or not they experience stress. Anxiety and depressive symptoms were also commonly used to assess participants’ overall stress levels, though in some cases, anxiety and depression were evaluated independently of stress.
By discussing how stress may be related to an elevated risk of preterm birth, this article will elucidate the significance of a holistic approach to perinatal care that emphasizes not only physical wellbeing, but also mental and social wellbeing. The etiology of preterm birth is complex and as such, consideration of all potential factors- not just those that have a biological or physiological basis- is important for improving maternal and child health around the world.
Stress and Preterm Birth:
In light of the observation that stress can take a toll on one’s physical health, research on PTB over the past few decades has shifted its focus from purely examining the biological and physiological mechanisms underlying this problem to also considering how things like stress may impact one’s risk of delivering prematurely. Multiple studies have found a statistically significant association between PTB and stress, be it perceived stress or stress resulting from objectively stressful situations or circumstances in life. For instance, one study found that maternal stress was significantly greater in postpartum Thai women who delivered preterm compared with those who delivered at term. After adjusting for maternal stress levels, perceived stress scores, marital status, alcohol consumption, intent to get pregnant, undergoing a divorce or separation, and sustaining physical or psychological trauma during pregnancy, it was found that both stress and perceived stress were significant predictors of PTB (Tanpradit and Kaewkiattikun). Furthermore, another study observed that maternal stress during pregnancy was more prevalent among women who delivered preterm than those who delivered at term (Lilliecreutz et al.). These results are supported by a study conducted by Szegda et al., which found that elevated levels of perceived stress at the midpoint of pregnancy increased the risk of PTB. This study observed a linear trend, with women in the highest quartile of stress experiencing three times the risk of PTB compared with women in the lowest quartile. Interestingly, this study found that stress early on in pregnancy was not associated with PTB. This result was also found by Hoffman et al. in their study on the effect of cortisol on PTB. In this study, the researchers observed that women who delivered preterm had a higher mean second trimester hair cortisol concentration compared with those who delivered at term, a difference that was not seen for the first and third trimester. Additionally, at 16 weeks gestation (which falls in the second trimester), they observed a significant difference in perceived stress scores between women who delivered preterm and women who delivered at term. This, in combination with the study by Szegda et al., suggests that stress may have the highest impact on risk for PTB in the second trimester. Hoffman et al. propose two reasons for this. They cite that in the first trimester, there is a small placental volume, low placental blood flow, and low oxygen tension in the fetoplacental unit, which may partially shield the embryo from the mother’s psychobiological environment. Moreover, they note that although cortisol levels are at their highest during the third trimester, there is also an increase in the levels of cortisol metabolizing enzymes, which may result in a reduced maternal response to cortisol in preparation for delivery.
There is a small subset of research that has found no statistically significant association between stress and PTB. In a study on the epigenetics linking stress and PTB, it was found that although high stress was moderately correlated with PTB, it was not associated with an elevated risk of PTB when compared to low levels of stress (Vidal et al.). The researchers note that this derivation from what the majority of the literature reports may be due to their use of a small, limited sample size. This study also focused primarily on stress in the first trimester. As previously established, evidence suggests that stress may not be correlated with PTB in the early and late stages of pregnancy. In evaluating this research, it is clear that the evidence which suggests an association between stress and PTB is much stronger than the limited evidence suggesting no relationship. Given that there is adequate data to suggest a relationship between stress and an elevated risk of PTB, medical professionals should do more to address their pregnant patients’ stress levels.
Anxiety and Depression:
Another possible contributing factor to PTB is anxiety. Anxiety may become worse during pregnancy, as women become familiar with the medical risks that accompany being pregnant. One study found that women with medium and high levels of pregnancy-related anxiety showed an increased risk of PTB, with the highest measures of pregnancy-related anxiety being associated with a twofold increase in risk. In this study, it was also found that women with higher pregnancy-related anxiety were at a higher risk of spontaneous PTB than of medically-indicated PTB (Dole et al.). In a similar vein, Kramer et al. reported that when adjustments were made for medical and obstetric risk, perception of pregnancy risk, and depression, pregnancy-related anxiety was the only factor significantly associated with an increased risk of PTB. The findings from both of these studies are further supported by research done by Orr et al., which found that women with higher levels of pregnancy-related anxiety had a significantly increased risk of spontaneous PTB.
Non-pregnancy related anxiety has also been shown to impact the risk of PTB. Sanchez et al. observed that, when compared with women who had minimal anxiety, women with mild anxiety had a modest increase in the odds of PTB and women with moderate-severe anxiety had a considerable increase in the odds of PTB. Notably, women with moderate-severe anxiety were found to have a greater than two-fold odds of PTB when compared with women who had minimal anxiety (Sanchez et al.). Becker et al. reported similar results, observing that women who were determined to have high levels of anxiety were at an increased risk of PTB when compared with women who had low levels of anxiety.
