Spontaneous preterm birth: Overview of interventions for risk reduction

INTRODUCTION — There are many risk factors for preterm birth (PTB) (table 1) and many pathways leading from these risk factors to the terminal cascade of events resulting in preterm labor. Normal uterine quiescence becomes disrupted when local uterine factors stimulate the parturition cascade prematurely and/or suppressive factors that inhibit the cascade are withdrawn prematurely.

Ideally, identification of risk factors for PTB both before conception and early in pregnancy will lead to interventions that help prevent this complication. However, few interventions have been proven to prolong pregnancy in individuals at risk. This goal has been elusive for several reasons: two-thirds of spontaneous PTB (sPTB) occur among individuals with no risk factors, causality has been difficult to prove (eg, a cofactor may be required, thus complicating the chain of causality), and no adequate animal model exists for the study of sPTB in humans.

An overview of potential interventions to mitigate the risk for sPTB, when possible, will be reviewed here. Pathogenesis and an overview of risk factors for sPTB, diagnosis and treatment of preterm labor, and long-term maternal prognosis after a PTB are discussed separately:

●(See "Spontaneous preterm birth: Overview of risk factors and prognosis".)

●(See "Spontaneous preterm birth: Pathogenesis".)

●(See "Preterm labor: Clinical findings, diagnostic evaluation, and initial treatment".)

●(See "Inhibition of acute preterm labor".)

POTENTIALLY EFFECTIVE INTERVENTIONS — Application of one or more of the following interventions may reduce the risk of PTB. For some patients, the risk factor for PTB is clear and may be mitigated by a specific intervention. For other patients, the factors may be less clear but still may be mitigated by a multifactorial approach involving prenatal and self-care.

Optimize status of maternal medical disorders — Identification and optimization of chronic medical disorders before and during pregnancy can improve overall maternal health and, in turn, pregnancy outcome. (See "The preconception office visit".)

Prescribe aspirin for patients at high risk of preeclampsia — In patients at high risk of developing preeclampsia, a daily dose of low-dose aspirin (typically 81 to 162 mg orally) starting at 12 to 16 weeks of gestation can reduce the chances of developing preeclampsia and need for indicated PTB. High-risk factors include:

●Previous pregnancy with preeclampsia, especially early onset and with an adverse outcome.

●Type 1 or 2 diabetes mellitus.

●Chronic hypertension.

●Multifetal gestation.

●Kidney disease.

●Autoimmune disease with potential vascular complications (antiphospholipid syndrome, systemic lupus erythematosus).

These data are reviewed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

Identify unhealthy behaviors and help patients achieve healthy behaviors — Cigarette smoking and misuse of alcohol and prescription and nonprescription drugs are unhealthy behaviors that increase the risk for PTB. The following interventions may reduce the risk of PTB and all promote personal health regardless of future pregnancy.

●Tobacco use – Identification of individuals who smoke tobacco products, education on the maternal and fetal risks associated with smoking, and help with smoking cessation are important to promote general health. It is likely that individuals who reduce or stop smoking will also reduce their risk for PTB, but this has not been proven. These data are reviewed separately. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Preterm birth' and "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

Since 2010, in the United States, Medicaid programs are required to cover tobacco-cessation counseling and drug therapy for pregnant people without cost sharing, which might increase utilization of these services [1].

●Substance use – Health care providers should ask about maternal substance use (eg, alcohol, misuse of prescription or nonprescription drugs), provide information on the maternal and fetal risks associated with the substance used, and help patients stop using the substance. Medication (methadone or buprenorphine) is recommended for those with an opioid use disorder. It is likely that this will reduce their risk for PTB, but this has not been proven. These data are reviewed separately. (See "Substance use during pregnancy: Screening and prenatal care" and "Opioid use disorder: Overview of treatment during pregnancy" and "Opioid use disorder: Pharmacotherapy with methadone and buprenorphine during pregnancy" and "Alcohol intake and pregnancy".)

