Results
anaemia, death, hypophosphatemia, Anaemia, pregnancy loss, malaria, inflammation, EventsHypophosphatemia, haemorrhage, parasitaemia, Death, Hypophosphatemia
ANAEMIA, ADVERSE REACTIONS, HYPOPHOSPHATEMIA, HYPOPHOSPHATAEMIA, HYPOPHOSPHATEMIA, REGRESSION, HYPERSENSITIVITY REACTIONS, PREMATURE BIRTH, INFLAMMATION, ADVERSE EVENT, INFLAMMATION, PREGNANCY LOSS, ADVERSE EVENTS, HAEMORRHAGE, IRON DEFICIENCY, ADVERSE EVENT, ANAEMIA, MALARIA, EVENT, SECONDARY, IRON DEFICIENCY ANAEMIA
Between Nov 12, 2018, and March 2, 2021, 21 258 women were screened, and 862 (4%) were randomly assigned to a study group (430 to ferric carboxymaltose group and 432 to standard of care group; Trial profileIPTp=intermittent preventative therapy. RDT=rapid diagnostic test. *Reasons for not meeting eligibility were assessed on the questions on the eligibility data collection forms; woman can be ineligible on more than one of the eligibility criteria. †Defined as those who answered no to the question “Accepts study procedures?” at enrolment. ‡Reasons for not receiving the treatment were collected on the participant randomisation form. §Defined as those who received IPTp with suldadoxine pyrimethamine at enrolment. ¶There were four twins born in the intravenous iron group and four in the standard of care oral iron group. ||The intention-to-treat basis indicates maternal and neonatal outcomes were analysed according to randomly allocated group of the woman, and included all available data. Home visits collecting capillary haemoglobin and adherence discontinued due to COVID-19 restrictions.Baseline characteristics, including prevalences of moderate (649 [76%] of 858) and severe (62 [7%] of 858) anaemia by venous testing, and prevalence of iron deficiency (366 [43%] of 844), inflammation (432 [51%] of 844), and HIV positivity (145 [17%] of 855) were similar between groups (Baseline characteristics of the participating pregnant womenParticipants were enrolled across two sites, Blantyre (n=139) and Zomba (n=723). Data are n (%), n/N (%), or mean (SD). Religion, education, marital status, income source, parity, gravidity, and HIV status were self-reported. RDT=rapid diagnostic test.If women met the anaemia criteria but had a positive RDT, they were treated for malaria as per local protocols and deferred from enrolment. These women were able to present for re-screening—no earlier than 7 days later—and be enrolled if they met the eligibility criteria (in these cases, parasitaemia was assessed using microscopy due to persistence of antigen detection via RDT).Malaria RDT positive was based on confirmatory RDT testing by laboratory personal on venous blood collected at enrolment.Data are missing for four participants in the ferric carboxymaltose group.Data are missing for 11 participants in the ferric carboxymaltose group and seven participants in the standard of care group.Iron deficient indicates serum ferritin <15 μg/L or ferritin <30 μg/L if C-reactive protein >5 mg/L, and iron deficiency anaemia indicates Hb <11 g/dL and serum ferritin <15 μg/L or ferritin <30 μg/L if C-reactive protein >5 mg/L.Inflammation indicates C-reactive protein >5 mg/L, and anaemia and inflammation indicates Hb <11·0 g/dL and C-reactive protein >5 mg/L.Effects of ferric carboxymaltose on maternal efficacy outcomesData are count (%), mean (SD), or median (IQR). p values and 95% CIs presented have not been adjusted for multiple comparisons for the secondary and other maternal and neonatal outcomes. The intervals should not be used in place of hypothesis testing. A prevalence ratio of ferric carboxymaltose versus standard of care is displayed following analyses using a modified Poisson model with robust standard errors and random intercept for participant. A mean difference of ferric carboxymaltose versus standard of care is following analyses using a likelihood-based longitudinal data analysis model. A geometric mean ratio is displayed for ferritin concentration after a log base e transformation due to skewness. An absolute mean difference between ferric carboxymaltose and standard of care is displayed following fitting a linear regression model. A risk ratio of ferric carboxymaltose iron versus standard of care is displayed following analyses using a log-binomial regression model. Anaemia indicates venous Hb <11·0 g/dL up to and including delivery and venous Hb <12·0 g/dL post partum. Moderate–severe anaemia indicates venous Hb <10 g/dL up to and including delivery and venous Hb <11·0 g/dL post-partum. Iron deficient indicates serum ferritin <15 μg/L or ferritin <30 μg/L if C-reactive protein >5 mg/L, and iron deficiency anaemia indicates Hb <11 g/dL and serum ferritin <15 μg/L or ferritin <30 μg/L if C-reactive protein >5 mg/L. Hb=haemoglobin.The Holm procedure was applied to the secondary maternal outcomes and secondary neonatal outcomes separately. The p value for ferritin (μg/L), iron deficiency, and iron deficiency anaemia at 36 weeks' gestation remained significant after controlling for multiple comparisons with the Holm procedure.In women randomly assigned to ferric carboxymaltose, there was a reduction in the prevalence of iron deficiency at 36 weeks' gestation compared with standard care (ferric carboxymaltose: 60 [18%] of 336 Compared with standard of care, ferric carboxymaltose did not change birthweight or incidence of low birthweight (Effects of ferric carboxymaltose on neonatal efficacy outcomesData are count (%) or mean (SD). p values and 95% CIs presented have not been adjusted for multiple comparisons for the secondary and other maternal