Antenatal Screening for Sexually Transmitted Infections to Reduce Preterm Birth or Low Birthweight (Philani Ndiphile Study): A Randomized Three-Group Trial

In a randomized trial among pregnant women in South Africa, neither one-time nor two-time antenatal screening and treatment for *Chlamydia trachomatis*, *Neisseria gonorrhoeae*, and *Trichomonas vaginalis* significantly reduced the composite outcome of preterm birth or low birthweight compared to standard syndromic care, although the two-time screening strategy was associated with a statistically significant 23% reduction in preterm birth alone.

The Gist

Imagine pregnancy as a long, delicate journey to a destination: a healthy baby. Along the way, there are invisible "roadblocks" called sexually transmitted infections (STIs) like Chlamydia, Gonorrhea, and Trichomonas. These roadblocks are tricky because most of the time, they don't cause any pain or visible signs (like a flat tire that makes no noise). If left unchecked, they can sometimes cause the journey to end too early (preterm birth) or the baby to arrive too small (low birthweight).

For a long time, doctors in many places only fixed these roadblocks if the driver (the mother) complained of a problem. This is called "Syndromic Management." But since these infections are often silent, many roadblocks were missed.

The Philani Ndiphile Study (which means "Healthy Mother, Healthy Baby" in the local language) asked a big question: What if we proactively check for these invisible roadblocks and fix them immediately?

The Experiment: Three Different Maps

The researchers in South Africa set up a massive experiment with nearly 2,250 pregnant women. They split them into three groups, giving each group a different "map" for handling these infections:

1. The "One-Time Check" Group: At their first visit, they got tested for the three infections. If anything was found, it was fixed immediately. If they had a positive test, they came back a few weeks later for a "test-of-cure" to make sure the fix worked.
2. The "Double-Check" Group: They got the same first check and fix. But, they also came back for a second check later in the pregnancy (between 30 and 34 weeks). This was to catch any new infections that might have popped up or any old ones that didn't fully go away.
3. The "Standard Care" Group: This group got the usual care. They were only treated if they had symptoms (like unusual discharge). They didn't get the proactive testing.

The Results: Did the Maps Work?

The researchers looked at the final destination: Did the babies arrive on time and at a healthy weight?

• The Big Picture: Overall, neither the "One-Time" nor the "Double-Check" strategy significantly improved the combined result of "on-time arrival AND healthy weight" compared to the standard care group.
• The Silver Lining (The Double-Check): However, when they looked at just one part of the result—preterm birth (babies arriving too early)—the "Double-Check" group did something special. They had 23% fewer early arrivals than the standard care group.
• The Missing Piece: Unfortunately, neither strategy helped much with low birthweight (babies being too small). It seems that while catching infections early helps keep the baby in the womb longer, it doesn't necessarily make the baby grow bigger if other factors are at play.

Why Did the "Double-Check" Work?

Think of the pregnancy like a garden.

• The One-Time Check is like weeding the garden once in the spring. It's good, but new weeds can grow, or old ones might come back before summer.
• The Double-Check is like weeding in the spring and again in late summer. By checking a second time, the researchers caught infections that had returned or new ones that had started. This extra layer of protection seemed to keep the "garden" stable enough to prevent the baby from being born too early.

The Takeaway

This study teaches us a few important lessons:

1. Silent Infections Matter: Most of these infections were found in women who felt perfectly fine.
2. Timing is Everything: Checking once is good, but checking twice might be better for preventing early births.
3. It's Complicated: While catching infections helps prevent early births, it doesn't solve every problem (like low birthweight), which suggests there are other factors involved in how big a baby grows.

In short: Proactively checking for these silent infections, especially doing it twice during pregnancy, is a powerful tool to help babies stay safe in the womb a little longer, even if it doesn't guarantee they will be bigger. It's a step toward a healthier start for mothers and babies everywhere.

Technical Summary

1. Problem Statement

Curable sexually transmitted infections (STIs)—specifically Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis—are associated with adverse birth outcomes, including preterm birth (PTB) and low birthweight (LBW). In low- and middle-income countries (LMICs), particularly in sub-Saharan Africa, the prevalence of these infections among pregnant women is high (>30%), yet most are asymptomatic.

Current World Health Organization (WHO) guidelines in resource-limited settings recommend syndromic management (treating only symptomatic women), leaving asymptomatic infections untreated. While point-of-care molecular diagnostics have made screening feasible, evidence regarding whether systematic antenatal screening and treatment actually improve birth outcomes remains inconclusive and heterogeneous. There is a critical lack of definitive randomized controlled trial (RCT) evidence from sub-Saharan Africa to inform regional policy.

