Patient factors associated with the risk of spontaneous preterm birth.
Although the rate of preterm delivery has decreased consistently over the past 7 years in the United States through 2013, (1) preterm birth (PTB) remains the leading cause of neonatal and infant deaths. (2) Several risk factors for preterm delivery have been described, including social, personal, and economic characteristics; medical and pregnancy conditions; and behavioral factors. (3) Prevention of preterm delivery can be divided into primary prevention, secondary prevention, and tertiary prevention, where primary prevention (or prevention of a disease before it occurs) is focused on women with known risk factors. (4) Unfortunately, many risk factors for preterm delivery, such as race or bleeding, are non-modifiable. In this context our objective is to review modifiable, potentially modifiable, and non-modifiable risk factors for preterm delivery (table i).
Modifiable risk factors
Body mass index (BMI)
For many years we have acknowledged the relationship between low BMI and an increased risk of spontaneous PTB. (5,6) However, we now have data to suggest that high and low BMI are both associated with an increase in PTB. (7,8) A study conducted by Cnattingius and colleagues in Sweden demonstrated maternal overweight and obesity during pregnancy were associated with increased risks of preterm delivery, especially extremely preterm delivery. As for the relationship of underweight to the risk of PTB, Girsen and colleagues showed an inversely proportional relationship between BMI and the rate of PTB. (8) They found that the lower the BMI, the higher the risk of PTB, with a 61% relative increase in the rate of preterm delivery for women with a BMI of less than 16 kg/[m.sup.2]. Gestational weight gain also modifies the risk of preterm delivery in women with a low BMI. (9) Underweight women with poor weight gain have a 6- to 7-fold increased risk of preterm delivery compared with normal-weight women who gain an average amount of weight. Obesity, previously thought to be protective, (5) is also a risk factor for spontaneous preterm delivery. (7) The proposed mechanism is through increased inflammation via adipokines in visceral fat. The mechanism through which extremes of BMI may lead to preterm delivery may be attributable to nutritional status. For example, women with low serum folate concentrations have been shown to have increased rates of preterm delivery, (10) and obesity is linearly correlated with lower concentrations of folic acid. (11)
Maternal smoking has been linked consistently with an increased risk of PTB, along with other poor pregnancy outcomes. (12-14) The exact mechanism is unknown, but a proposed mechanism relates to the vasoconstrictive properties of nicotine on uterine blood flow. (6) Investigators have also shown that smoking cessation mitigates the risk of preterm delivery, (15,16) making this an important modifiable risk factor to address prior to and during pregnancy.
Potentially modifiable risk factors
Multiple gestation is a well-recognized risk factor for PTB, increasing the risk of this complication up to 6-fold. (6) While these pregnancies only account for 2% to 3% of infants, they disproportionally account for 15% to 20% of PTBs. (17) It is thought that the antecedent to preterm delivery in multiples is uterine overdistention. (18,19) Currently, there are no established therapies to reduce the risk of preterm delivery in higher order multiples. (20) Pregnancies conceived of by assisted reproductive technologies are also at increased risk to be twins or higher order multiple gestations. A higher fetal number is associated with an earlier gestational age at delivery. Multifetal pregnancy reduction of higher order multiples to a twin gestation is an option for some women to decrease the risk of prematurity, (21) though reduction of twins to a singleton is controversial. (22)
Short or prolonged interpregnancy interval
The literature suggests that extremes of interpregnancy interval, defined as time from delivery to next pregnancy, increase the risk for preterm delivery. (17,23,24) An interpregnancy interval of <6 months in one series conferred a 2-fold increase in risk for preterm delivery. (23) Authors also found an increase in neonatal deaths for this short interval. At the other extreme pregnancies with an interval of >59 months were associated with an increased risk of preterm delivery (OR, 1.20; 95% Cl, 1.17-1.24). (24) Postpartum and preconceptional counseling may help mitigate the risks of pregnancy spacing and decrease rates of preterm delivery.
