Reviewer's report
Title:Malaria morbidity among pregnant women on combined insecticide treated
nets (ITNs) and intermittent preventive treatment (IPTp) with sulphadoxine -
pyrimethamine in Yaounde, Cameroon.
Version: 2Date:19 September 2013
Reviewer: Stephen Rogerson
Reviewer's report:
Dr Mbu and colleagues have performed a potentially interesting study to define
the characteristics of pregnant women experiencing malaria in what appears to
be a prospective cohort study of Cameroonian women. Of 2500-odd women, 166
apparently developed “acute attacks” and these women were matched 1:1 to
women who did not develop attacks. Young, primigravid, poorly educated women
who did not receive all SP doses in a timely way were significantly more likely to
develop “acute attacks”. The study has the potential to add to our knowledge
both of the importance of clinical malaria in pregnancy, and to the role of teenage
pregnancy and poor education as risk factors for malaria, but the presentation
currently leaves a lot to be desired.
Major compulsory revisions
1. There are two big omissions in this paper: one is a clear definition of what is
meant by an acute attack (what exclusion criteria were used? What were parasite
densities? Did all women have parasitemia)? The term “acute attack” is
meaningless and should be replaced with (e.g.) clinical malaria or symptomatic
malaria, with a clear definition of this. Perhaps more important still is the lack of
clarity in how the 166 controls were selected. This process is critical to the
validity of the data but the section “selection of cases” does not make this at all
clear. Specifically the phrase “nested-in the same moment” (P4) is not at all
clear. (To my mind a better comparison would have been the 166 women with
malaria and the rest of the cohort followed up, if as suggested the data on the
whole cohort was complete. This would limit biases introduced during selection of
controls).
2. The Introduction contains a lot of information that is of limited relevance to the
study, on RBM and chloroquine resistance. This could be cut.
3. The actual malaria parasitaemia data should be presented. What was the
prevalence of parasitaemia at first ANC visit (the D1 time point described) and at
the time of admission? Median or geometric mean and range would be
appropriate.
4. Two important studies from recent years are not cited. Tagbor, H., J. Bruce, et
al. (2008). "Malaria in pregnancy in an area of stable and intense transmission: is
it asymptomatic?" Trop Med Int Health.and Bardaji, A., B. Sigauque, et al. (2008).
"Clinical malaria in African pregnant women." Malar J 7: 27. These are in
complementary ways very relevant to the present study.
5. Stats. “We used multivariate linear regression models for the estimation of the
differences in means by case status after adjustment for confounders”. I cannot
see where these results are presented? The only results are clearly univariate
odds ratios. (a multivariate analysis presenting adjusted odds ratios using these
different associated variables would be of interest as there is significant
co-linearity between age, gravidity and parity for example- which is more
important? )
6. I also do not understand the “parasite density change”. Is this the arithmetic
increase in parasite density as a proportion of D1? If so it appears very modest.
As stated elsewhere please include actual parasite densities instead. Many
women have parasitaemia and are pregnant but not sick, and it is important to
consider the specificity of the definition of malaria in the cases, as no
confirmatory tests other than blood slide have been performed to rule out e.g.
UTI or gastroenteritis, or viral infections such as dengue or other arboviruses
which may present similarly.
7. There is so little data presented, it would be useful to have a table of patient
characteristics of cases and controls (e.g. proportions with each symptom listed
in the definition of malaria, mean age, gravidity breakdown etc. This is standard
in papers like this and allows us readers to assess the study populations and not
just the statistics
8. Discussion: Like the introduction this contains a lot of largely irrelevant
material and/or not very pertinent references. For example the discussion of how
cytokines act. What would be more relevant would be to discuss adolescent
pregnancy in poor under-educated girls as a risk factor for malaria and other
pregnancy problems. This remains a pressing problem in Cameroon and other
countries across the world and the study nicely draws attention to them in the
results, but the discussion does not maintain this focus.
