Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Cutts, Julia C.; Agius, Paul A.; Zaw Lin; Powell, Rosanna; Moore, Kerryn; Draper, Bridget; Simpson, Julie A.; Fowkes, Freya J. I.

doi:10.1186/s12916-019-1467-6

Table 2 Characteristics of studies described in narrative terms in the systematic review

From: Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review

Author, year	Region, country	Enrolment period	Endemicity	Study design (n)	Gravidity; % PG	Mean (SD) age^a	IPTp use	Antibody responses	Ab time	Clinical outcomes^b	Key findings relating to review inclusion criteria
Ataide, 2010 [76]^c	Blantyre, Malawi	2000–2002	Intermediate	CS (263)^d	PG	20.0 (3.3)	SP	pRBC: CS2 (total IgG and phagocytic Abs)	T3	PM	Total IgG and phagocytic Abs higher in PM+ than PM−
										LBW	No association with Ab responses
										Anaemia^e	No association with Ab responses
Ataide, 2011 [64]^c	Blantyre, Malawi	2000–2002	Intermediate	CS (187)^f	SG	20.0 (3.3)	SP	pRBC: CS2 (total IgG and phagocytic Abs)	T3	PM	Total IgG and phagocytic Abs higher in PM+ than PM−
										Hb	No correlation of IgG or phagocytic Abs w/ Hb.
										Birthweight	+ve correlation between phagocytic Abs (but not total IgG) and birthweight
Babakhanyan, 2015 [65]	Yaounde, Cameroon	1996–2001	Intermediate	CC (420)^g	MG	PM+ : 27.6 (4.6); PM- 29.4 (5.6)	No	VAR2CSA: FV2, DBL1; DBL2; DBL1+2; DBL3, DBL4; DBL5; DBL6; DBL4	Delivery	PM	Ab levels similar in PM+ and PM- women; proportion of high avidity FV2 Abs was higher in PM- than PM+ women
Chandrasiri, 2016 [66]	Mangochi District, Malawi	2011–2012	High	RCT (1002)^h	All; 19.9)	24.5 (5.8)	SP	pRBC: CS2 (total IgG and opsonizing Abs)	T2	Hb at 36 weeks	+ve association between total IgG and opsonizing Abs to CS2 and Hb at 36 gw
Chandrasiri, 2016 [66]	Mangochi District, Malawi	2011–2012	High	RCT (1002)^h	All; 19.9)	24.5 (5.8)	SP	pRBC: CS2 (total IgG and opsonizing Abs)	T2	Birthweight	No association
Feng, 2009 [67]	Blantyre, Malawi	2003–2004	Intermediate	RCT (141)ⁱ	All; 56.7)	21.2 (4.7)	SP, SP + azithromycin or SP + artesunate	pRBC: CS2 (total IgG and opsonizing Abs)	T2	Anaemia^e	Both higher levels of IgG and opsonic phagocytosis to CS2 were associated with decreased anaemia at delivery
Feng, 2009 [67]	Blantyre, Malawi	2003–2004	Intermediate	RCT (141)ⁱ	All; 56.7)	21.2 (4.7)	SP, SP + azithromycin or SP + artesunate	pRBC: CS2 (total IgG and opsonizing Abs)	T2	LBW	No association
Hommel, 2010 [68]	Blantyre, Malawi	1998–2000	Intermediate	CC (62)^j	All; DNS	PM+ 20.9, PM- 21.5	SP	pRBC: Pf2006-CSA; Pf2004-CSA;3D7-CSA; HCS3; HB3-CSA; XIE-CSA CS2	Delivery	PM	PM+ PG had had higher Ab levels to isolates than PM- PG. Difference not observed for MG PM+ versus MG PM- women.
Khattab, 2004 [34]	Lambaréné, Gabon	2002	Intermediate	CS (151)	All; 27.2	PG 19.1 (1.9), MG 22.9 (4.0)	DNS	pRBC: Gb218, Gb337,vip43, and vip42	Delivery	PM	PM+ PG had higher Ab levels than PM- PG; association not observed for MG.
Mayor, 2011 [69]	Manhiça, Mozambique	2003–2005	Intermediate	CS from RCT^k (90)	All; 33.3	PG 19.1 (1.9); MG 22.9 (4.0)	Placebo group for IPTp trial	pRBC:193 T, CS2, FCR-CSA, Plac1–4, Mot1–8	Delivery	PM	PM+ had higher Abs to all parasites tested.
Mayor, 2013 [70]	Manhiça, Mozambique	2003–2005	Intermediate	CS from RCT (293)^l	All; 27	Placebo 24.3 (6.6); SP 24.0 (6.6)	Randomized to SP or placebo	pRBC: Plac1, Plac2 VAR2CSA: DBL3X, DBL2X, DBL5ε, DBL6ε	Delivery	PM	PM+ had higher Abs against all pRBC and antigens tested.
										PI	Abs levels not associated with PI after adjusting for PM.
										Birthweight	Higher Abs against DBL2X and Plac2 associated with lower birthweight; Among women w/. ≥ 1 malaria episode during pregnancy, high Abs to Plac2, DBL3X and DBL6ε associated with increased BW.
