Treatment of Iron Deficiency Anaemmia in Pregnancy Study. The Clinical Impact of Treatment for Iron Deficiency Anaemia using an Optimized Care Pathway in accordance with national guidelines

Treatment of Iron Deficiency Anaemmia in Pregnancy Study. 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The Clinical Impact of Treatment for Iron Deficiency Anaemia using an Optimized Care Pathway in accordance with national guidelines David Churchill, Hind Ali, Samaher Sweity, Dianne Bautista, Mahmoud Moussa, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3933791/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Aug, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted 12 You are reading this latest preprint version Abstract Iron deficiency anaemia is a common disorder affecting up to 30% of pregnant women. Treatment guidelines for iron deficiency anaemia in pregnancy exist, which if adopted, can reduce the associated risks of maternal and fetal morbidity and mortality. Objective: To optimise the implementation of the British Society of Haematology (BSH) guidelines, for the treatment of iron deficiency anaemia (IDA) in pregnancy, assessing response rates and predictability of response. Study population: A prospective cohort study of pregnant women with IDA at a single site. Methods: Women with anaemia were offered follow-up through a dedicated anaemia clinic. First line treatment was with ferrous sulphate 200mg three time a day as per earlier BSH guidelines. The response was assessed 2 to 4 weeks later by measuring the haemoglobin (Hb) concentration. A response was defined in 2 ways; i) a haematological response (HRes), a 10g/L increase in Hb and ii) adjusted obstetric response (ORes), a 10g/L increase in Hb and/or gestationally adjusted normalisation of the Hb. Education and advice were provided to women, with on-going follow-up at clinic appointments including an assessment of side effects. Continuing non-response led to an offer of intravenous iron infusion (IVI). Following a response with oral iron, treatment was continued for a further 3 months when the women were again reviewed. Results: The initial rate of HRes to a first course of oral iron was 36.5% and for ORES at 55.2%. At the end of all follow up, post-delivery, the HRes rate was 70.5% and ORes 88.5% (excluding 9 women lost to follow up). Responders (HRes) to oral iron had lower median Hb at diagnosis 95g/L compared to non-responders 100g/L. The responders median Hb was 113g/l versus 103g/L for non-responders at first follow-up and was Hb 122g/L versus 110 g/L, respectively, at the end of the study. The same pattern was seen for ORes. Non-responders reported more side effects than responders 15% versus 5% respectively. Logistic modelling suggested Hb at diagnosis, ethnicity, trimester at recruitment, marital status and parity had a predictive accuracy for a response of 75%. The specificity was high 89.8% but sensitivity low 42.9%. Conclusion: Oral iron treatment for IDA in pregnancy is challenging to deliver due to side effects and poor adherence, despite national guidelines. High rates of non-response were seen even in the setting of a specialist anaemia clinic. Alternative strategies such as prevention of IDA need to be evaluated. Anaemia Response Iron Diagnosis Adherence Prediction Figures Figure 1 Figure 2 Figure 3 Background Current approaches to address the on-going high burden of anaemia during pregnancy, caused by iron deficiency, have been described in mutliple guidelines, including a recently updated British Society for Haematology guideline [ 1 – 5 ]. Timely recognition and treatment of iron deficiency anaemia (IDA) during pregnancy is recommended, given that the reported risks associated with anaemia for the mother and infant, include stillbirth and neonatal death [ 7 , 8 ]. In the first and second trimesters, IDA has also been correlated with low birth weight and pre-term birth, both of which lead to significant morbidity lasting into infancy and sometimes adult life [ 9 – 13 ]. However, our recent nationwide prospective audit reported a high incidence of anaemia at 30% during pregnancy and 20% post-delivery [ 6 ]. This suggests on-going challenges with implementation, despite the presence of clear standards of care through guidelines. The increased demand for iron in pregnancy is driven by the expanded blood volume of the mother and the requirements of the developing fetus and placenta. The aim of this study was to report our findings for women seen in the clinic, to assess the effectiveness of guideline recommendations and describe the natural history of iron deficiency anaemia in pregnancy when adopting the guidance on treatment. Specific study objectives were to: describe haematological and clinical responses to iron treatment, including an assessment of side effects and adherence, explore the effect of demographic, clinical and laboratory variables in predicting response to treatment. Methods Study design This prospective, single centre, cohort study recruited pregnant women with iron deficiency anaemia. Women who consented to participate were offered support, treatment, and follow-up through a dedicated anaemia research clinic. Eligible participants with IDA were identified in two ways; 1) those diagnosed de novo in the hospital antenatal and/or community clinics and antenatal maternity ward or 2) from a daily download of blood results of routine screening samples taken either at the first trimester or the 28th week gestation antenatal visit. Eligible women were approached by the research staff and given information about the project, prior to seeking consent. The diagnostic thresholds of anaemia were defined by the criteria described in British Society Haematology (BSH) guidelines and by the World Health Organization, which are gestationally adjusted haemoglobin thresholds of: first trimester < 110g/L, second and third trimester < 105g/L, and postpartum < 100g/L. Sample Participants Inclusion criterion was any pregnant women aged between 18 and 45 years with a diagnosis of IDA up to 35 weeks’ plus 6 days gestation. Exclusion criteria were: women presenting at or after 36 weeks, as it was judged that there could be insufficient time between diagnosis and the end of pregnancy to complete assessments, a diagnosis of a major haemoglobinopathy (women with a trait were not excluded) signs of sepsis; allergies to iron; women with hyperemesis gravidarum / persistent vomiting or inflammatory conditions such as Crohn’s, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis; and women with chronic renal failure. Interventions This was a non-interventional study, and clinical management of IDA followed recommendations detailed in national guidelines [ 4 , 5 ] adopted into local guidance documents. To attempt better practice for anaemia management in pregnancy, we introduced a dedicated anaemia research clinic, modelled on the pre-operative anaemia clinic services, as advocated nationally