1 Service de Psychiatrie de l'Enfant et de l'Adolescent, CHU Clemenceau, Caen, France.
2 Laboratoire d'Informatique Médicale et Épidémiologie, CHU Clemenceau, Caen, France.
3 Clinique de Gynécologie-Obstétrique et de la Reproduction Humaine, CHU Clemenceau, Caen, France.
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ABSTRACT |
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anxiety; body mass index; corticotropin-releasing hormone; depression; labor, premature; pregnancy; risk factors
Abbreviations: CI, confidence interval; OR, odds ratio; SD, standard deviation
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INTRODUCTION |
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Preterm delivery still represents a major obstetric complication, affecting between 5 and 10 percent of pregnancies (1), resulting in a variety of disorders and potential hazards to the child's development. A major cause of preterm delivery is spontaneous preterm labor (2
). It is defined as the association of regular uterine contractions with changes in the cervix. The early diagnosis, mechanism, and management of preterm labor remain unresolved issues in obstetrics (3
, 4
). Preterm labor often leads to hospitalization and tocolytic therapy in an attempt to stop preterm delivery. The cost of such preventive measures is very high, their results remain controversial (3
), their safety has been seriously questioned (5
), and they may have harmful psychological consequences (6
).
Several authors have suggested that spontaneous preterm labor could be the reflection of a psychosomatic disorder (7). The underlying mechanism could involve the limbic system whose stimulation could lead, possibly through the action of glucocorticoids, to an elevation of the secretion of placental corticotropin-releasing factor. This neuropeptide plays an important role in uterine contractility and cervical ripening.
To our knowledge, literature on the association of psychological factors with preterm labor has been very scarce. We were able to find only one report specifically devoted to preterm labor (8). In this retrospective study, women with and without preterm labor did not differ significantly in terms of anxiety. More attention has been paid to preterm delivery. The role of perceived stress has been clearly demonstrated (9
12
), while findings about depression have been more controversial. A positive association was reported in one study (13
); in another case, the association was found to be close to significance in Black women and not significant among White women (14
); in two other cases, no link could be evidenced (15
, 16
). Regarding anxiety, the latest studies seem to agree on the absence of a relation (15
18
).
It would be hazardous to infer specific risk factors for spontaneous preterm labor from findings on spontaneous preterm delivery (19). As mentioned by Kramer et al. (20
), the two complications should be clearly distinguished. First, spontaneous preterm delivery is not always induced by preterm labor but may also be the result of preterm prelabor rupture of the membranes. Second, spontaneous preterm labor does not necessarily result in preterm delivery. From a review of the literature, it appears that preterm labor, when diagnosed prospectively, has a positive predictive value of about 50 percent for the prediction of preterm delivery, depending on diagnostic criteria and date of diagnosis (the earlier the diagnosis, the lower the predictive value) (3
, 4
). Risk factors for spontaneous preterm labor and those for spontaneous preterm delivery could therefore differ. Moreover, in some studies, no distinction was made between spontaneous and induced preterm delivery.
The aim of this cohort study, which completes previously published preliminary results (21), is to investigate in a prospective manner the role of psychological factors in the occurrence of spontaneous preterm labor, while controlling for other potential sociodemographic and medical risk factors. We have especially concentrated on anxiety and depression, because their incidence during pregnancy is now more widely recognized (22
, 23
), and because these factors are both easy to identify and accessible to treatment, with potential benefits for the health of the pregnant woman.
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MATERIALS AND METHODS |
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Measures
Sociodemographic and biomedical characteristics were extracted from the data systematically collected for obstetric records, which provided exhaustive information. Self-administered questionnaires were used for psychological assessment and were filled out at enrollment. The median gestational age at completion of the questionnaires was 22 weeks with a quartile range of 3 weeks. Women were encouraged to participate by a psychologist and a midwife, who could also provide help with the questionnaires. The protocol for this research has been approved by the Regional Committee for Protection of Individuals in Biomedical Research.
Sociodemographic characteristics. These included age (<20, 2034, 35 years); marital status (living alone or not); ethnicity (European origin or another origin); school education, divided into three categories according to the French educational system: primary school (5 years of education), secondary school (612 years), higher education (over 12 years); occupation (unemployment, lower level of employment, middle or higher level of employment); and smoking habits during pregnancy (nonsmoking, smoking less than 10 cigarettes daily, smoking 10 cigarettes or more a day).