										GA	Higher Abs against DBL2X associated with younger GA; Among women w/. ≥1 malaria episode during pregnancy, high Abs to Plac2, DBL3X and DBL6Ɛ associated with increased GA.
										Hct	No association
O’Neil-Dunne, 2001 [38]	Yaounde, Cameroon	DNS	Intermediate	CS (198)	All; 23.7	G1: 20; G2: 22; G3: 24; G ≥ 5: 31	No	pRBC: 3D7 (CSPG adhesion inhibitory Abs)	Delivery	PM or PI: “malaria”	Malaria+ve/−ve women had similar levels of anti-adhesion Abs. Malaria +ve women w/ high anti-adhesion Abs had lower levels of placental parasitaemia.
Salanti, 2004 [27]	Kilifi, Kenya	1996–1997	Intermediate	CS (110)	All; DNS	DNS	No	VAR2CSA: DBL5ε	Delivery	Birthweight	PM+ women w/. high levels of anti- DBL5ε IgG gave birth to heavier babies.
Serra-Casas, 2010 [71]^m	Manhiça, Mozambique	2003–2005	Intermediate	RCT (302)	All; 24	Placebo: 23.9; SP: 24.6	Randomized to SP (152) or placebo (150)	pRBC: CS2	Delivery	PM	PM+ women had higher Abs to CS2 than PM- women
										PI	PI+ women at delivery had higher Abs to CS2 than PI- women
										Anaemiaⁿ	No association
										LBW	No association
										PTB	No association
Siriwardhana, 2017 [72]	Yaoundé, Cameroon	1996–2001	Intermediate	CS (1377)	All; 35.7	25.8 (5.9)	No	VAR2CSA: FV2, DBL1+2, ID1-ID2a, DBL1, DBL2, DBL3, DBL4, DBL5, DBL6	Delivery	PM	PM+ women recognized more DBL domains than PM- women and had higher IgG to FV2, DBL1+2, DBL2, DBL3, DBL4, DBL5, DBL6 and ID1-ID2a (3D7).
Tuikue Ndam, 2006 [39]	Thiadiaye, Senegal	2001	Low	cohort (275)	All; 21.8	24.1 (6.1)	No	VAR2CSA: DBL5ε, DBL6ε, DBL1-x at	T1/T2, delivery	PM	PM+ women had higher Ab levels than PM- women at delivery but no difference in Ab levels at T1/T2.
										Birthweight	No significant association with Abs
										Anaemia^o	No significant association with Abs
Tuikue Ndam, 2015 [73]	Comé, Benin	2008–2010	High	cohort (710)	All; 18.2	26.4 (6.2)	SP	pRBC: FCR3 (CSPG binding inhibition and total IgG); VAR2CSA: FV2, DBL1-2, DBL3, DBL4, DBL5, DBL6	T1/T2, delivery	PM	High DBL3 Abs at T1/T2 associated with reduced prevalence of PM at delivery. Trend between strong anti-FCR-3 VSA Abs and reduced prevalence of PM. For PI –ve women at inclusion, higher CSPG-binding inhibitory capacity at delivery (but not T1/T2) was associated with lower risk of PM.
										PI	High FV2 and DBL3 Abs at T1/T2 associated w/ reduced risk of PI during pregnancy
										LBW	High Abs to DBL1-DBL2 and DBL3 at T1/T2 were associated with reduced prevalence of LBW babies; High CSPG-binding inhibitory activity at delivery but not T1/T2 associated with reduced risk of LBW. No association with total IgG to FCR3
										PTB	For women PI –ve at inclusion, higher CSPG-binding inhibitory capacity, but not total IgG, associated with lower risk of PTB.
										Anaemia^e	No significant association with Abs
Tutterrow, 2012a [74]	Ngali II and Yaounde, Cameroon	2001–2005	Ngali II: High Yaounde: intermediate	cohort (Ngali II 27; Yaounde 48)^p	All; Ngali 33.3; Yaounde 34.0	Ngali II: 23.2 (5.4); Yaounde: 25.0 (5.1)	CQ prophylaxis	VAR2CSA: DBL1, DBL3, DBL4, DBL5, DBL6, DBL1+2	T1, T2, T3	PM	PM- women from high transmission Ngali II, but not low transmission Yaoundé had higher Ab levels to DBL3, DBL4, DBL5, and DBL6 domains, but not to DBL1, throughout pregnancy, compared to PM+ women from the same village.
Tutterrow, 2012b [75]	Ngali II and Yaounde, Cameroon	2001–2005	Ngali II: High Yaounde: intermediate	cohort (Ngali II 27; Yaounde 48)^p	All; Ngali 33.3; Yaounde 34.0	Ngali II: 23.2 ± 5.4; Yaounde: 25.0 ± 5.1	CQ prophylaxis	pRBC: 7G8; VAR2CSA: FV2	T1, T2, T3	PM	PM- had higher Abs to FV2 (FCR3) than PM+ women throughout pregnancy. In Ngali II women, high avidity FV2 Abs at T2 were associated with reduced risk of PM.