Identify an abnormal BMI and encourage prepregnancy weight loss or gain — Pregnant individuals with adequate nutrition and a normal body mass index (BMI) have better pregnancy outcomes than individuals who do not, which suggests that dietary interventions may have a role in preventing PTB in selected populations. Regardless of its effect on pregnancy, weight loss before pregnancy should be recommended for individuals with obesity because of the general health benefits. (See "Overweight and obesity in adults: Health consequences".)

Evidence suggests that weight loss before pregnancy in individuals with obesity and appropriate weight gain during pregnancy can reduce the risk for PTB, but the data are not definitive. In a meta-analysis of randomized trials of the effects of dietary and lifestyle interventions in pregnancy on maternal weight and obstetric outcomes, the reduction in PTB was not statistically significant (relative risk [RR] 0.78, 95% CI 0.60-1.02, 13 trials, 2652 participants) [2]. However, these trials had significant heterogeneity and were of low quality. (See "Obesity in pregnancy: Complications and maternal management" and "Gestational weight gain".)

Patients with eating disorders can benefit from interventions to achieve a normal weight. Management of eating disorders and outcome are reviewed separately. (See "Eating disorders in pregnancy".)

Discuss optimal pregnancy spacing and avoiding unplanned pregnancies — Individuals planning pregnancy are advised to space pregnancies at least 18 months apart. Short interpregnancy intervals (<6 months) are associated with an increased risk of PTB and other adverse pregnancy outcomes (table 2). However, the interval between pregnancies should not be excessive. A meta-analysis calculated that an interval ≥60 months also increased the risk for PTB (odds ratio [OR] 1.20, 95% CI 1.17-1.24) [3]. The data behind these recommendations are reviewed separately. (See "Interpregnancy interval: Optimizing time between pregnancies".)

Approximately 50 percent of pregnancies in the United States are unplanned. Providing contraception to prevent unintended pregnancies may reduce PTB as such pregnancies are associated with a higher risk of PTB [4]. Providing postpartum contraception before the first postpartum visit can be helpful. In a large cohort study that examined the impact of postpartum contraceptive coverage within 18 months of birth, the odds of PTB decreased by 1.1 percent for every month of contraceptive coverage [5]. (See "Contraception: Counseling and selection" and "Contraception: Postpartum counseling and methods".)

Reduce the iatrogenic occurrence of multifetal gestations — In patients undergoing assisted reproduction, strategies should be utilized to reduce the likelihood of a multiple gestation and particularly a high order multiple gestation (triplets and above). These strategies include single embryo transfer in patients undergoing in vitro fertilization (IVF). In patients undergoing ovulation induction without IVF, strategies include use of either clomiphene citrate or aromatase inhibitors, as appropriate, rather than gonadotropins. In patients with an excessive number of mature follicles, conversion to IVF or cycle cancellation should be considered. If a high order multiple gestation occurs, multifetal pregnancy reduction can improve neonatal outcome. (See "Strategies to control the rate of high order multiple gestation" and "Multifetal pregnancy reduction and selective termination".)

Consider effects of cervical/uterine surgery on future pregnancies

●For patients undergoing pregnancy termination, procedural termination may be associated with higher rates of subsequent PTB than medication abortion. Appropriate use of cervical ripening agents may reduce the risk of cervical injury before procedural evacuation. For patients undergoing miscarriage, avoiding surgical evacuation of uterine contents (if safely possible) by expectant management or medical induction may reduce PTB risk in subsequent pregnancies. These interventions are discussed separately. (See "Overview of pregnancy termination" and "Pregnancy loss (miscarriage): Counseling and comparison of treatment options and discussion of related care".)

●For patients with some types of fibroids (eg, submucosal) and a history of pregnancy loss or previable PTB, myomectomy before pregnancy may improve pregnancy outcome. Decision-making is reviewed separately. (See "Uterine fibroids (leiomyomas): Issues in pregnancy" and "Recurrent pregnancy loss: Management", section on 'Uterine abnormalities'.)

●Patients undergoing treatment of cervical intraepithelial neoplasia should undergo the procedure that best diagnoses or prevents cervical cancer and also incurs the lowest risk of reproductive effects. Serial cervical length measurements should be performed in subsequent pregnancies before making a diagnosis of cervical insufficiency or providing prophylactic treatment (see following bullet on monitoring cervical length). (See "Reproductive effects of cervical excisional and ablative procedures" and "Short cervix before 24 weeks: Screening and management in singleton pregnancies".)

Monitor cervical length; treat patients with a short cervix or cervical insufficiency — Patients at high risk of cervical insufficiency should undergo cervical length measurement at approximately 16 weeks of gestation and serially thereafter (every 1 to 2 weeks through 24 weeks) (algorithm 1). Some authorities, including the Society for Maternal-Fetal Medicine, consider routine midtrimester cervical length measurement at the fetal anatomy scan reasonable regardless of risk of PTB [6]. (See "Short cervix before 24 weeks: Screening and management in singleton pregnancies".)

●Progesterone supplementation – For patients with singleton pregnancies and no history of prior PTB who have a short cervix (≤25 mm) on transvaginal ultrasound examination at 18 to 24 weeks, we prescribe daily vaginal progesterone to reduce the risk for PTB. Progesterone supplementation appears to reduce the risk of PTB by approximately 20 percent in these individuals. A review of evidence is available separately. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with a short cervix'.)

For patients with singleton pregnancies and a positive history of prior PTB, we would offer vaginal progesterone to those with a short cervix (≤25 mm) on transvaginal ultrasound examination at 16 to 24 weeks. Cerclage is another option. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with prior preterm birth'.)

●Cerclage – We often suggest cerclage for:

•Patients with two or more second-trimester pregnancy losses/PTBs associated with painless cervical dilation (history-indicated cerclage). (See "Cervical insufficiency", section on 'Obstetric history-based diagnosis of cervical insufficiency' and "Cervical insufficiency", section on 'Obstetric history-based cervical insufficiency'.)

•Patients with a history of sPTB in whom the diagnosis of cervical insufficiency is uncertain, but a short cervical length (≤25 mm) is detected on transvaginal ultrasound examination at 18 to 24 weeks (ultrasound-indicated cerclage). (See "Cervical insufficiency", section on 'Ultrasound-based diagnosis of cervical insufficiency' and "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency'.)

•Patients with physical examination-based cervical insufficiency before 24 weeks of gestation. (See "Cervical insufficiency", section on 'Physical examination-based diagnosis of cervical insufficiency' and "Cervical insufficiency", section on 'Physical examination-based cervical insufficiency'.)

•Patients with a very short cervical length (<10 or 15 mm) measured on transvaginal ultrasound examination at 16 to 24 weeks. (See "Short cervix before 24 weeks: Screening and management in singleton pregnancies", section on 'Patients with NO prior spontaneous preterm birth'.)

Reduce maternal infection risk

●Perform a routine first-trimester urine culture and treat asymptomatic bacteriuria – A first-trimester urine culture is routine in all pregnancies [7,8]. In addition, serial prenatal urine culture screening is recommended for patients at high risk for asymptomatic bacteriuria (eg, individuals with sickle cell trait, recurrent urinary tract infections, diabetes mellitus, underlying kidney disease). Reliance on symptoms to prompt screening is inadequate because symptoms such as frequency and nocturia are often attributed to the pregnant state. (See "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Asymptomatic bacteriuria'.)

Pregnant persons with asymptomatic bacteriuria should be treated with antibiotics to reduce their risk of developing pyelonephritis and possibly reduce the risk of PTB. In a meta-analysis (14 randomized trials), treatment of asymptomatic bacteriuria clearly and substantially decreased the frequency of asymptomatic bacteriuria (RR 0.25, 95% CI 0.14-0.48), pyelonephritis (RR 0.23, 95% CI 0.13-0.41) [9], and low birth weight (RR 0.66, 95% CI 0.49-0.89), but a difference in PTB was not established.

●Reduce the risk of acquiring malaria in endemic areas – Prevention of malaria infection by mosquito avoidance and prophylactic drug therapy, and treatment of established malaria infection, can reduce the risk for PTB. Issues related to malaria in pregnancy are discussed separately. (See "Malaria in pregnancy: Prevention and treatment".)

Surgically correct some congenital uterine abnormalities — Surgical correction of a uterine septum, bicornuate uterus, or communicating hemiuterus may reduce the risk for recurrent miscarriage or very early PTB or miscarriage. Selection of candidates, procedures, and prognosis are reviewed separately. (See "Congenital uterine anomalies: Surgical repair".)

Tocolytic treatment of acute preterm labor — We prescribe tocolytic therapy as part of the management of acute preterm labor. Short-term tocolysis is endorsed by most guidelines since delaying delivery for 48 hours enables maternal administration of glucocorticoids to achieve the maximum fetal effect [10]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

Tocolytic therapy of an acute episode of idiopathic preterm labor often abolishes contractions temporarily but does not remove the underlying stimulus that initiated the process of parturition (eg, infection, inflammation, uterine overdistention, decidual hemorrhage, cervical insufficiency) or reverse parturitional changes in the uterus. The net effect is that tocolytics may delay delivery by a few days, but do not consistently prolong pregnancy by weeks or months. These data are reviewed separately. (See "Inhibition of acute preterm labor".)

INEFFECTIVE AND UNPROVEN INTERVENTIONS

Progesterone supplementation for patients with a prior preterm birth — Neither hydroxyprogesterone caproate (Makena) nor vaginal progesterone reduces the risk of recurrent PTB in this population. These patients should be followed sonographically to identify those with a short cervix at 16 to 24 weeks. Vaginal progesterone appears to be useful in patients with a short cervix; cerclage is another option. (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with a short cervix' and "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with prior preterm birth' and "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency'.)

Monitoring uterine contraction frequency — Although an increase in uterine activity is a prerequisite for labor, randomized trials and a meta-analysis have shown that measuring the frequency of uterine contractions by self-palpation/detection of signs of labor or through use of a home uterine activity monitor appears to increase the use of tocolytics without leading to a clear clinically meaningful reduction in the rate of PTB [11,12]. Moreover, such an approach increases the frequency of unscheduled antenatal visits. The American College of Obstetricians and Gynecologists (ACOG) recommends not using home uterine activity monitoring as a strategy for prediction or prevention of PTB [13].

Prophylactic tocolytics — We do not prescribe prophylactic tocolytic medication. Prophylactic tocolytic therapy for prevention of PTB in high-risk asymptomatic pregnant people was not effective in randomized trials, although few such trials have been conducted [14,15]. Maintenance tocolysis, which has been studied more extensively, was also ineffective in randomized trials. These data are reviewed separately. (See "Management of pregnancy after resolution of an episode of acute idiopathic preterm labor".)

Low-dose aspirin — We do not prescribe low-dose aspirin for prevention of PTB in patients at low risk of developing preeclampsia. We agree with ACOG's guidelines (published before the ASPIRIN and APRIL trials [described below]), which state that low-dose aspirin should not be used in an attempt to prevent sPTB but should be considered for patients with risk factors for preeclampsia to prevent this disorder and its consequences, including indicated PTB [16].

Although the putative beneficial effects of low-dose aspirin on PTB is most likely explained by the prevention of indicated PTB due to preeclampsia, an independent effect on sPTB is plausible and should be studied further. It has been hypothesized that low-dose aspirin may reduce the risk of sPTB by inhibiting the inflammatory and uteroplacental ischemia pathways leading to this outcome (figure 1).