Maternal stress and depression
Both maternal stress and, to a lesser extent, depression are associated with higher rates of preterm delivery. (6,25-28) Hoffman and colleagues found that the link between maternal stress and preterm delivery is mediated by an increase in maternal cortisol. (26) The investigators prospectively followed 92 low-risk women registering for prenatal care in the first trimester and conducted a battery of psychosocial tests. Women who perceived stress had an increase in both second trimester hair cortisol concentrations (r=0.28, P=.007) and an earlier gestational age at delivery (r=-0.30, P<.01). Maternal depression is also independently associated with an increased risk of preterm delivery. (2,728) One series of more than 7000 women found an increased risk of preterm delivery for depressed women after adjusting for numerous confounders (OR, 1.27; 95% Cl, 1.04-1.55). (27)
Education and socioeconomic status
Education and socioeconomic status are often correlated, and low levels of either have been linked to higher rates of preterm delivery. (29,31) Women with few years of education, regardless of race, are more likely to have a preterm delivery, though racial and ethnic disparities persist even with women who have had at least 16 years of education. (6) Socioeconomically disadvantaged women are also at increased risk for preterm delivery. (6,31) When evaluating the rate of preterm delivery by socioeconomic status, accounting for race, black women who are socioeconomically advantaged continue to have higher rates of preterm delivery compared with equally-advantaged white women, where this advantage decreases the rate of preterm delivery. (32)
Genital tract infections have long been considered risk factors for PTB. (6,17) It is generally believed that these infections are acquired during pregnancy, (6) and studies of treating women presumed to have chronic colonization prior to pregnancy have shown no benefit. (33) Bacterial vaginosis (BV) has consistently been linked to an increased risk of preterm delivery from epidemiologic studies. (34) However, treatment of asymptomatic women with BV did not decrease the rate of preterm delivery in a large, multicenter randomized trial. (35) Further, newer microbiological studies involving molecular techniques are able to identify bacteria in samples with negative traditional cultures. (36,37) However, advanced techniques to identify microbial colonization have also found bacteria present in the amniotic fluid in 70% of women delivering by elective cesarean at term. (38)
The mechanism by which infection leads to preterm delivery is thought to be related to activation of cytokines after micro-organisms are detected by toll-like receptors, initiating the cascade. (17,18) Genetic predisposition for preterm delivery is also linked to infection. Women with a polymorphism of tumor necrosis factor alpha were more likely to have a preterm delivery when bacterial vaginosis was present. (39)
Non-modifiable risk factors
It is well documented that black race carries a higher risk of preterm delivery than any other racial or ethnic group. (6,40,41) Attempts to understand this disparity have adjusted for several confounders including education, socioeconomic status, and other psychosocial issues; yet black women remain at highest risk, even if they are highly educated and in an advantaged socioeconomic class. (42) There are complex factors that may explain this disparity. For instance, it is noted that non-American black women have lower rates of preterm delivery than American black women. (43) A similar phenomenon exists with Hispanic women--named the Hispanic paradox. (41,44) Described primarily among Mexican immigrants, those with similar individual-level risk for preterm delivery including late prenatal care, low socioeconomic status, or low education seemingly have similar rates of PTB to non-Hispanic white women. (44) Interestingly, as a Hispanic woman integrates into society--a phenomenon called acculturation--she is more likely to develop a risk of preterm delivery, similar to a non-Hispanic black woman. (45)
Vaginal bleeding during the first or second trimesters of pregnancy has been consistently associated with an increased risk of PTB. (17,46) This is true whether the bleeding is from a known entity, such as placenta previa or abruption, or whether the bleeding is of unknown origin. (47) One series found a 2- to 3-fold increase in the rate of preterm delivery and a more modest increase in the rate of postpartum hemorrhage for women with an unknown etiology of vaginal bleeding. (47) The exact mechanism relating bleeding to preterm delivery is unclear, but one theory is that decidual hemorrhage leads to thrombin formation, which can initiate a proteolytic casade that results in contractions and preterm premature rupture of the membranes. (18)
A history of preterm delivery is a major risk factor for recurrent preterm delivery, such that many obstetric preventative interventions have been focused on this cohort. (48,49) The likelihood of recurrence is further modified by the gestational age at the prior delivery and number of prior preterm deliveries; such early and multiple preterm deliveries result in a high rate of recurrence. One series found a 41% rate of recurrent preterm delivery if there were 2 prior preterm deliveries at <34 weeks. (50) Investigators grouped over 19,000 women with 3 consecutive live births to identify the risk of recurrent preterm birth if the first 2 deliveries were very preterm (21-31 weeks' gestation), moderately preterm (32-36 weeks' gestation), or term ([greater than or equal to] 37 weeks' gestation). (51) They found that women who had 2 births at <31 weeks had a 57% rate of recurrent preterm delivery (figure i).