Abbreviations: Abs antibodies, CSPG chondroitin sulfate proteoglycan, GA gestational age, Hb haemoglobin, Hct, haematocrit, LBW low birthweight, MG multigravidae, PI peripheral infection,
PM placental malaria, PG primigravidae, PTB preterm birth, SG secundigravidae, T1 first trimester, T2 second trimester, T3 third trimester
^aAge is presented as mean (SD) except where indicated
^bWe only tabulate those antibody responses and clinical outcomes that met the inclusion criteria of this review. In some studies, other antibody responses and outcomes were measured. Where outcomes were presented as both continuous and categorical variables in original papers (e.g. birthweight and low birthweight), we report on findings for the categorical variable
^cAtaide et al. [76] and [64] describe the same study cohort, with the gravidity of subjects differing between publications (as specified)
^dWomen were selected based on HIV status, thus 40% of women in this study were HIV positive
^eAnaemia defined as haemoglobin < 110 g/l
^fWomen were selected based on HIV status, thus 65% of women in this study were HIV positive
^gRetrospective case-control study using archival plasma samples from a cross-sectional study. All PM⁺ women meeting inclusion criteria (≥ 3 pregnancies, 18 years or older, singleton live deliveries; babies that were > 28 weeks of gestation, women positive for Ab to FV2) were included (n = 96). For comparison, a random selection of PM− women that met the inclusion criteria were included (n = 324)
^hTrial of maternal nutrient supplementation to increase birth weight
ⁱWomen who were 14–26 weeks pregnant and were positive for peripheral parasitaemia by blood film examination were eligible to participate in trial and were randomized to one of three antimalarial treatment groups
^jSame matched case-control study as Beeson et al. [53]. Infected women were individually matched by gravidity, age (± 2 years), and date of delivery (± 2 months) to women without evidence of current or previous placental infection according to the results of placental histological analysis and placental, peripheral, and cord blood smears, and/or to women with evidence of past placental infection (malaria pigment present by placental histological analysis but no parasites seen, together with negative placental, peripheral, and cord blood smears)
^kSubgroup of women randomly selected from women who received placebo in IPTp trial
^lThis study included the last 200 women who received SP or placebo in a randomized controlled trial and delivered in 2005, plus a random selection of 20% of the women who received placebo and delivered in 2003 or 2004
^mSame IPTp trial as Mayor et al. [69] and [70]
ⁿMaternal anaemia was defined as haematocrit < 33%
^oDefinition of anaemia not shown
^pAll women had confirmed malaria infection during ≤ 6 months of pregnancy based on slide or PCR data

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