●The ASPIRIN trial evaluated the use of low-dose aspirin for prevention of PTB as the primary outcome [17]. Nearly 12,000 nulliparous individuals with singleton pregnancies in six low- and middle-income countries were randomly assigned to receive 81 mg aspirin or placebo beginning at 6+0 to 13+6 weeks of gestation and continuing until 36+6 weeks.

Aspirin reduced PTB <37 weeks (11.6 versus 13.1 percent, relative risk [RR] 0.89, 95% CI 0.81-0.98) and <34 weeks (3.3 versus 4.0 percent, RR 0.75, 95% CI 0.61-0.93) and also reduced fetal loss and perinatal mortality; other maternal or neonatal outcomes were similar between groups. These benefits occurred in part because of a 60 percent reduction in participants who gave birth before 34 weeks with a hypertensive disorder of pregnancy (0.1 versus 0.4 percent); the incidence of hypertensive disorders in late pregnancy was not reduced.

Limitations of the trial included lack of data on the effect of aspirin in participants who were multiparous, carrying a multiple gestation, living in a high-income country, or residing in an area where low-dose aspirin is routinely recommended for patients at moderate or high risk for developing preeclampsia. The trial also did not distinguish between sPTB and indicated PTB.

●The APRIL trial was the first trial to evaluate aspirin (80 mg) versus placebo in patients (n = 387) with singleton pregnancies plus a history of sPTB [18]. The intervention was initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery.

Aspirin prophylaxis did not result in a statistically significant reduction in total PTB <37 weeks (21.2 versus 25.4 percent in the placebo group; RR 0.83, 95% CI 0.58-1.20), including in patients with ≥80 percent medication adherence (19.2 versus 24.8 percent; RR 0.77, 95% CI 0.48-1.25). The two subgroups of spontaneous and indicated PTB <37 weeks of gestation also did not significantly differ between participants allocated to aspirin versus placebo.

A major limitation of the trial was that the PTB rate in both groups was less than anticipated, possibly because nearly two-thirds of participants were prescribed progesterone supplementation and approximately 10 percent underwent cervical cerclage. The findings suggest that a trial would need to be 10-fold larger than APRIL to determine whether aspirin can prevent recurrent PTB [19].

Trials evaluating the use of aspirin for prevention of preeclampsia in high-risk patients are discussed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

Pessary — We do not prescribe pessaries for patients with a short cervix as the body of evidence does not support using a pessary to prolong gestation or improve neonatal outcome. This evidence is reviewed separately. (See "Cervical insufficiency", section on 'Pessary'.)

Bed rest — Bed rest improves uteroplacental blood flow and can lead to a slight increase in birth weight, but there is no evidence that it decreases the incidence of PTB [20-22], even in patients with a short cervix [23,24]. Although underpowered, the only randomized trial attempting to determine whether hospitalization of patients with arrested preterm labor improved outcome found hospitalized patients had a similar rate of PTB as those who were discharged home and thus presumably more active [25]. In patients with a short cervix, observational studies have reported a paradoxical higher rate of PTB in those with reduced physical activity [23,26].

Bed rest also has potential harms: it increases the risk of thromboembolic events, has negative psychosocial effects, and leads to physical deconditioning [27-30].

Avoiding sexual intercourse — There is no evidence of harm from sexual activity during pregnancy, therefore abstinence has no role in strategies to prevent PTB [31,32].

Routinely screening for cervicovaginal and sexually transmitted infections — We screen for chlamydia, gonorrhea, and syphilis according to US Centers for Disease Control and Prevention guidelines. The purpose is to prevent maternal disease and transmission. (See "Prenatal care: Initial assessment", section on 'Standard panel' and "Prenatal care: Initial assessment", section on 'Selective screening'.)

Some trials have reported a reduction in PTB with routine screening and treatment for asymptomatic vaginal infection in the early second trimester [33], while others have reported no benefit [34,35]. Discordant findings may be due to confounding by recolonization or reinfection after therapy, intercurrent use of nonprotocol antibiotics, and failure to culture fastidious bacteria (eg, Mycoplasma hominis, Ureaplasma urealyticum), leading to misclassifications of individuals as noninfected.