Familial patterns in preterm delivery suggest a genetic predisposition for PTB. Porter and colleagues showed that women who were born preterm are more likely to have preterm deliveries than women born at term (OR, 1.18; 95% Cl, 1.02-1.37). (52) This difference was more marked if the preterm delivery was at <30 weeks' gestation (OR 2.38; 95% Cl, 1.37-4.16). One study identified single-nucleotide polymorphisms in 7 genes associated with spontaneous PTB in black women. (53) Others have described various genetic variants related to preterm delivery in specific subgroups. (39,54,55)
As has been well described in the literature, the shorter the cervical length, the higher the risk of preterm delivery. (56-58) One of the largest studies to document this phenomenon was performed by the Maternal-Fetal Units Medicine Network. (56) In this prospective observational trial, nearly 3000 women had cervical length measurements at 24 and 28 weeks' gestation. The 10th percentile was defined as <25 mm, with a corresponding relative risk of preterm delivery of 6.19 (95% Cl, 3.84-9.97). Cervical length has also been shown to correlate with a risk of preterm delivery as early as 16 weeks, (59) but measurements earlier than that gestational week are not predictive. (60) Cervical funneling has been shown to be highly variable and adds little over cervical length in the prediction of preterm delivery. (61) The most accurate assessment of cervical length is by a transvaginal scan. Whether universal transvaginal cervical length screening should be performed on low-risk women remains controversial, (62,63) but serial endovaginal assessments of the cervix in high-risk women improve the prediction for preterm delivery. (64)
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Cynthia Gyamfi-Bannerman, MD, MSc, has nothing to disclose.
Cynthia Gyamfi-Bannerman, MD, MSc
Ellen Jacobson Levine and Eugene Jacobson Associate Professor of Women's Health In OBGYN
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine
Columbia University Medical Center
New York, NY
TABLE 1 Risk factors for preterm delivery Modifiable Potentially modifiable Non-modifiable Low BMI/obesity Short or prolonged Black race interpregnancy interval Smoking Maternal stress/ Genetics depression (Higher order) multiple Prior preterm birth gestations Education and Short cervix socioeconomic status Infection/inflammation First or second trimester vaginal bleeding Abbreviation: BMI, body mass index. FIGURE 1 Recurrence of preterm birth by gestational age and number of preterm deliveries (51) Preterm delivery risk (%) Very/Very 57 Moderate/Very 50 Very/Moderate 40 Moderate/Moderate 38 Term/Very 23 Term/Moderate 21 Term/Very 15 Term Moderate 12 Term/Term 5 Preterm delivery risk based on outcomes from prior 2 pregnancies. Very preterm (21-31 weeks' gestation), Moderately preterm (32- 36 weeks' gestation), Term ([greater than or equal to] 37 weeks' gestation). Reprinted from Am J Obstet Gynecol, 196(6), McManemy J, Cooke E, Amon E, Leet T, Recurrence risk for preterm delivery, e571-576, 2007, with permission from Elsevier.
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