e.g. https://hospital.blood.co.uk/patient-services/patient-blood-management/pre-operative-anaemia . Women identified as anaemic were offered the option of management and follow-up through this clinic, supported by a research fellow and consultant obstetrician. The study started when earlier BSH guidance was in place, which recommended daily iron dose of 100-200mg elemental iron per day; prescribed as 200mg ferrous sulphate three times a day (65mg elemental iron per tablet x 3 = 195mg). All women were offered a full blood count (FBC) to screen for IDA usually 8–12 weeks’ gestation and then 28 weeks’ according to standard practice [ 2 ]. Women who consented to participate were started on oral iron no longer than 14 days from the point of diagnosis (Visit 1). Enrolled women were given verbal instructions, and written information on the correct way to take the tablets to maximise absorption. Women were asked to return for a follow up visit, between 2 and 4 weeks after initiating treatment, when a peripheral blood count was taken to assess the therapeutic response and assessments were made of side effects and adherence (Visit 2). The variation in follow up visits was to coincide with a woman’s obstetric appointments. Iron has a marketing authorisation (MA) in the UK and is being used in this study in its marketed presentation and packaging bearing the MA number. Non-response to therapy Participants who didn’t have the expected rise in haemoglobin of 10g/L minimum, at Visit 2, were classified as non-responders and the reasons for not responding were explored with these women. If the non-response was due to side effects a modified regimen of twice daily iron administration was implemented along with further advice on how best to consume iron, symptomatic treatment for side effects was also given where necessary, e.g. laxative for constipation. Blood samples were also taken for vitamin B12 and folic acid estimation. Women were asked to continue with the modified treatment regimen and continue recording in their treatment diary. They were reviewed in a further 2 weeks (Visit 3), when the same process as in Visit 2 was followed. Women who had increased their haemoglobin into the normal range for pregnancy were maintained on oral iron. As per routine practice, women who continued to be non-responders, when assessed at visit 3, were offered intravenous iron to treat their anaemia. Women, whose anaemia worsened between any of the visits, were offered intravenous iron as per standard care in local guidelines. All women who received intravenous iron were also asked to return to the clinic after a further 2 weeks for repeat blood sampling (including research blood samples) to ensure that they responded to treatment. Therefore, the total number of visits for each participant was dependent upon their clinical need according to the guidance. Data collection Baseline demographic, clinical and laboratory data were collected from the patient care record and laboratory information systems. Additional data were collected at each visit, and obstetric outcome data collected at the postnatal follow up visit 6 weeks after birth. At each visit, the frequency and severity of symptoms experienced by the participant and associated with IDA was assessed using an adapted version of a published pregnancy symptomatology tool [ 14 ]. The frequency of side effects was assessed by examining the pre-piloted tolerability and symptom tool adapted from a questionnaire developed to assess gastrointestinal symptoms after oral ferrous sulphate supplementation [ 15 ]. Finally, participants were asked to complete a Well-being in Pregnancy (WiP) questionnaire [ 16 ]. Participants were also requested to keep a diary, recording the time at which they took their medication, the symptoms of anaemia experienced at the time and the side effects suffered since the last tablet was taken. The completed diary was returned at the follow up visits and supplemented the information gathered through questionnaires on adherence and side effects/symptoms suffered since the preceding visit. Blood sampling Routine blood samples were collected at baseline and follow up visits (see Fig. 1 ) for a peripheral venous blood count, iron studies and general biochemistry. An additional sample of blood was taken, processed, and stored at -80 degrees Celsius, for more specialist iron and inflammatory biomarker studies and will be the subject of a separate report. Outcomes The Primary outcome measure was the proportion of women with physiological recovery from anaemia defined as an increase in Hb by ≥ 10 g/L, 2-4weeks after the start of treatment. This was classified as a haematological response (HRes). The secondary outcome measures were: An alternative obstetric definition of response (ORes), which was either an HRes and/or the normalization of the haemoglobin concentration, adjusted for gestational age. This was to recognize that the physiological changes of pregnancy result in haemodilution and thus a fall in the concentration of haemoglobin across gestation. the longitudinal changes in haemoglobin, red cell indices, iron, transferrin, ferritin, CRP. the change in frequency and severity of symptoms associated with anaemia in pregnancy and assessed by the pregnancy symptomatology questionnaire [ 14 ], the frequency and severity of side effects induced by iron therapy by an adapted published tolerability tool [ 15 ], and general wellbeing [ 16 ]. Statistical Analysis Sample size As this was an exploratory cohort study and did not involve a novel intervention, we did not perform a sample size calculation and pragmatically proposed to recruit 120 women. This number was based on estimated numbers of anaemic women seen in the antenatal clinics and wards during the study and to support secondary and exploratory analyses to meet the objectives. Differences between responders and non-responders were explored by comparing baseline demographic data, haematological, and iron parameters. Distributions of haematological and iron parameters between responders and non-responders at V2 and V5 were compared and checked for equality using the Mann-Whitney U test. Statistical significance was defined as a p-value < 0.05. The primary outcome HRes was described as a percentage for the group. These data were also interrogated using the adjusted definition of response ORes, a secondary outcome described above. To calculate the response rate to oral treatment the results for visit 2 & 3 were combined and are shown in Table 3 . This was to mimic normal practice, which was to explore adherence and adjust the treatment plan before abandoning oral treatment. Categorical variables were summarized using percentages and quantitative variables were summarized using mean, standard deviation, median, interquartile range. The proportion of women achieving HRes and ORes were estimated using the observed sample proportion and 95% confidence intervals were calculated using the Wilson-Score Method. Women who dropped out at V2 or V5 were considered as non-responders. Logistic