We conducted a secondary analysis of the WHO ANC Trial dataset following the publication of a Cochrane review that suggested the risk of perinatal mortality was slightly higher in reduced-frequency, goal-oriented antenatal care packages for low-risk pregnancies in developing countries [4]. The analysis found that both high- and low-risk women in the intervention group had an increased relative risk of fetal death between 32 and 36 weeks gestation. While any association between antenatal care interventions and fetal death is cause for concern, these findings are hypothesis-generating rather than conclusive and must be interpreted with caution.
The Cochrane review included data from developed and developing countries and the reviewers acknowledged that there is considerable variation within and between these trials on numbers of visits, making interpretation difficult [4]. While the increase in perinatal mortality in the three cluster-randomized trials was a consistent finding, only the pooled estimate reached borderline statistical significance [4].
Women in these countries differed greatly in baseline health risks and health resource availability, making comparisons problematic. Additionally, the 1996 Zimbabwe trial and WHO ANC Trial were in mostly urban settings [10, 13], while the 2007 Zimbabwe trial was rural [14]. This heterogeneity needs to be considered when interpreting the marginal increase in perinatal mortality on pooled analysis. Furthermore, data from the two Zimbabwean trials showed that overall, women had similar numbers of visits between intervention and controls groups, suggesting that any increase in the risk of fetal death in the intervention groups may be due to factors other than the number of antenatal visits [13, 14]. Secondary analyses of the two Zimbabwean trials have not yet been published.
In retrospect, the disparities in fetal mortality could have been more thoroughly investigated and given greater prominence in the published findings of the WHO ANC Trial. One possible explanation for these findings is that lower number of visits or other elements of the new antenatal care package decrease the identification of fetuses at risk of fetal death between 32 and 36 weeks. This may be attributable to prolonged gaps between antenatal visits (particularly between the second and third trimester) or issues with the quality of antenatal care delivered. The number of antenatal visits cannot necessarily act as a proxy for high quality care and measuring the effective delivery of antenatal interventions is difficult. Reducing the number of antenatal visits may not necessarily translate into fewer visits of higher quality for more women in low-resource settings. It may also be that control clinics were providing other interventions that were of some benefit.
This analysis has several limitations. Control clinics in the WHO ANC Trial used a regimen based on local protocols; it is therefore likely that visit frequency differed both within and between control clinics. 47.6% of women in the new model and 19.6% of women in the standard model had fewer than five visits, rendering differences in visit frequency negligible for this sub-group. Cluster-randomized trials are an efficient study design for trialing complex interventions in low-resource settings, but it can be difficult to account for all potential confounders that may differ between clusters. For example, antenatal care providers in the WHO ANC Trial were known to differ between study sites and clinics, as well as rates of smoking, education, hospital admission, previous gynecological surgery and late booking for antenatal care [10]. Complete blinding in trials of antenatal care is impossible, increasing the chance of a selection or information bias emerging. However, it is reassuring that after adjustment for identifiable, potential risk factors, the crude and adjusted results are similar. It is also worth noting that in high-risk women the increased fetal mortality was accompanied by a statistically significant drop in neonatal mortality (Adjusted RR 0.47; 95% CI 0.30, 0.72). While the reasons for these findings are unclear, it could be secondary to the higher number of fetal deaths during pregnancy.
In many low-income countries, where resources are limited, antenatal care coverage is poor and many women receive little or no antenatal care [15], and as such focusing on the provision of effective antenatal care at a reduced frequency seems advantageous. On the other hand, additional antenatal visits may serve to reinforce maternal education and compliance, or provide an opportunity for screening and treatment of a condition that had been missed, omitted or deteriorated since the previous visit. The reduced visit model has been adapted and implemented in the north-east region of Thailand and is currently being scaled up to the whole country. The model has been modified with an added visit around 20 weeks for an ultrasound scan. Initial monitoring of perinatal mortality has not revealed any adverse outcomes in the north-east region. (P Lumbiganon, personal communication).