9. Was there any pregnancy outcome data on cases and controls? This would be
very interesting. How did the malaria episodes affect birth weight for example?
Did any miscarriages or stillbirths occur in either group? If available this would
add to the paper.
10. Discussion end of first paragraph P 6. The authors are confusing two topics
in this paragraph: the increased susceptibility of pregnant over non-pregnant
women, and the particular increase in this susceptibility in primigravid over
multigravid women. They should also reference studies showing increase in
susceptibility in pregnancy.
11. The following paragraph references 4 papers none of which is by Macgregor,
who is stated to be the source of the figures presented. Please check figures are
correct (they don’t make sense at present) and insert appropriate references.
12. Similarly in the next paragraph references 20-25 are cited. Many of these
appear quite unrelated to the topic. Please replace with some more pertinent
references.
13. Top of page 7. Is there any other data to suggest that university educated
women are better protected against malaria than secondary educated? The only
studies I know (and our experience) is that the increase in risk is limited to
women with primary or no education. If not please cut this speculative text.
14. In discussing the gap between doses it would be very relevant to cite the
latest WHO policy on IPTp which suggest repeated dosing a month apart from
quickening to delivery. If that policy were followed, it would impact on malaria
case numbers in this population.
Minor essential revisions.
1. There are many spelling errors in the paper, and incorrect terminology for
malaria species, which should be Plasmodium falciparum or P. falciparum (both
in italics), not as written. There is also a confusion between UK spelling (e.g.
anaemia) and US spelling (e.g parasitemia), sometimes in the same paragraph.
Careful proofing and correction of the text is essential.
2. Introduction. Latest WHO figures for malaria deaths suggest a burden of
600-700,000, not the very high numbers quoted. Like much of the paper this
reflects a tendency to cite old and outdated literature.
3. Last paragraph of introduction: what is meant by “greater proportions of our
daily hospital admissions”? Greater than what? Is there any data (e.g. internal
audits?) to support this claim that there are a lot of cases? Do the 166 episodes
in 5 years represent a large or small proportion of all admissions?
4. Methods: the opening paragraph and later descriptions are contradictory. It
appears there was a cohort, and from this a case control study was derived, but
this is not stated clearly. (See other comments re selection of cases).
5. Were all cases P falciparum? This is not stated.
6. In the abstract it states that the malaria burden is unchanged but substantial
data show recent declines in malaria deaths globally and in specific countries.
Remove the statement.
7. Methods P 3 SP administration- the doses were scheduled for certain
gestations but it is clear they were not always given then, as the text states they
were. Please modify.
8. P 4. Malaria parasites are not found in serum. Blood density should be
recorded. More details need to be provided about slide reading- read once? Or
twice? By whom? Number of field examined? Were actual NWBC measured or
was an estimated WBC count used?
9. Why were D 1 parasite counts collected 2 weeks after first SP dose? One
would expect counts to be zero in almost all women at this time as SP is still
highly effective in Cameroon. This makes comparison of D1 and D2 parasite
counts somewhat meaningless. Instead present D2 counts alone. (This section of
methods can then be made much more compact.)
10. In the discussion (and elsewhere) correct all percentages to one decimal
place, and correct all p=0.000 to p<0.001.
11. Also essential is correction of the reference list. Not only are these often
poorly chosen and outdated, they are also frequently incorrect in terms of
spelling of authors names and other factors. The authors should download
journal articles into a Reference Manager or Endnote database directly from
Pubmed. For other publications (e.g. available on internet) a URL should be
provided and a publisher for Government reports.
12. Antimalarial generic names (e.g. chloroquine) and Malaria should not be
capitalised, nor should Platform (abstract), whereas names of institutions and
departments generally are.”
13. Conclusion: the authors speak of malaria in “first half of pregnancy” but this is
not accurate. The cases they are concerned with mostly occur in third quarter ie
20-30 weeks.
14. The table needs correction from 10 hrs to 10 weeks. Also the title needs
changing as many of the factors listed are not outcomes but patient
characteristics.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests'