Keywords

1 Background

Infection is a major risk factor for PTB, accounting for 40–50% of all deliveries before 37 completed weeks of gestation. The most common route of infection is via the genital tract and subsequent microbial ascension and invasion of the amniotic cavity (25–40% of the total number of PTBs) [1,2,3,4]. Routine ANC provides an opportunity for health-care professionals to assess a pregnant woman’s risk of PTB and other adverse pregnancy outcomes. High rates of maternal bacterial and viral infections are reported in LMICs, and it is in these settings where most PTBs occur (approximately 81%) [5].

2 Evidence Statement

Infection in pregnancy is associated with an increased risk of PTB. Current guidelines recommend routine testing and treatment for human immunodeficiency virus (HIV), hepatitis B virus, malaria (context dependent), and syphilis. The aim of this testing is to improve health outcomes of mothers and their babies and/or to prevent mother-to-child transmission.

The increased risk of PTB from other infections such as asymptomatic bacteriuria (ASB) should prompt testing a clean-catch midstream urine by microscopy, culture, and sensitivity, where available, and providing antibiotic treatment as appropriate. Pregnant women should be offered testing for lower genital tract infections in high-risk populations or cases of suspected disease, with or without symptoms, as evidence has shown that such treatment decreases PTB risk.

3 Synopsis of Best Evidenced Infectious Risk Factors for Preterm Birth

For a summary of the evidence of infectious risk factors for preterm birth, please see Table 1, in Sect. 5.

Table 1 Evidenced infection-associated risk factors for PTB and effectiveness of interventions
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3.1 Human Immunodeficiency Virus

HIV is more prevalent in LMIC than HIC settings. HIV has been shown to increase the risk of spontaneous PTB 2.1-fold when compared to HIV-negative controls (17% vs. 8%; OR 2.27; 95% CI:1.2–4.3). Furthermore, a 3.2-fold increased risk for PTB was reported in HIV-positive women, and this was strongly associated with the use of highly active antiretroviral therapy (HAART) in the second trimester, OR 6.2 (95% CI:1.4–26.2) [6].

3.2 Malaria

Malaria infection is a risk factor for PTB. A systematic review and meta-analysis of 58 studies with 134,801 participants across 21 East African countries reported increased risks of PTB (aOR of 3.08 (95% CI:1.2–4.3) and also when malaria is a co-infection with HIV (aOR 2.59; 95% CI:1.84–3.66) [8]. Intermittent preventive treatment of malaria in pregnancy (IPTp) is an integral part of antenatal care in areas with moderate to high malaria transmission, alongside use of long-lasting insecticidal nets (LLINs), prompt diagnosis, and effective treatment of malaria infections.

3.3 Syphilis

Infection with syphilis-causing bacteria, Treponeda pallidum, is more common in LMIC than HIC settings. Syphilis is associated with an increased risk of PTB where mothers present late to antenatal care (OR 2.09; 95% CI:1.09–4.00) [9].

3.4 Urinary Tract Infections (UTI)

UTIs are frequently reported as a risk factor for PTB, with studies stating odds ratios (OR) of 1.8 (95% CI: 1.4–2.1) [10], 1.8 (95% CI: 1.3–2.4) [11] and 5.05 (95% CI: 1.16–21.8) [12, 13]. Low quality evidence from a systematic review and meta-analysis conducted across 21 East African countries reported an OR of 5.27 (95% CI: 2.98–9.31) [8]. Symptomatic urinary tract infections should be treated with antibiotics, and repeated urine testing is advised in low- and high-risk women [8].

3.5 Asymptomatic Bacteriuria (ASB)

Many infections during pregnancy present subclinically or are asymptomatic, subsequently delaying treatment and diagnosis. Untreated ASB is associated with PTB (aOR 1.6; 95% CI: 1.5–1.7) and has been shown to develop into acute pyelonephritis, itself an independent risk factor for PTB (OR: 2.6; 95% CI: 1.7–3.9) [7, 14, 26]. Increased rates of spontaneous PTB in patients with pyelonephritis have been reported (10.3% vs 7.9%; OR:1.3; 95% CI:1.2–1.5) [27]. Routine urine dipstick testing is not advised by the WHO due to high false-positive rates (118/1000) leading to unnecessary treatment and antimicrobial resistance [7].

3.6 Sexually Transmitted Infections (STIs)

STIs of the lower genital tract have been linked to increased risk of PTB; the most robust evidence available reports an OR of 1.3 (95% CI:1.1–1.4) [17] in cases of trichomoniasis (caused by the Trichomonas vaginalis parasite). However, Gulmezoglu and Azhar (2011) reported T. vaginalis treatment with metronidazole to appear to increase risk of PTB (RR 1.78; 95%CI:1.19 to 2.66) [21, 28]. Odds ratios of 2.2 (95% CI:1.03–4.78) and 3.2 (95% CI:1.08–9.57) at <37 weeks delivery and < 35 weeks delivery, respectively, are reported where infection with Chlamydia trachomatis bacteria has been diagnosed [18, 19].

3.7 Bacterial Vaginosis (BV)

A 2014 prospective cohort study found a significant increase in PTB risk in women with higher levels of BV-associated bacteria and a previous history of PTB, adjusted OR (aOR) 16.4 (95% CI: 4.3–62.7) [22]. Strategies to treat BV have failed to lower PTB risk [4].

3.8 Systemic Viral Pathogens

Infection with some systemic viral pathogens is a risk factor for PTB; the available best evidence reports odds ratios for cytomegalovirus (CMV), 1.6 (95% CI:1.14–2.27) [24], any herpesvirus, 1.51 (95% CI:1.08–2.10) [24], and influenza A (H1N1), 2.21 (95% CI:1.47–3.33) [25].

3.9 Factors Not Yet Shown to Be Associated with Increased Risk of Preterm Birth

  • A systematic review and meta-analysis including one study of periodontal disease (PD) carried out in East Africa reported it as a risk factor for PTB (aOR 2.32; 95% CI:1.33–4.35) [8]. Currently, there is insufficient evidence to directly establish a connection between PTB and periodontal infection [4].

  • There is limited evidence suggesting infection by Neisseria gonorrhoea bacteria as a risk factor for PTB (OR 2.50; 95% CI:1.39–4.50) [19].

  • Estimations of global burden of tuberculosis (TB) found little evidence of increased risk of PTB in TB-infected pregnant women [29].

  • Colonisation by Group B Streptococcus (GBS) has previously been described as a risk factor for PTB; a 1989 meta-analysis found non-bacteriuric patients had half the risk of PTB as those with ASB resulting from GBS colonisation (RR 0.5; 95% CI:0.36–0.70) [30]; however, more recent evidence is lacking.

4 Practical Clinical Risk Assessment Instructions for PTB

Health-care workers conducting the antenatal booking assessment should determine the risk of infections linked to PTB. This enquiry should determine likelihood of specific infections known to be risk factors for PTB to inform testing and management as follows:

  • Urinary tract infections (UTI): UTIs and progression to pyelonephritis are risk factors for PTB. Information on frequency of urination and presence of dysuria or suprapubic pain should be sought. Point of care dipstick testing should be undertaken where symptomatic bacteriuria is suspected.

  • Pyelonephritis: Along with determining symptoms of a UTI, detail of any fever or loin pain should also be elicited where pyelonephritis is suspected.

  • Asymptomatic bacteriuria (ASB): A urine specimen, preferably a clean catch urine (CCU) specimen, should be collected from all women at the antenatal booking clinic. Where not feasible, a midstream urine (MSU) specimen will suffice. Dipstick testing should not be performed due to a lack of sensitivity. CCU/MSU should be sent to the laboratory for culturing.

  • Bacterial vaginosis (BV): Routine screening is not recommended for asymptomatic BV. Symptomatic BV information should be elicited through asking pregnant women about any changes to odour or consistency of vaginal discharge and/or vaginal itching.

  • Syphilis, HIV, and hepatitis B: Routine blood testing should be offered to all women at the booking clinic for syphilis, HIV, and hepatitis B. Both syphilis and HIV have been shown to be risk factors for PTB.

Enquiries and testing, where appropriate, should lead to categorisation of risk of PTB and appropriate treatment and management.

5 Interventions for Evidenced Risk Factors for PTB

The evidenced effective interventions to address infections associated with preterm birth are shown in Table 1.

6 Summary of ANC Infection Interventions to Reduce PTB

These are depicted in Table 2.

Table 2 Benefit statements of infection interventions to reduce PTB risk
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7 Research and Clinical Practice Recommendation

Clinical practice should focus on promoting awareness of infections prior to and during pregnancy rather than routine testing of all infections linked to PTB. Further research is required to consider routine testing for chlamydia in target populations and effectiveness of dipstick testing for ASB in LMIC settings.