regression models were explored to identify predictors of HRes from the set of baseline demographic (index of deprivation quintile, ethnicity, marital status), obstetric (parity, trimester of recruitment), and routinely collected haematological and iron indices. Principal component analyses were further utilized to derive scores representing combinations of haematological and iron indices. Positive and negative predictive values were obtained to assess the predictive utility of the model and positive predictive values of at least 75% were considered useful for practice. Statistical analyses were performed using statistical analysis software (SAS/STAT, Version 9 of the SAS System for Windows, SAS Institute, Inc., Cary, NC). The report has been prepared using the STROBE guidelines for reporting observational cohort studies. Results Baseline Socio-Demographic and Clinical Characteristics The flow diagram (Fig. 1 ) shows the number of individuals at each stage of the study and the reasons for withdrawal. The characteristics of enrolled pregnant women is shown in Table 1 and was representative of the general maternity population served by the hospital located in a central urban environment. Their mean age was 29.6 years and the proportions for body mass index and socio-economic deprivation were as expected, with 65.6% of the population being in the most deprived quintile when measured by the index of multiple deprivation score produced by the Office of National Statistics, UK. The ethnic diversity reflected that of the local population where around 62.5% are from ethnic minority groups. Table 1 Baseline Socio-Demographic and Clinical Characteristics Antenatal (N = 96) Antenatal with ≥ 1 follow-up visit (N = 87) Age (years) Mean (SD) 29.6 (5.88) 29.8 (5.74) Median (Min – Max) 29 (19–45) 30 (19–45) Ethnicity, n (%) Asian 32 (33.3) 31 (35.6) Black 17 (17.7) 14 (16.1) Mixed 11 (11.5) 10 (11.5) White 36 (37.5) 32 (36.8) Marital status, n (%) Married 47 (49.0) 43 (49.4) Gestation at recruitment (days) Mean (SD) 170.0 (62.9) 171.4 (62.31) Median (Min – Max) 203.0 (51–250) 203 (51–250) Gravida 1 26 (27.1) 21 (24.1) 2 30 (31.3) 29 (33.3) 3 16 (16.7) 15 (17.2) 4 14 (14.6) 13 (14.9) >=5 10 (10.4) 9 (10.3) Missing 0 0 Parity, n (%) Multiparous 63 (65.6) 59 (67.8) Obesity Class Non-overweight 47 (49.0) 44 (50.6) Overweight 26 (27.1) 24 (27.6) Obese 23 (24.0) 19 (21.8) I 15 (15.6) 13 (14.9) II 2 (2.1) 1 (1.1) III 4 (4.2) 4 (4.6) Super-morbid 2 (2.1) 1 (1.1) Medical comorbidities, n (%) Present 21 (21.9) 19 (21.8) Asthma 5 (5.2) 5 (5.7) Sickle Cell Trait 3 (3.1) 3 (3.4) GDM 3 (3.1) 3 (3.4) Mood Disorders 3 (3.1) 3 (3.4) Index of Multiple Deprivation 1 63 (65.6) 58 (66.7) 2 14 (14.6) 13 (14.9) 3 8 (8.3) 6 (6.9) 4 7 (7.3) 6 (6.9) 5 1 (1.0) 1 (1.1) Not reported 3 (3.1) 3 (3.4) 98 women agreed to enter the study 2 were found to ineligible and so were excluded. 96 women were therefore included in the data analysis. 8 women were lost to follow up between entry into the study and the follow up visit. 1 woman suffered a miscarriage in the same period. Therefore, 87 women had 1 or more follow up visits. The 9 women withdrawn from the data set had no material impact on the data with no significant differences found between the whole group and the 87 with follow up data. Primary outcome The overall haematological response rate, (HRes), to antenatal oral iron treatment at follow up was 36.5%. For the adjusted obstetric definition, (ORes), the response rate was 55.2%. By the end of treatment, defined as 3 months following diagnosis, the HRes rate was 57.3% and for ORes 71.9%. When the rates are calculated for only the women with observed outcomes, n = 87, then the HRes is 70.5% and ORes 88.5%. [Table 2 ]. Of those who failed to respond after adjustments were made to oral iron treatment, 17 were offered intravenous iron. Table 2 Response, Remission and Retention Rates according to BCSH 2012 guidelines Outcomes Categories Post oral iron therapy follow-up (V2&V3) End of iron therapy follow-up (V5 end of treatment 3 months after the diagnosis) N Incidence 1 (95% CI) N Incidence 1 (95% CI) Overall Response HRes 2 35 36.5 (27.6–46.4) 40.2 (30.4–50.7) § 55 57.3 (47.3–66.7) 70.5 (59.8–79.7) § Ores 3 53 55.2 (45.3–64.8) 60.9 (50.4–70.7) § 69 71.9 (62.2–79.7) 88.5 (80.0–94.1) § Attrition 4 9 9.4 (5.0–16.9) 18 18.7 (12.2–27.0) Overall 34 35.4 (26.6–45.4) 39.1 (29.5–49.6) § 9 9.4 (5.0–16.0) 11.5 (6.2–20.5) § Types of Non-Response 5 Insufficient Hb increase 16 47.1 (31.1–63.5) § 0 0.0 (0.0–23.8) § No change 3 8.8 (2.5–21.7) § 0 0.0 (0.0–23.8) § Worsening 15 44.1 (28.5–60.7) § 9 100.0 (76.2–100.0) § Overall 45 46.9 (37.2–56.8) 51.7 (41.3–62.0) § 69 71.9 (62.2–79.7) 88.5 (80.0–94.1) § Remission by severity 6 of baseline Hb deficit Non-severe (n V2V3 = 54; n V5 = 47) 33 61.1 (47.8–73.3) § 39 83.0 (70.4–91.6) § Severe (n V2V3 = 33; n V5 = 31) 12 36.4 (21.6–53.4) § 30 96.8 (85.9–99.6) § Overall 87 90.6 (83.6–95.3) 78 81.3 (72.6–88.1) Retention Asian (n = 32) 31 96.9 (86.3–99.7) 29 90.6 (77.0–97.3) Black (n = 17) 14 82.4 (60.0–94.8) 14 82.4 (60.0–94.8) Mixed (n = 11) 10 90.9 (64.7–99.0) 10 90.9 (64.7–99.0) White (n = 36) 32 88.9 (75.7–96.1) 25 69.4 (53.3–82.6) 1 Incidence of response, attrition, remission and overall retention calculated based on total eligible antenatal population (N = 96). § Incidence of response, non-response and remission calculated based on participants with observed outcomes, i.e., n = 87 at V2/V3 and n = 78 at V5. 2 HRes response is defined as attainment of ≥ 10 increase in Hb from baseline. 3 ORes response is defined as attainment of ≥ 10 increase in Hb from baseline or remission, i.e., normalisation of Hb (based on trimester-specific thresholds). 4 Attrition due to loss to follow-up or miscarriage: at V2/V3, 8 were lost to follow-up and 1 miscarried; at V5, 9 more participants were lost to follow-up. 5 Non response with respect to standard definition; 34 of 87 participants (at V2/V3) and 9 of 78 (at V5) failed to respond to iron therapy. 6 Non severe baseline Hb is defined as Hb requiring < 10 g/dL units to normalise; Severe baseline Hb is defined as Hb requiring ≥ 10 g/dL to normalise The scatter plot (Fig. 2 ) shows haemoglobin of the group of women, (represented by the orange dots), who failed to increase their haemoglobin by 10g/L at visit 2, but normalized their haemoglobin based upon the gestation specific levels used for pregnancy. Their median baseline haemoglobin was higher than the group as a whole and those who demonstrated the HRes. The women who responded (HRes) to oral iron therapy had lower median levels of haemoglobin at diagnosis than those who did not respond, median Hb at baseline 95g/L versus 100g/L. After treatment, the median Hb level in the responder group (HRes) was higher than the non-responders, at V2, 113 g/L versus 103 g/L and this difference persisted throughout pregnancy. At the final assessment visit, 3 months after the original diagnosis had been made, the median Hb for those who responded to oral treatment was 122 g/L and for the non-responders 111g/L. When the ORes definition was applied then the same pattern emerged, although the median baseline haemoglobin was the same in both groups, the increase in the responders (ORes) was also maintained throughout the period of treatment and follow up and above that of non-responders. Figure 3 shows responses of haemoglobin at V2. The change in haemoglobin was compared between the baseline visit, the initial and final follow up visits. At both time points there was a significant difference in the change in haemoglobin concentration between responders and non-responders. By the final visit (V5) all women had given birth and there were no statistical differences between the responders and non-responders. Nevertheless, the maintenance of a higher haemoglobin concentration implies a greater improvement in iron stores in women who responded to oral iron. All women who met the HRes response criteria also normalized their gestationally adjusted haemoglobin concentration. Of the 37 women who did not meet the HRes definition of a response, 22 increased their haemoglobin concentration above the gestationally adjusted threshold to no longer fall into the defined criteria as being anaemic for a pregnant woman. The response rates to oral iron for both definitions have been mapped against each other and are shown in Table 3 . The pattern of changes in haemoglobin was mirrored by the changes in haematocrit (see supplementary Table 5). Table 3 The numbers of responders and non-responders by each definition showing that 41.6% of women failed to respond to treatment by either definition and 33.7% responded by both definitions. The difference in final response rates between the definitions were the 24.7% of women who normalised their Hb for the gestation of pregnancy but failed to obtain a 10g/L increase in haemoglobin concentration in the required time frame for follow up. ORes > 10g/L and/or normalisation for gestation Total HRes >10g/L only No Yes No 37 (41.6) 22 (24.7) 59 (66.3) Yes 0 (0.0) 30 (33.7) 30 (33.7) Total 37 (41.6) 52 (58.4) 89 (100.0) Other outcomes Adherence To assess adherence, we used the Ores response. Pragmatically, women who did not reach the threshold for HRes, but normalized their haemoglobin concentration for pregnancy continued their original dose rather than have it increased or be offered intravenous iron. Thus, reflecting clinical practice. Self-reported adherence was similar in both groups, with 71% of responders and 67.7% of non-responders stating they had taken their medication as instructed. Women who reported being adherent were less likely to suffer from nausea, p = 0.032. But for the other symptoms associated with iron there were no statistically significant differences between women who were adherent and those that were not. There were no differences noted for the total number of side effects (Supplementary Table 6). Ninety five percent (95%) of non-responders reported one or more side effect attributed to the medication compared to 85% of participants who were recorded as responding. Of the women who reported a high number of side effects 4 or 5 out of a possible 5, 18.6% were in the group of non- responders and 12.5% in the group of responders. The incidence of black stools in the non-responder group was 23% higher than responders to treatment. But there were no statistically significant differences between the groups for each of the side effects and for the side effects in total (Supplementary Table 7). When we examined these differences by ethnic group, we discovered that black women (women of African / Caribbean heritage) and women of mixed racial heritage were less likely to respond to treatment, OR 0.15 (ci 0.017,0.949) and OR 0.11 (ci 0.005, 0.93) respectively. There was no difference in response rates between Asian and White women OR 0.92 (ci 0.22, 3.98). The differences between the ethnic groups remained even after adjustment for side effects. We found no statistical difference between those that responded to oral iron and those that did not for general wellbeing. Modelling We used logistic regression modelling to test if these data could identify women who were more likely to respond to oral iron treatment. Model 1 using the haemoglobin at diagnosis and the variables, ethnicity, trimester at recruitment, marital status and parity had a predictive accuracy of 75%. The specificity was high at 89.8% but the sensitivity low at 42.9%. We then tested to see how much baseline laboratory data improved the predictability of the model. Using principal component analysis (PCA), two models were constructed, PC1, which included alkaline phosphatase, Albumin, Transferrin, calculated total iron binding capacity (TIBC), iron saturation and iron, and PC2, which included mean cell volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC). The laboratory models showed a marginal gain in the specificity to 92.3% but a reduction in the sensitivities to 30.8% and 34.6% (Table 4 ). The overall predictive accuracy fell slightly from 74.7% with Model 1 to 71.8% and 73% when laboratory measures were included in the models. The overall predictive accuracy was not adjusted and so the differences could be due to random chance. Table 4 Principle component models used to predict most likely to respond. Models True positive rate True negative rate Positive predictive value Negative predictive value Overall predictive accuracy** Model 1 (Baseline) n = 87 42.9 89.8 66.7 76.8 74.7 Model 2* n = 77 (Model 1 + PC1 and PC2), 44.0 88.5 64.7 76.7 74.0 Model 3 n = 78 PC1 + PC2, 30.8 92.3 66.7 72.7 71.8 Model 4 n = 78 Hb1 + PC1, 34.6 92.3 69.2 73.8 73.0 Summary of (crude) predictive ability: Model 1 Baseline = haemoglobin at diagnosis, ethnicity, trimester at recruitment, support staus, and parity. PC1 = alkaline phosphatase, albumin, transferrin, total iron binding capacity iron saturation and iron. PC2 = mean cell volume, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration. *In Model 2, Hb at recruitment was dropped because Hb is already in PC2. **Not corrected for chance We also examined the impact of socio-economic deprivation on the predictive ability of the models. Using the index of multiple deprivation (IMD), as a single measure and then each of its component parts were included in the models. There were no material changes to the results (Supplementary Table 8). Discussion We successfully followed up a cohort of women with anaemia during pregnancy in the setting of a dedicated maternity anaemia clinic and on a background of a challenging period of delivery of maternity services in the NHS during COVID19. In this study, we focused on following best practice guidance as closely as possible to evaluate the success of iron treatment for anaemia. Our study findings suggest that even after optimising the management pathway for treating iron deficiency anaemia, closely following national guidelines, a significant proportion of women identified (and labelled) as iron deficient failed to demonstrate a haematological response according to recognised criteria [ 4 , 5 ]. This study was started prior to updated guidance which promotes lower daily doses of oral iron, but we believe our findings have value as an evaluation of practice and in the context of implementing guidelines. It should also be noted that evidence for lower doses has largely been derived from studies of iron absorption in health volunteers and not pregnancy. Key findings of our study are that 1) around two thirds of affected women failed to increase their haemoglobin concentration by the criteria of 10g/L 2 to 4 weeks following the start of treatment with oral iron and educational support. Even when the definition of response to treatment was adjusted to account for the physiological changes in pregnancy, around a half of women still appeared to fail to respond to oral iron therapy. 2) Self-reported levels of adherence were similar between responders and non-responders. No significant differences for each specific side effect were identified between the two groups, although being a pragmatic study we were not specifically powered to show any differences. 4) Factors that may predict positive response to therapy suggested that haemoglobin at the time of diagnosis, ethnicity, trimester at recruitment, marital/support status and parity are positively associated with response. But the models have a low predictive ability and cannot be improved with the addition of routinely collected haematological and iron studies. Published quality improvement projects show that it is possible to improve the processes of management of iron deficiency anaemia and iron deficiency resulting in a reduction in the use of blood transfusion [ 17 , 18 ]. But they have not addressed the issue of expected response from treatment and the reasons why many women fail to respond. It is possible that non-responders may be less adherent with their medication. When we examined the side effect profile 15% of responders did not report any side effects whereas the rate was 5% for non-responders. Overall, the trend in the incidence of side effects namely, black stools, constipation, diarrhoea, heartburn, and nausea, was consistently lower among responders compared to non-responders, although the uncertainty surrounding estimates of the differences was high. It is widely reported that the troublesome gastrointestinal side effects caused by oral iron result in problems with adherence [19–22]. However, in this study, self-reported levels of adherence were similar between responders and non-responders. Those women who responded had, on average, lower levels of haemoglobin at diagnosis when compared to non-responders. Also, responders had at the follow up visit, increased their haemoglobin more significantly than the non-responders, who tended to show a much smaller increment in the level of Hb. At the end of follow up post birth, the responders still had a higher level of Hb than the non-responders. This pattern was replicated by the level of haematocrit, suggesting that the haemodilution effect seen in pregnancy was not influencing the findings. The differences between the women who responded to treatment and those who failed to respond might be accounted for in several ways. Non-responders may have been more severely affected by the side effects leading to a reduction in adherence. Although we were unable to measure the severity of the side effect profiles, these data show that the percentage reporting each side effect was consistently higher in the non-responder group. But self-reported adherence was similar between the groups. It is possible that the women who did not respond to treatment were not as iron depleted. As a group, their Hb concentration at the time of diagnosis was higher than women who did respond, a state that was mirrored in their haematocrit. This highlights the difficulties that are encountered with the diagnosis of IDA in pregnancy. The physiological haemodilution lowers the haemoglobin threshold for diagnosis in the second and third trimesters and it is possible that a group of women labelled as having IDA are in fact simply showing the normal changes of a healthy pregnancy [23]. This would be consistent with the finding that “mild anaemia” improves some obstetric outcomes [24,25]. It has been suggested that a measured ferritin level is used to improve the diagnosis. However, this approach has problems too. While ferritin is a good marker of iron stores the cut-off point in pregnancy is disputed and it is not a measure of functional iron [26–30]. Therefore, we cannot exclude the possibility that some women diagnosed with IDA are in fact iron replete and have haemoglobin concentrations lower than the gestational threshold because of the haemodilution. Attempts have been made to utilize other haematological and iron indices to improve the accuracy of the diagnosis of IDA during pregnancy and predict response [23]. Using PCA, we derived scores, combining haematological and iron biomarkers and clinical features, in our logistic regression models. None of our models reached acceptable thresholds to be recommended for clinical practice. Strengths and Limitations of the study The guidance on management of iron deficiency anaemia in pregnancy was applied in the anaemia clinic with a high level of follow-up, supporting full assessments of the rates of response and non-response. However, in addition to being a single centre evaluation, one limitation was the change in guidance for oral iron treatment during the study period. The recommendations for dosing with ferrous sulphate 200mg three times a day were changed, reducing it to 65mg (one 200mg tablet) of elemental iron per day. This was because of the finding that even one tablet of iron triggers Hepcidin release from the liver and as a result the amount of iron absorbed in subsequent oral doses is reduced [31,32]. Recent evidence also shows that alternate day compared to consecutive day dosing does not result in higher levels of ferritin but does have reduced numbers of gastrointestinal side effects [35]. It remains possible that some of our results were affected by the dosing frequency, but this has yet to be shown in clinical studies of pregnant women. Implications for practice and research In our maternity centre we adopted a model of anaemia care based on well-established pre-operative anaemia clinics, but our findings suggest this model may not support better anaemia care in maternity services. The attrition rate at the follow up visits 2 and 3 was 10%, and at the end of treatment (V5), the attrition was 20%. Since women who dropped out were automatically considered as ‘non-responders’ this means that the estimate of overall response at the end of treatment which is 57.3% is a lower bound or the worst-case scenario estimate of the proportion of responders. Further research on the value of a dedicated anemia clinic including economic impact needs to be undertaken. Research