Biomedical risk factors. After reviewing the literature and consulting with obstetric experts, we considered 14 variables to be possible confounding factors. The variables related to the current pregnancy were as follows: parity (0, 1 or 2, 3); prepregnancy body mass index, defined as weight (kg) divided by height (m)2 and split into three categories according to a classification commonly used in France (body mass index of <19 (underweight), 19<25 (normal),
25 (overweight)); antenatal care indirectly assessed by gestational age at first consultation (12 weeks or less, over 12 weeks); conditions of conception (natural, medically assisted, contraception failure); vaginal bleeding; urinary tract infection; cervical or vaginal infection; and other medical risk factors (hydramnios, preeclamspia, uncontrollable vomiting, cervix incompetence, ovarian cyst, uterine fibroid, accidental injury, appendicitis, or other acute abdominal syndrome). Medical risk factors were taken into account if they occurred before the onset of preterm labor or before 37 weeks of gestation in the absence of preterm labor. The variables related to obstetric history included the following: previous preterm labor, preterm birth, miscarriage, elective termination of pregnancy, and other previous complications (therapeutic abortion, ectopic pregnancy, gestational trophoblastic disease, delivery of an abnormal newborn, stillbirth, neonatal death). The type of enrollment consultation was also controlled for in terms of stress, because it could influence the psychological state. It was categorized into two types: not stressful and stressful (morphologic examination for suspected malformation, amniocentesis, hospitalization).
Outcome variable. The diagnosis of preterm labor was made on the following three criteria: gestational age between 20 and 37 completed weeks of gestation, at least one contraction every 10 minutes for at least an hour (24, 25
), and at least one cervical change such as dilatation or effacement as assessed by Bishop's score (26
). To ascertain gestational age we verified at enrollment that each woman had ultrasonographic examination by 20 weeks (usually at 12 or 13 weeks). The diagnosis of regular uterine contractions was usually assisted by tocographic measurement. Cervical assessment was conducted using digital or transvaginal ultrasonographic examination. All cases that met the above definition of preterm labor were clinically diagnosed by obstetricians as preterm labor or threatened preterm delivery and treated accordingly. They were usually administered tocolytics (91.7 percent), which at the time of the study were the most common treatment for preterm labor.
Psychological factors. The widely used 20-item forms of the Spielberger State-Trait Anxiety Inventory, form Y (27), were chosen for the assessment of state anxiety and trait anxiety. The two questionnaires have been adapted and validated in French in 1993 (28
). Items were rated on a four-point Likert scale ranging from 1 (not anxious) to 4 (highly anxious), with overall scores varying from 20 to 80. In our study, internal consistency was found to be high for both measures (Cronbach's
= 0.94 and 0.88, respectively). The 75th percentiles of the two distributions were used as thresholds to indicate high levels of anxiety. The Edinburgh depression scale was used to assess antenatal depression. This 10-item scale was first developed for the assessment of postnatal depression under the name "Edinburgh Postnatal Depression Scale" (29
). It was then validated in childbearing women (30
) and in non-postnatal women with older children (31
). The French version of the scale was validated in 1995 (32
). Each item is scored on a four-point scale (from 0 to 3), with minimum and maximum overall scores varying from 0 to 30. The internal consistency of the scale was found to be good in the current study (Cronbach's
= 0.85). We used a cutoff value of 1415, which indicates major antenatal depression, as recommended by Murray and Cox (30
).
Statistical analysis. A total of 51 women (7.4 percent) were excluded from the analysis because of a large number of missing values: 50 women left completely unanswered at least one of the questionnaires while another woman completed only one half of the items. These exclusions will be discussed in terms of a possible bias. In 46 of the 634 remaining women, a single item was missing throughout the questionnaires, for eight women two items were missing, and for one woman, three. Missing values were in those cases replaced by the median value calculated on all the answers to the corresponding item. Sixty-five values were thus imputed, which represents a mere 0.2 percent of the overall questions presented to the 634 women. The association between preterm labor and each of the explanatory variables was first assessed using univariate logistic regression models. All continuous variables were transformed into categorical data because the assumption of linearity in the logit was not verified, especially where psychological scores were concerned. Crude odds ratios and 95 percent confidence intervals were computed. A backward multiple logistic regression analysis was then applied to isolate the effect of each factor adjusted for all of the others. The initial model incorporated the main predictor variables (psychological factors) and the potential confounding covariates related to the outcome variable at the p < 0.25 level in the univariate analysis. The adjusted odds ratio with 95 percent confidence interval was computed. We verified that the fit of the model was not affected by possible collinearities among the predictive variables. A good indicator is aberrantly large estimated standard errors of the regression coefficients. In a final step, all the psychological factors and covariates remaining in the final model were tested for significant interactions. Statistical significance was defined as p < 0.05. Data were analyzed with SPSS software, version 9.0 (33).