●Chlamydia, gonorrhea, syphilis – There is no evidence that treatment of chlamydia, gonorrhea, or syphilis prolongs gestation. The only controlled trial that evaluated the effect of treatment of chlamydia on gestational duration did not show a reduction in PTB [36]. However, screening for and treatment of these infections is recommended to prevent other maternal and neonatal sequelae. (See "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents" and "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents" and "Syphilis in pregnancy" and "Treatment of Chlamydia trachomatis infection".)

●Bacterial vaginosis (BV), Ureaplasma, group B Streptococcus (GBS) – Prospective controlled studies and meta-analyses have reported either a modest or no effect of antibiotic treatment on prolonging gestation in asymptomatic patients who screened positive for BV [35,37-40], Ureaplasma urealyticum [41,42], or GBS [43], although these studies are likely confounded by recolonization or reinfection after therapy and intercurrent use of nonprotocol antibiotics. GBS screening in late pregnancy and chemoprophylaxis for prevention of early-onset neonatal GBS infection is recommended. (See "Prevention of early-onset group B streptococcal disease in neonates".)

Patients with BV and a previous PTB may benefit from BV screening and treatment, but there are insufficient data to recommend this as a routine practice. This is discussed in detail separately. (See "Bacterial vaginosis: Initial treatment", section on 'Asymptomatic pregnant persons'.)

●Trichomonas – Screening and treatment of asymptomatic Trichomonas infection in pregnant females who are not infected with HIV is not recommended because treatment did not reduce PTB in randomized trials [34,44-46]. By contrast, screening and treatment are recommended for pregnant patients infected with HIV to reduce the risks for pelvic inflammatory disease. (See "Trichomoniasis: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation' and "Trichomoniasis: Treatment", section on 'Pregnant'.)

Empiric antibiotic therapy — Empiric antibiotic therapy in patients with intact membranes does not reduce PTB. A meta-analysis of 17 randomized trials evaluated use of prophylactic antibiotics for prevention of PTB based on abnormal vaginal flora (12 trials), a previous PTB (three trials), and a positive fetal fibronectin test result (two trials) [47]. There was no significant association between antibiotic treatment and reduction in PTB regardless of the criteria used to assess risk, the antimicrobial drug administered, or gestational age at the time of treatment (overall combined random effect for delivery <37 weeks RR 1.03, 95% CI 0.86-1.24).

Another meta-analysis of randomized trials limited studies of antibiotic prophylaxis in the second or third trimester also found that the intervention did not significantly reduce the risk of PTB (RR 0.85, 95% CI 0.64-1.14, five trials, 1480 participants) or preterm prelabor rupture of membranes (RR 0.31, 95% CI 0.06-1.49, one trial, 229 participants); however, the included studies were of low methodologic quality [48]. Subsequent randomized trials have also not shown a benefit [49].

Enhanced prenatal care — Enhanced prenatal care has not reduced the risk for PTB compared with routine prenatal care. These data are reviewed separately. (See "Prenatal care: Initial assessment", section on 'Effectiveness'.)

Nevertheless, implementation of case management programs or specialty clinics for PTB prevention continue to be advocated and can facilitate implementation of the potentially effective interventions described above, provide social and emotional support to reduce stress (eg, assign a race- and language-matched Doula, refer for mental health services), and address socioeconomic factors associated with a high risk of PTB [50].

Treatment of periodontal disease — Although treatment of periodontal disease contributes to overall oral health, there is no strong evidence that treatment of periodontal disease improves pregnancy outcome. A 2023 meta-analysis (12 randomized trials, over 5700 pregnant participants) found that periodontal treatment (scaling and root planing) had no significant benefit in reducing PTB and low birth weight except when combined with chlorhexidine mouthwash [51]. There were many limitations to the trials, such as concerns about survival bias, lack of information about adherence with chlorhexidine mouthwash, and inability to assess for potential effect modification by factors such as oral health status at baseline. A large well-designed randomized trial is needed to determine the effect of periodontal treatment with/without oral antimicrobial rinsing on obstetric outcomes.