continues to be required into the diagnosis and optimal management of IDA, including the role of iv iron, so that future guidelines and their recommendations can be made with a stronger evidence base [34]. Declarations Ethics approval and consent to participate. Ethics approval was granted by the West Midlands – Black Country Ethics committee. Ref number 18/WM/0090. All participants provided informed consent to participate in the study in writing using the ethically approved consent form. Consent for publication. Not applicable. Availability of data and materials. Data is provided with the manuscript or supplementary information files. All source dta can be obtained by request from the corresponding author. Competing Interests. D Churchill was formerly a member of the Multi-disciplinary Iron Deficiency Anaemia Steering (MIDAS) committee supported by Pharmacosmos. All other authors do not have any competing interests. Author contributions: D Churchill designed the project over saw its execution analysed the data and authored the manuscript prior to comments from the study team. S Stanworth assisted with the design of the project, analysis of the data and co-wrote the final draft of the paper. H Ali and M Moussa assisted with the design of the project, recruited, and collected data and commented on the final draft of the paper. D Bautista carried out the statistical analysis while working at NHS Blood and Transplant and co-authored the final draft of the paper. S Sweity coordinated the study set up assisted with the study design and co-authored the final paper, L Devison and J Icke assisted with recruitment, data collection and co-authored the final draft of the paper. Funding: The project was supported by a grant from the Rotha Abraham Trust a charitable fund at New Cross Hospital, Wolverhampton. Acknowledgements : Rotha Abraham Charitable Trust for funding the project. Study numbers IRAS 244013 ISRCTN 13007439 ORCID: David Churchill - https://orcid.org/0000-0003-0548-2953 Simon J Stanworth - https://orcid.org/0000-0002-7414-4950 References Royal College of Obstetricians and Gynaecologists. Blood Transfusions in Obstetrics. Green-top Guideline No. 47. 2015. Available from: https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/blood-transfusions-in-obstetrics-green-top-guideline-no-47/ National Institute for Health and Care Excellence. Antenatal Care. NICE guideline [NG201]. Available from: https://www.nice.org.uk/guidance/ng201 World Health Organization. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Available from: https://www.who.int/publications/i/item/WHO-NMH-NHD-MNM-11.1 Pavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2012;156(5):588-600. Pavord S, Daru J, Prasannan N, Robinson S, Stanworth SJ, Girling J, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2020;188(6):819-830. Churchill D, Ali H, Moussa M, Donohue C, Pavord S, Robinson SE, et al. Maternal iron deficiency anaemia in pregnancy: Lessions from a national audit. Br J Haematol. 2022;199(2):277-284. Nair M, Churchill D, Robinson S, Nelson-Piercy C, Stanworth SJ, Knight M. Association between maternal haemoglobin and stillbirth: a cohort study among a multi-ethnic population in England. Br J Haematol. 2017;179(5):829-837. Nair M, Choudhury MK, Choudhury SS, Kakoty SD, Sarma UC, Webster P, et al. Association between maternal anaemia and pregnancy outcomes: a cohort study in Assam, India. BMJ Glob Health. 2016;1(1):e000026. Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ. 2013;21;346:f3443. Huifeng S, Chen L, Wang Y, Sun M, Guo Y, Ma S, et al. Severity of Anaemia during pregnancy and adverse maternal and fetal outcomes. JAMA Netw Open, 2022; 5(2):e2147046. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol 2006;13(3):158-165. Lukowski AF, Koss M, Burden MJ, Jonides J, Nelson CA, Kaciroti N, et al. Iron deficiency in infancy and neurocognitive functioning at 19 years: Evidence of long term deficits in executive function and recognition memory. Nutr Neurosci 2010,13(2):54-70. McCann JC, Ames BN. An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioural function. Am J Clin Nutr 2007;85(4);931-945. Foxcroft KF, Calloway LK, Byrne NM, Webster J. Development and validation of a pregnancy symptoms inventory. BMC Pregnancy Childbirth 2013;13:3. Pereira DAI, Couto Irving SS, Lomer MCE, Powell JJ. A rapid, simple questionnaire to assess gastrointestinal symptoms after oral ferrous sulphate supplementation. BMC Gastroenterology 2014;14:103. Alderdice F, McNeill J, Gargan P, Oliver P. Preliminary evaluation of the Well-being in Pregnancy (WiP) questionnaire. J Psychosom Obstet Gynaecol. 2017;38(2):133-142. Abdulrehman J, Lausman A, Tang GH, Nisenbaum R, Petrucci J, Pavenski K, et al. Development and implementation of a quality improvement toolkit, iron deficiency in pregnancy with maternal iron optimization (IRON MOM): A before-and-after study. PLoS Med. 2019;16(8):e1002867. Flores CJ, Sethna F, Stephens B, Saxon B, Hong FS, Roberts T, et al. Improving patient blood management in obstetrics: snapshots of a practice improvement partnership. BMJ Qual Improv Rep. 2017; 23;6(1):e000009. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843. Pena-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;2015(7):CD004736. Hyder SM, Persson LA, Chowdhury AM, Ekström EC. Do side-effects reduce compliance to iron supplementation? A study of daily-and weekly-dose regimens in pregnancy. J Health Popul Nutr. 2002;20(2):175-179. Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. Am J Nutr. 2003;78(1):145-153. Bresani CC, Braga MC, Felisberto DF, Tavares-de-Melo CE, Salvi DB, Batista-Filho M. Accuracy of erythrogram and serum ferritin for the maternal anemia diagnosis (AMA): a phase 3 diagnostic study on prediction of the therapeutic responsiveness to oral iron in pregnancy. BMC Pregnancy Childbirth. 2013;13:13. Steer P, Alam MA, Wadsworth J, Welch A. Relation between maternal haemoglobin concentration and birth weight in different ethnic groups. BMJ. 1995;310:489-491. Dewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017;106(Suppl 6):1694S-1702S. van den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in pregnant women: which measurements are valid? Br J Haematol. 1998;103(3):817-824. Volpi E, De Grandis T, Alba E, Mangione M, Dall’Amico D, Bollati C. [Variations in ferritin levels in blood during physiological pregnancy] Minerva Ginecol. 1991;43(9):387-391. Milman N: Iron and pregnancy - a delicate balance. Ann Hematol. 2006;85:559-565. World Health Organization. Iron deficiency anaemia: assessment, prevention and control. A guide for program managers. 2001. Available from: https://www.who.int/publications/m/item/iron-children-6to23--archived-iron-deficiency-anaemia-assessment-prevention-and-control Nair M, Choudhury SS, Rani A, V. SC, Kakoty SD, Medhi R, Rao S, Mahanta P, Zahir F, Roy I, Chhabra S, Deka G, Minz, B, Deka R, Opondo C, Churchill D, Lakhal-Littleton S, Nemeth E, on behalf of the MaatHRI coolaboration. American Journal of Haematology. 