and neonatal outcomes. The intervals should not be used in place of hypothesis testing. Risk ratios of ferric carboxymaltose iron versus standard of care are following analyses using a log-binomial regression model. An absolute mean difference between ferric carboxymaltose and standard of care is displayed following fitting a linear regression model. Hb=haemoglobin.The composite adverse birth outcome was at least one adverse birth outcome of low birthweight, pregnancy loss or stillbirth, premature birth, or small for gestational age. The total number of the composite adverse birth outcome is therefore smaller than that of the components.Totals consist of n=395 liveborn neonates plus n=7 pregnancy loss or stillbirth in the ferric carboxymaltose group and n=401 liveborn neonates plus n=9 pregnancy loss or stillbirth in the standard of care group.Small for gestational age is defined as a birthweight below the tenth percentile for gestational age according to INTERGROWTH-21 standards.Total number of neonates reduced due to procedural missing data (version control).Prespecified subgroup analyses were conducted on the primary and key secondary maternal and neonatal outcomes (Subgroup analyses of the treatment effect on maternal anaemia at 36 weeks' gestation and birthweight according to baseline characteristics(A) A prevalence ratio of ferric carboxymaltose versus standard of care is displayed for anaemia at 36 weeks' gestation using a Poisson model with robust standard errors. Subgroup (main effect) and subgroup-by-treatment-by-visit interaction (and subgroup-by-treatment and subgroup-by-visit interaction) have been added to the model to evaluate how the treatment effect differs between subgroup categories. (B) An absolute mean difference for birthweight between ferric carboxymaltose and standard of care is displayed following fitting a linear regression model. Subgroup (main effect) and subgroup-by-treatment interactions terms have been added to the models to evaluate how the treatment effect differs between subgroup categories. The p values and 95% CIs presented have not been adjusted for multiple comparisons. The intervals cannot be used in place of hypothesis testing. FCM=ferric carboxymaltose. SOC=standard of care.No women died during the trial. Adverse reactions during ferric carboxymaltose administration were reported by 28 (7%) of 430 participants; there were no serious adverse events including no serious hypersensitivity reactions (Effects of ferric carboxymaltose on maternal and neonatal safety outcomesThe p values and 95% CIs presented have not been adjusted for multiple comparisons. The intervals should not be used in place of hypothesis testing. Risk ratios of ferric carboxymaltose iron versus standard of care are following analyses using a log-binomial regression model. Prevalence ratios of ferric carboxymaltose versus standard of care is displayed following analyses using a modified Poisson model with robust standard errors and random intercept for participant. CRP=C-reactive protein. ICU=intensive care unit. NA=not applicable. RD=rapid diagnostic test.Includes all women who were treated, presented according to treated group. This includes four mothers with multiple pregnancies.The composite severe medical event outcome was women with at least one severe medical event of dealth, haemorrhage, blood transfusion, or ICU care recorded for the mother. Death, haemorrhage, blood transfusion, and admission to ICU are captured across the whole trial period.Adverse events were coded using version 5.0 of the Common Terminology Criteria for Adverse EventsHypophosphatemia is defined as PO4 <0·80 mmol/L. Hypophosphatemia was seen at baseline in 15 (3·6%) of 418 women treated with ferric carboxymaltose and 2 (5·6%) of 425 women treated with standard of care. Mild hypophosphatemia is defined as (0·64≤PO4<0·80 mmol/L), moderate hypophosphatemia is defined as (0·32 ≤PO4 <0·64 mmol/L) and severe hypophosphatemia is defined as (PO4<0·32 mmol/L). Severity of hypophosphatemia does not have statistical testing due to sparse data.Inflammation indicates C-reactive protein >5 mg/L.Includes all liveborn neonates (with the exception of the death and pregnancy loss outcome) born to women who were treated, presented according to treated group of the mother; this includes eight twins.Ferric carboxymaltose is recognised to induce transient hypophosphataemia.Among the 796 babies born alive, 27 (3%) died during the first 28 days of life: ten (3%) born to mothers who received ferric carboxymaltose and 17 (4%) to mothers who received standard of care (RR 0·60 [95% CI 0·28–1·29], p=0·19). At least one adverse event was reported in 30 (8%) neonates born to mothers randomly assigned to ferric carboxymaltose and 35 (9%) born to mothers who received standard of care (RR 0·87 [0·55, 1·39], p=0·56; We conducted several additional analyses to confirm the robustness of the findings to the analysis assumptions or methods, which did not alter the results (We did one unplanned analysis after unblinding. The original primary outcome definition was designed to characterise the effect of ferric carboxymaltose on anaemia as women reached delivery; we recognised the amended primary outcome would miss women who delivered before 36 weeks' gestation. For this reason, we analysed a post-hoc outcome: anaemia at 36 weeks' gestation or at delivery—whichever occurred sooner. Ferric carboxymaltose did not reduce the prevalence of anaemia at this post-hoc composite timepoint compared with standard of care (ferric carboxymaltose: 187 [52%] of 357 