While there has been limited research on depression as a potential contributor to PTB, there is some evidence that suggests that depressive symptoms may be associated.
Sanchez et al. found that mild and moderate-severe depressive symptoms were statistically significantly associated with increased odds of PTB compared with minimal depressive symptoms. They argue that depression is a biologically-plausible contributor to PTB, noting previously determined associations between psychiatric disorders and overactivation of the hypothalamic-adrenal-pituitary (HPA) axis, as well as the proposition that depression may increase the release of corticotropin-releasing hormone (CRH) from the placenta. However, while there is some research that supports the association between depression and PTB, evidence has been contradictory. Dole et al., for instance, found that negative life events, social support, and depression were not associated with PTB. Given the conflicting evidence on this topic, further research should be undertaken to deepen our understanding of the association between depression and PTB. The presence of studies that have found an association between PTB and/or depression and anxiety should not be ignored. By learning more about how these factors may be related to PTB, we can generate the evidence needed to implement initiatives to improve pregnancy outcomes by addressing pregnant patients’ mental health.
Social Determinants of Health that May Impact PTB:
As previously established, data shows that PTB is especially prevalent in developing countries and among individuals of a lower socioeconomic status. This points to the fact that one’s environment and circumstances in life may be related in some way to their risk of PTB. While research on this particular area is limited, there is some evidence that suggests social factors are linked to PTB. For example, Dole et al. observed that a high score on a standardized racial discrimination scale was associated with an increased risk of PTB. Moreover, they found that women with the highest scores on a gender discrimination scale, as well as those who had a high perception of living in an unsafe neighborhood, showed a slightly increased risk of PTB. Many studies have also found that being of a minority race or ethnicity (especially African American), coming from a low-income household, and having a low level of education are associated with PTB. For instance, one study found that being African American and having a low level of education was associated with PTB (Copper et al.).
Another interesting subset of research on PTB has hypothesized that living in a stressful environment may make individuals more likely to engage in harmful behaviors, which can contribute to an elevated risk of PTB. Copper et al. found that stress was significantly associated with drug and tobacco use, two things that have been associated with a higher risk of PTB. Likewise, a similar study found that women who reported “feeling more depressed” on a standardized depression scale were more likely to smoke cigarettes or marijuana, consume alcohol, do cocaine, and/or experience unhealthy weight gain, all of which can contribute to negative gestational outcomes including PTB (Zuckerman et al.). While these are insightful studies, it should be noted that these results do not point to whether stress and depressive symptoms are a cause or an effect of negative health behaviors. Nonetheless, while some of these studies make it difficult to determine the direction of causality, there is a good deal of evidence which suggests that factors like socioeconomic status are in some way related to PTB. As such, social determinants of health cannot be completely ignored as possible contributors to an elevated risk of PTB.
Limitations and Future Research:
While the studies presented in this article are an important contribution to the discussion surrounding the etiology of preterm birth, they are not without limitations. One of the biggest restrictions is that the majority of studies presented here are observational, which presents the possibility of issues like residual confounding and recall bias. Additionally, many of the more niche studies, such as those on the relationship between stress and unhealthy behaviors, have not been replicated. While results of such studies may have been significant, repetition of these studies is needed to draw more concrete conclusions. A third limitation is that the subjects in many of the presented studies were primarily of a lower socioeconomic status. This does not invalidate the results of any of these studies, but it does mean that research involving subjects of other demographic characteristics must be conducted in order to generalize the results to a wider population.
While the body of literature on the relationship between stress and preterm birth has grown significantly over the past few decades, additional research is needed to strengthen the current literature and bring the issue of stress to the attention of medical and public health professionals. Because the direct mechanisms responsible for preterm are physiological in nature, more research should focus on how the body’s response to stress may elevate one’s risk for premature delivery. Furthermore, it should be acknowledged that most of the current literature focuses on preterm birth in the United States. Given that the prevalence of preterm birth is highest in countries in Africa and Asia, more research should be done on these populations.
As it stands, physical wellbeing remains the primary concern of prenatal care. While it cannot be understated that physical health is vital to a healthy pregnancy, research suggests that addressing the psychological needs of soon-to-be mothers is also incredibly important. From the available data, we see supporting evidence for a correlation between PTB and stress, anxiety, depression, and/or other psychosocial factors. Information generated by these studies demonstrates the need for a greater focus on mental and psychosocial health among pregnant patients. Furthermore, such research serves as a foundation for future research, which will further convince the medical community of the importance of evaluating the impact that stress and related issues may be having on those who are pregnant. By embracing the current literature and conducting further research on the relationship between psychosocial factors and preterm birth, we can begin to take initiatives to improve perinatal care and lower the incidence of preterm birth.
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