2023; 98:1721-1731. Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126(17):1981-1989. Shinar,S. Skornick-Rapaport,A, Maslovitz S. Iron supplementation in singleton pregnancy: is there a benefit to doubling the dose of elemental iron in iron-deficient pregnant women? A randomized controlled trial. J Perinatol. 2017;37(7):782-786. Stoffel NU, Zeder C, Brittenham GM, Moretti D, Zimmerman MB. Iron absorption from supplements is greater with alternate day dosing in iron deficiency anaemic women. Haematologica. 2020;105(5):1232-1239. Shand AW. Iron preparations for iron deficiency anaemia in pregnancy: which treatment is best? Lancet Haematol. 2021;8(7):e471-e472. von Siebenthal HK, Nessler S, Vallelian F, Steinwender J, Kuenzi U-M, Moretti D, et al. Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomised double-blind placebo-controlled study. EClinicalMedicine. 2023;65:102286. Roberts I, Phyllis Jones C. Structural racism and iron deficiency anaemia. Lancet. 2023;402(10405):834-835. Additional Declarations Competing interest reported. Competing Interests. D Churchill was formerly a member of the Multi-disciplinary Iron Deficiency Anaemia Steering (MIDAS) committee supported by Pharmacosmos. All other authors do not have any competing interests. Supplementary Files TIAPsupplementaryTable5HBandHctchanges.docx TIAPsupplementaryTable6sideeffects.docx TIAPsupplementaryTable7sideeffectsby.docx TIAPsupplementaryTable8PCA.docx Cite Share Download PDF Status: Published Journal Publication published 19 Aug, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted Editorial decision: Revision requested 20 Aug, 2024 Reviews received at journal 15 Aug, 2024 Reviewers agreed at journal 01 Aug, 2024 Reviews received at journal 29 Jul, 2024 Reviewers agreed at journal 25 Jul, 2024 Reviews received at journal 08 Mar, 2024 Reviewers agreed at journal 26 Feb, 2024 Reviewers invited by journal 16 Feb, 2024 Editor assigned by journal 16 Feb, 2024 Editor invited by journal 15 Feb, 2024 Submission checks completed at journal 15 Feb, 2024 First submitted to journal 06 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3933791","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":272960382,"identity":"5c23ec3f-94ff-44e8-b161-5a8e0c0d8d63","order_by":0,"name":"David Churchill","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIie3OMWvCQBTA8XcUMh1mfQd+iCeB1CHEr5IjkCkUwcWpCIXbdK7gh3B0PMngcuga0EEoZHKIW7c2tUVQOMWtw/254Tjux3sALtd/TDeHAyTN1YOk3+U+8IcIYVuMfgneInAmQBiRvkNaK9PRB4hfaFtU+z0hD7bjomaL6NVGhMlpOYN0QOvsmZrFeLhbZ8hMZp1COksKDlrODffwRMo8BKYKO9lUVyR4z4OaqS87KVN9SQhzQqa0lYjyQy9nlMqp8cITwWYxlCoVIwtpbeRbfRjGcmKeKvE5jHr+z2JHFfu2KX/rXT8kt/+7XC6X607f+nBVu9otPCwAAAAASUVORK5CYII=","orcid":"","institution":"The Royal Wolverhampton Hospital NHS Trust, New Cross Hospital","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"","lastName":"Churchill","suffix":""},{"id":272960383,"identity":"58209522-71ab-4292-a6b6-77552418cc39","order_by":1,"name":"Hind Ali","email":"","orcid":"","institution":"The Royal Wolverhampton Hospital NHS Trust, New Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hind","middleName":"","lastName":"Ali","suffix":""},{"id":272960384,"identity":"995c865f-9955-402c-b173-6f4948577e58","order_by":2,"name":"Samaher Sweity","email":"","orcid":"","institution":"NHS Blood and Transplant","correspondingAuthor":false,"prefix":"","firstName":"Samaher","middleName":"","lastName":"Sweity","suffix":""},{"id":272960385,"identity":"147d09b7-742c-4211-88dc-edc98c332804","order_by":3,"name":"Dianne Bautista","email":"","orcid":"","institution":"NHS Blood and Transplant","correspondingAuthor":false,"prefix":"","firstName":"Dianne","middleName":"","lastName":"Bautista","suffix":""},{"id":272960386,"identity":"f4e0ef75-32cb-4578-8634-27705703e7b6","order_by":4,"name":"Mahmoud Moussa","email":"","orcid":"","institution":"Great Western Hospitals NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Mahmoud","middleName":"","lastName":"Moussa","suffix":""},{"id":272960387,"identity":"76bdb448-3130-46e7-86e1-13eaac650e93","order_by":5,"name":"Laura Devison","email":"","orcid":"","institution":"The Royal Wolverhampton Hospital NHS Trust, New Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Devison","suffix":""},{"id":272960388,"identity":"9f3b7489-e79e-45f8-bff9-eb39a2448003","order_by":6,"name":"Julie Icke","email":"","orcid":"","institution":"The Royal Wolverhampton Hospital NHS Trust, New Cross Hospital","correspondingAuthor":false,"prefix":"","firstName":"Julie","middleName":"","lastName":"Icke","suffix":""},{"id":272960389,"identity":"71791844-d758-49f3-9808-9912463251e3","order_by":7,"name":"Simon J Stanworth","email":"","orcid":"","institution":"NHS Blood and Transplant","correspondingAuthor":false,"prefix":"","firstName":"Simon","middleName":"J","lastName":"Stanworth","suffix":""}],"badges":[],"createdAt":"2024-02-06 12:14:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3933791/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3933791/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12884-025-07938-w","type":"published","date":"2025-08-19T16:12:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51234672,"identity":"f4d96080-6b51-44e7-aad8-60795366a7e3","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1011418,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant Flowchart\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/17b1b3039dd5c59c52f520ab.jpeg"},{"id":51234669,"identity":"6e966ff9-26f8-48fd-b659-e8349a932f35","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":369168,"visible":true,"origin":"","legend":"\u003cp\u003eA scatter plot of haemoglobin at diagnosis by response haemoglobin at the follow up visit. The orange dots represent the women who became responders when the ORes definition was used.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/7a691092d320ad17ca8c638c.jpeg"},{"id":51234671,"identity":"ac73fdf0-57c2-4448-8810-fd8ba1caae94","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":274707,"visible":true,"origin":"","legend":"\u003cp\u003eChange in haemoglobin concentration from baseline to visit 2 and then 5, the end of the study separated by response by both the HRes and ORes definitions of response.