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RESULTS |
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Spontaneous preterm labor occurred in 11.4 percent of women (72/634). The median gestational age at which women presented with preterm labor was 32 weeks with a quartile range of 5 weeks. Covariates significantly associated with the outcome in the univariate analyses (table 2) were found to be maternal age (p < 0.05), marital status (p = 0.05), prepregnancy body mass index (p < 0.001) with a nice linear trend, prior preterm labor (p < 0.001), prior preterm birth (p < 0.01), vaginal bleeding (p < 0.05), and cervical or vaginal infection (p < 0.05). Women with high depression scores had a risk of spontaneous preterm labor twice as high as nondepressed women (odds ratio (OR) = 2.1, 95 percent confidence interval (CI): 1.1, 4.1). The association was close to statistical significance for both state anxiety (OR = 1.7, 95 percent CI: 0.97, 2.8) and trait anxiety (OR = 1.7, 95 percent CI: 1.0, 2.8).
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DISCUSSION |
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It could be argued that these positive associations are the results of a selection bias if the psychological factors were negatively associated with the outcome among the nonresponders. To test this hypothesis, we compared the responders with the 51 excluded women. The rate of spontaneous preterm labor was found to be slightly higher among nonresponders (13.7 percent vs. 11.4 percent), although the difference was not statistically significant (p = 0.60, 2 test). The two groups were also similar in terms of sociodemographic and biomedical characteristics. Statistically significant differences concerned only three factors: age (more women under 20 years of age among the nonresponders), occupation (more unemployed women), and smoking habits (more heavy smokers), suggesting that the excluded women may be a little more depressed or anxious than the rest. This result, combined with the slight increase in preterm labor rate, suggests the existence of a positive association between psychological factors and outcome among nonresponders also.
Another selection bias could be created by the fact that a more anxious woman would consult more easily. This cannot result in a bias because all pregnant women in France have to attend several compulsory prenatal visits, of which one should take place between 20 and 28 weeks of amenorrhea, which is the time of our enrolment phase. However, the fact that an anxious woman might prefer to visit the hospital rather than a private practice cannot be ruled out. We do not know of any study on the subject in France.
Classification bias must also be considered. In particular it may be feared that an anxious woman would more often complain of uterine contractions or abdominal pain. Although this draws the clinician's attention, it seems unlikely it would influence investigation or diagnosis of preterm labor. First, cervicovaginal examination is systematically conducted at each compulsory visit in our hospital, regardless of the pregnant woman's mental state. Second, the diagnosis is based on standardized criteria.
The exploratory strategy we adopted to investigate interactions led to a rather great number of statistical tests. The consequence is an increase of the probability of finding a significant interaction merely "by chance." The tests being dependent, it is very difficult to determine this probability. In the case of independence, it can be demonstrated using the binomial law that there are three chances in 100 that the three significant interactions were so by chance. Moreover, as we shall see further, physiopathologic mechanisms could explain the effects that were observed, and interactions between depression and body mass index have been reported previously in the literature.
The scales we chose to measure anxiety and depression are valid and reliable tools that were adapted and validated in French. Spielberger's State-Trait Anxiety Inventory has been administered to a variety of populations, including pregnant women. The Edinburgh depression scale is also now widely used during and after pregnancy. The items are reputed to be unintrusive and well accepted in a community sample, which we were able to verify in the present study; the questionnaire took less than 5 minutes to complete. Unlike some other scales, the Edinburgh depression scale does not include items unsuitable in the perinatal period. Its validation was established by comparing mean scores with the research diagnostic criteria for minor to major depression (34). A cutoff value of 1415 was found to be optimal for the detection of major depression in childbearing women, with a sensitivity of 100 percent, a specificity of 95 percent, and a positive predictive value of 60 percent (30
). Major depressions, which are usually not queried during pregnancy, represent a serious, easily detectable disorder, which can carry over into the postpartum period if left untreated (23
).
Several commonly accepted risk factors for preterm delivery (1, 2
, 20
, 35
38
) were found to be associated with spontaneous preterm labor in our study: age, marital status, prepregnancy body mass index, prior preterm labor, prior preterm delivery, vaginal bleeding, and cervical and vaginal infection. The impact of smoking on preterm birth is controversial (12
, 39
). This factor was not significantly associated with preterm labor in our study. Urinary tract infection was not associated with the outcome either, but the data collected did not distinguish between upper and lower infection or specify the germ involved. More surprisingly, the levels of education and employment, indirectly reflecting social background that is known to have an impact on the occurrence of preterm delivery (12
), were not found to be significantly associated with preterm labor. However, the population in our region is not very heterogeneous socially, and the studied women were provided early antenatal care, which could significantly improve pregnancy outcome in socially deprived women (2
).