Several hypotheses have been proposed to explain why periodontal treatment does not clearly reduce the risk for adverse pregnancy outcomes. Possibilities include [52]:

●Lack of causality. Periodontitis may not be a direct or indirect cause of PTB or low birth weight.

●Shared risk factors may mitigate the effect of treatment. Some risk factors for both periodontitis and poor pregnancy outcome (eg, smoking) are not affected by periodontal treatment. Furthermore, PTB is likely the end result of a variety of environmental, behavioral, social, biological, and possibly genetic factors so periodontal treatment alone is unlikely to have a major impact on reducing risk.

●Underpowered trials. Very large trials would be required to detect significant reductions in very or extreme PTB rates since these are much less common than late PTBs.

●Lack of a consistent definition of periodontal disease. This has led to inclusion of individuals with mild disease whose pregnancies may not benefit from treatment.

●Treatment of periodontal disease in the trials was inadequate to affect pregnancy outcome. To demonstrate a beneficial effect, treatment may have to start before pregnancy or very early in pregnancy, continue longer, or be more intense. If PTB is related to changes in the genital tract microbiome induced by changes in the oral microbiome, local treatment of oral inflammation may not reverse genital tract changes.

Dietary modification — In systematic reviews, isocaloric protein supplements [53], balanced protein/energy supplements [54], and high protein supplements [54] did not reduce the rate of PTB. Most studies show that vitamin supplements during pregnancy do not reduce the risk of PTB [55-61], although they have other health benefits. There may be potential benefits of micronutrient supplementation in specific subpopulations of pregnant people, such as those who are undernourished or infected with HIV [62].

In a 2018 meta-analysis of placebo-controlled randomized trials of omega-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) supplements or dietary additions during pregnancy, n-3 PUFAs reduced PTB <37 and <34 weeks, with a corresponding trend for reduction in perinatal death [63]. These and subsequent discordant data and recommendations regarding fish consumption and n-3 PUFA supplementation during pregnancy are discussed in detail separately. (See "Fish consumption and marine omega-3 fatty acid supplementation in pregnancy".)

Retiring from the workforce — Individuals with uncomplicated pregnancies who are employed where there are no greater potential hazards than those encountered in routine daily life may continue to work without interruption until the onset of labor. Nevertheless, the physical demands of the job should be considered, especially in individuals at high risk of PTB, and working hours and occupational physical activity during pregnancy should be limited using common sense and local guidelines [64-67].

The effects of reducing occupational fatigue on PTB rates have not been evaluated in randomized trials. Maternity legislation in many European countries has regulated work schedules and working conditions for pregnant people; however, none of the European countries except France has experienced a reduction in PTB rates [68]. Nevertheless, paid maternity leave, guaranteed job protection, and regulation of hazardous working conditions remain desirable societal goals.

Social support and stress reduction — Although social support during pregnancy has resulted in improvements in short-term psychosocial outcome, it has not significantly reduced the rate of PTB. A systematic review concluded that social support was not sufficiently powerful to improve the obstetric outcome of the pregnancy in which it was provided, possibly because of the immense social deprivation experienced by most of the participants in the trials examined [69].

There are limited data on other interventions for reducing stress in pregnant people (eg, relaxation or mind-body therapies [eg, meditation, massage, yoga, breathing exercises, music therapy, aromatherapy]). Available trials are small and of poor quality; clear effects on birth outcomes have not been proven [70].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Preterm labor and birth".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Preterm labor (The Basics)")

●Beyond the Basics topics (see "Patient education: Preterm labor (Beyond the Basics)" and "Patient education: Bacterial vaginosis (Beyond the Basics)" and "Patient education: Management of a cervical biopsy with precancerous cells (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors for preterm birth (PTB) – There are many maternal and fetal risk factors for preterm birth (PTB) (table 1). Some are reversible, others are not. Identification of risk factors for PTB before conception or early in pregnancy ideally leads to interventions that could help prevent this complication. (See "Spontaneous preterm birth: Overview of risk factors and prognosis", section on 'Risk factors'.)

●Approach to risk mitigation – For some patients, the risk factor for PTB is clear and may be mitigated by a specific intervention. For other patients, the factors may be less clear but still may be mitigated by a multifactorial approach involving prenatal and self-care. Potentially effective interventions are listed in the table (table 3) and discussed in detail in separate topic reviews. They include the following (see 'Potentially effective interventions' above):

•Optimize management of any maternal medical disorders (see "The preconception office visit")

•Prescribe low-dose aspirin for patients at high risk of developing preeclampsia (see "Preeclampsia: Prevention", section on 'Low-dose aspirin')

•Provide counseling and intervention to reduce tobacco and substance use (see "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options" and "Substance use during pregnancy: Screening and prenatal care")

•Identify individuals with abnormal body mass index (BMI) and encourage prepregnancy weight loss or gain (see "Obesity in pregnancy: Complications and maternal management" and "Gestational weight gain" and "Eating disorders in pregnancy")

•Provide counseling regarding optimal pregnancy spacing and avoiding unplanned pregnancies (see "Interpregnancy interval: Optimizing time between pregnancies" and "Contraception: Postpartum counseling and methods")

•Reduce iatrogenic multifetal gestations (see "Strategies to control the rate of high order multiple gestation" and "Multifetal pregnancy reduction and selective termination")

•Consider the impact of cervical/uterine surgery on future pregnancies (eg, prior surgical evacuation for pregnancy termination or miscarriage, myomectomy for fibroids, surgical treatment of cervical intraepithelial neoplasia) (see "Overview of pregnancy termination" and "Pregnancy loss (miscarriage): Counseling and comparison of treatment options and discussion of related care" and "Uterine fibroids (leiomyomas): Issues in pregnancy" and "Reproductive effects of cervical excisional and ablative procedures")

•Monitor for short cervix (≤25 mm) and treat affected patients with vaginal progesterone or cerclage; identify cervical insufficiency and treat affected patients with cerclage (see "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with a short cervix' and "Cervical insufficiency" and "Short cervix before 24 weeks: Screening and management in singleton pregnancies")

•Address maternal infection risk, including:

-Routinely perform a first-trimester urine culture and treat asymptomatic bacteriuria (see "Urinary tract infections and asymptomatic bacteriuria in pregnancy", section on 'Asymptomatic bacteriuria')

-Reduce the risk of acquiring malaria in endemic areas (see "Malaria in pregnancy: Prevention and treatment")

•Surgically correct congenital uterine abnormalities, when appropriate (see "Congenital uterine anomalies: Surgical repair")

•Treat acute preterm labor with tocolytics (see "Inhibition of acute preterm labor")

●Ineffective and unproven interventions – Other interventions to mitigate the risk of spontaneous PTB (sPTB) have been proposed. However, based on the available evidence, these strategies are either ineffective or uncertain. In particular, we would not use the following interventions for prevention of sPTB:

•Routine monitoring of uterine contraction frequency (see 'Monitoring uterine contraction frequency' above)

•Prophylactic tocolytics (see 'Prophylactic tocolytics' above)

•Routine use of low-dose aspirin in the absence of a high-risk factor for preeclampsia (see 'Low-dose aspirin' above)

•Bed rest (see 'Bed rest' above)

•Prophylactic empiric antibiotic therapy (see 'Empiric antibiotic therapy' above)

•Progesterone supplementation for patients with a history of PTB but without a short cervix (See "Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth", section on 'Singleton pregnancy with prior preterm birth'.)

Other unproven strategies are discussed above. (See 'Ineffective and unproven interventions' above.)