2. Methodology

Study Design:

• Type: Three-group, individually randomized, open-label clinical trial.
• Setting: Four government health clinics in the Buffalo City Metropolitan District, Eastern Cape, South Africa (a high STI and HIV prevalence setting).
• Participants: 2,247 pregnant women aged ≥18 years, enrolled before 27 weeks' gestation.
• Intervention Groups:
  1. One-Time Screening: Screening and treatment for CT, NG, and TV at enrollment (<27 weeks) with a "test-of-cure" 3–5 weeks later if positive.
  2. Two-Time Screening: Screening and treatment at enrollment (<27 weeks) plus a repeat screening and treatment between 30–34 weeks (third trimester). No test-of-cure was performed in this group.
  3. Standard-of-Care (Control): Syndromic management only (presumptive treatment for vaginal discharge syndrome per national guidelines). Real-time STI testing was not performed; stored swabs were tested retrospectively.

Procedures:

• Diagnostics: GeneXpert® CT/NG and TV assays (point-of-care molecular testing).
• Treatment: Immediate treatment upon positive results (Azithromycin for CT, Ceftriaxone for NG, Metronidazole for TV).
• Primary Outcome: A composite of preterm birth (<37 weeks) or low birthweight (<2,500 g).
• Secondary Outcomes: Preterm birth and low birthweight analyzed individually.
• Analysis Population: Modified intention-to-treat (mITT) including participants with live births.

3. Key Contributions

• First Large-Scale RCT in Sub-Saharan Africa: This is the first definitive trial in the region comparing different screening frequencies (one-time vs. two-time) against standard syndromic management.
• Pragmatic Design: The trial utilized real-world clinical settings and point-of-care diagnostics, enhancing the generalizability of findings to public health systems.
• Differentiation of Screening Strategies: It specifically isolates the impact of repeat screening (Two-Time) versus single screening with test-of-cure (One-Time), addressing the gap in knowledge regarding optimal timing and frequency.
• High-Quality Data: Utilized gold-standard molecular diagnostics and rigorous follow-up (94% outcome retrieval).

4. Results

Primary Outcome (Composite: PTB or LBW):

• Standard-of-Care: 23.2%
• One-Time Screening: 22.9% (Risk Ratio [RR] 0.99; 95% CI 0.81–1.21)
• Two-Time Screening: 20.6% (RR 0.89; 95% CI 0.72–1.09)
• Conclusion: Neither screening strategy significantly reduced the composite primary outcome compared to standard care.

Secondary Outcomes (Individual Components):

• Preterm Birth (<37 weeks):
  • Standard-of-Care: 18.8%
  • One-Time Screening: 18.9% (RR 1.00; 95% CI 0.80–1.26)
  • Two-Time Screening: 14.5% (RR 0.77; 95% CI 0.60–0.99)
  • Significance: The Two-Time screening strategy was associated with a 23% relative reduction in preterm birth.
• Low Birthweight (<2500 g):
  • No significant reduction was observed in either screening group compared to standard care.

Subgroup and Safety Findings:

• STI Positivity: Baseline STI prevalence was ~25–29%. Approximately 80% of infected women were asymptomatic.
• Adherence: Treatment uptake was 95% at baseline. Test-of-cure attendance in the One-Time group was 56%; third-trimester screening attendance in the Two-Time group was 68%.
• Adverse Events: No serious adverse events were attributed to the screening interventions.
• Distribution of PTB: The reduction in the Two-Time group was driven largely by a shift toward late preterm births (34–<37 weeks), suggesting the intervention may delay delivery rather than prevent very early preterm birth.

5. Significance and Interpretation

• Policy Implications: The study suggests that syndromic management alone is insufficient for preventing preterm birth in high-prevalence settings, but a single screening event (even with test-of-cure) is also insufficient.
• The "Two-Time" Advantage: The significant reduction in preterm birth with the Two-Time Screening strategy indicates that repeat screening in the third trimester is crucial. This likely addresses:
  1. Incident infections: New infections acquired after the first visit.
  2. Persistent infections: Failures of initial treatment or reinfection.
  3. Timing: The second screen occurs closer to the period of highest risk for preterm labor.
• Mechanism: The lack of effect on Low Birthweight suggests that STI-related inflammation may primarily drive the timing of delivery (preterm labor) rather than fetal growth restriction, or that growth restriction mechanisms are less reversible by antibiotic treatment alone.
• Contextual Nuance: Unlike the WANTAIM trial in Papua New Guinea (which showed no benefit), this study found a benefit for preterm birth. Differences may be attributed to the higher baseline rate of preterm birth in South Africa, the absence of malaria prophylaxis (which has anti-chlamydial effects in the control group of WANTAIM), and different substance use patterns.
• Future Directions: The findings support a conditional recommendation for repeat antenatal STI screening in high-prevalence settings. Further research is needed to determine the optimal timing of the second screen and to explore integrated interventions addressing non-infectious drivers of preterm birth.