No other prospective study, to our knowledge, has investigated the effect of anxiety on the occurrence of spontaneous preterm labor. One case-control study on a small number of women (n = 45) has been published (8), in which neither trait anxiety nor state anxiety was found to be associated with preterm labor. Regarding the influence of anxiety on preterm delivery, recent research seems to agree on the absence of a relation (15
18
). Interestingly, no association could have been evidenced in the present study without interaction analysis. An impact could be demonstrated only when anxiety was associated with another factor. Our findings on state anxiety are consistent with the conclusions of Lobel et al. (9
), who stated that the association of a stressful event (vaginal bleeding in the present case) with an anxious response (as measured with the State-Trait Anxiety Inventory, form Y) and perceived stress (which we did not assess here) provides a model for measuring prenatal stress with good predictive value for prematurity. The same explanatory model could be hypothesized for trait anxiety, in which pregnancy would act as a reminder of an original stressor (prior preterm labor) in trait-anxious women.
Until the last decade, little attention had been paid to the role of depression in the onset of obstetric complications. More recent studies demonstrate an increasing interest in the subject, especially as far as preterm delivery is concerned. Results are somewhat conflicting. A significant (or close to significance) association was reported by Steer et al. (13) and Orr and Miller (14
); no link could be evidenced on the other hand in the studies of Perkin et al. (15
) and Copper et al. (16
). Several differences in the design of these studies may account for the discrepancies in the results: The populations differed, various instruments were used to assess depression, and the way depression scores were coded in the logistic models also differed (dichotomized scores, quartiles, continuous variable). Evidence of the strong association that we found between depression and preterm labor among underweight women had never been observed before. In previous studies, either the interaction effects were not tested (13
15
) or data concerning the prepregnancy body mass index were not collected (16
). However, it is interesting to note that this interaction has been reported in contexts other than preterm labor. Cliver et al. (40
) showed that a poor psychosocial profile (including depression) was significantly associated with an increased rate of fetal growth retardation and low birth weight infants in thinner women only (prepregnancy body mass index of <22). Similarly, Rantanen et al. (41
) found that, in older men, a depressed mood was associated with an increased risk of a steep decline in strength, mainly in men with a low body weight (body mass index of <20).
The biologic model underlying the study rested in part on the known fact that depression, stress, and anxiety are associated with an increase in hypothalamic corticotropin-releasing factor release and plasma cortisol concentrations (42) and in part on the fact that an elevation of placental corticotropin-releasing factor could initiate uterine contractions and cervical ripening (43
). We hypothesized, as Hobel et al. (44
) suggested for stress, that anxiety and depression also influence the secretion of placental corticotropin-releasing factor. This would occur as a regulation of the corticotropin-releasing factor gene in the placenta, either directly or indirectly through the secretion of cortisol (45
), which could act paradoxically as a stimulant. The rate of placental corticotropin-releasing factor was observed to rise during pregnancy following the injection of synthetic glucocorticoids (46
), while an increase in placental corticotropin-releasing factor under the action of cortisol was demonstrated in vitro (47
).
The interactions we evidenced could be integrated into this primary model. A low body mass index could, as has been demonstrated with anorexia nervosa (48), induce an increase in hypothalamic corticotropin-releasing factor release and plasma cortisol concentrations, thus reinforcing the effect of depression by synergic action. Concerning vaginal bleeding, a proven risk factor of preterm delivery, several authors, among them Lockwood (49
), have suggested that the action of decidual hemorrhage on uterine contractility could be mediated by placental corticotropin-releasing factor, in reaction to ischemic phenomena associated with the hemorrhagic syndrome. For the last interaction, it is known that chronic anxious states are accompanied by overalertness involving the central norepinephrine system, which might exacerbate the memory of disturbing or stressful events (50
). In this context the recollection of previous preterm labor could result, through the action of the amygdala, in an increased stimulation of specific areas of the brain, especially the locus ceruleus, which plays a decisive role in increasing the production of corticotropin-releasing factor and glucocorticoids (42
, 50
).
We identified in this study specific groups of women at high risk of spontaneous preterm labor: anxious women with vaginal bleeding or a history of preterm labor and underweight, depressed women. Future research will have to verify the biologic plausibility of the interactions and to determine whether appropriate interventions aimed at reducing anxiety and depression in these subpopulations may lower the incidence of spontaneous preterm labor. Moreover, detecting and treating anxiety and major depression during pregnancy would in itself be beneficial to mother and child.
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ACKNOWLEDGMENTS |
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The authors thank Nathalie Lamandour and Geraldine Levavasseur for their assistance with data collection.
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NOTES |
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REFERENCES |
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