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/171f4a6bc9a0dd2749b02899.jpeg"},{"id":89847122,"identity":"59555892-95be-4032-b293-cee03a364f4c","added_by":"auto","created_at":"2025-08-25 16:40:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2669032,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/6cd26105-42c0-45b7-965b-2df75d9b5698.pdf"},{"id":51234670,"identity":"6332e926-2fe6-4ab0-a54e-6e515537290d","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":22728,"visible":true,"origin":"","legend":"","description":"","filename":"TIAPsupplementaryTable5HBandHctchanges.docx","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/ba88172a3560efb693f8a909.docx"},{"id":51234673,"identity":"c860fa1d-bdba-4a3d-a2aa-039e5567a13e","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":20195,"visible":true,"origin":"","legend":"","description":"","filename":"TIAPsupplementaryTable6sideeffects.docx","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/db48709df53ae96948e2426c.docx"},{"id":51235036,"identity":"e89d6384-8921-4360-b9e5-eea5d4c06497","added_by":"auto","created_at":"2024-02-16 16:10:57","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":22982,"visible":true,"origin":"","legend":"","description":"","filename":"TIAPsupplementaryTable7sideeffectsby.docx","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/76c8e2812e72449cbef96ab4.docx"},{"id":51234674,"identity":"54b8b29d-78b2-4a8f-8fa5-9e7094e11226","added_by":"auto","created_at":"2024-02-16 16:02:57","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":21710,"visible":true,"origin":"","legend":"","description":"","filename":"TIAPsupplementaryTable8PCA.docx","url":"https://assets-eu.researchsquare.com/files/rs-3933791/v1/cbd68b84aaf71a66b808a8d2.docx"}],"financialInterests":"Competing interest reported. Competing Interests. D Churchill was formerly a member of the Multi-disciplinary Iron Deficiency Anaemia Steering (MIDAS) committee supported by Pharmacosmos. \nAll other authors do not have any competing interests.","formattedTitle":"Treatment of Iron Deficiency Anaemmia in Pregnancy Study. The Clinical Impact of Treatment for Iron Deficiency Anaemia using an Optimized Care Pathway in accordance with national guidelines","fulltext":[{"header":"Background","content":"\u003cp\u003eCurrent approaches to address the on-going high burden of anaemia during pregnancy, caused by iron deficiency, have been described in mutliple guidelines, including a recently updated British Society for Haematology guideline [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Timely recognition and treatment of iron deficiency anaemia (IDA) during pregnancy is recommended, given that the reported risks associated with anaemia for the mother and infant, include stillbirth and neonatal death [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In the first and second trimesters, IDA has also been correlated with low birth weight and pre-term birth, both of which lead to significant morbidity lasting into infancy and sometimes adult life [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, our recent nationwide prospective audit reported a high incidence of anaemia at 30% during pregnancy and 20% post-delivery [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This suggests on-going challenges with implementation, despite the presence of clear standards of care through guidelines. The increased demand for iron in pregnancy is driven by the expanded blood volume of the mother and the requirements of the developing fetus and placenta.\u003c/p\u003e \u003cp\u003e The aim of this study was to report our findings for women seen in the clinic, to assess the effectiveness of guideline recommendations and describe the natural history of iron deficiency anaemia in pregnancy when adopting the guidance on treatment.\u003c/p\u003e \u003cp\u003eSpecific study objectives were to:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003edescribe haematological and clinical responses to iron treatment, including an assessment of side effects and adherence,\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eexplore the effect of demographic, clinical and laboratory variables in predicting response to treatment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis prospective, single centre, cohort study recruited pregnant women with iron deficiency anaemia. Women who consented to participate were offered support, treatment, and follow-up through a dedicated anaemia research clinic. Eligible participants with IDA were identified in two ways; 1) those diagnosed de novo in the hospital antenatal and/or community clinics and antenatal maternity ward or 2) from a daily download of blood results of routine screening samples taken either at the first trimester or the 28th week gestation antenatal visit. Eligible women were approached by the research staff and given information about the project, prior to seeking consent. The diagnostic thresholds of anaemia were defined by the criteria described in British Society Haematology (BSH) guidelines and by the World Health Organization, which are gestationally adjusted haemoglobin thresholds of: first trimester\u0026thinsp;\u0026lt;\u0026thinsp;110g/L, second and third trimester\u0026thinsp;\u0026lt;\u0026thinsp;105g/L, and postpartum\u0026thinsp;\u0026lt;\u0026thinsp;100g/L.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSample Participants\u003c/h2\u003e \u003cp\u003eInclusion criterion was any pregnant women aged between 18 and 45 years with a diagnosis of IDA up to 35 weeks\u0026rsquo; plus 6 days gestation.\u003c/p\u003e \u003cp\u003eExclusion criteria were:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ewomen presenting at or after 36 weeks, as it was judged that there could be insufficient time between diagnosis and the end of pregnancy to complete assessments,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ea diagnosis of a major haemoglobinopathy (women with a trait were not excluded)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003esigns of sepsis;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eallergies to iron;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ewomen with\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ehyperemesis gravidarum / persistent vomiting or\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003einflammatory conditions such as\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eCrohn\u0026rsquo;s, ulcerative colitis,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003esystemic lupus erythematosus,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003erheumatoid arthritis; and\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ewomen with chronic renal failure.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eThis was a non-interventional study, and clinical management of IDA followed recommendations detailed in national guidelines [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] adopted into local guidance documents. To attempt better practice for anaemia management in pregnancy, we introduced a dedicated anaemia research clinic, modelled on the pre-operative anaemia clinic services, as advocated nationally e.g. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://hospital.blood.co.uk/patient-services/patient-blood-management/pre-operative-anaemia\u003c/span\u003e\u003cspan address=\"https://hospital.blood.co.uk/patient-services/patient-blood-management/pre-operative-anaemia\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Women identified as anaemic were offered the option of management and follow-up through this clinic, supported by a research fellow and consultant obstetrician. The study started when earlier BSH guidance was in place, which recommended daily iron dose of 100-200mg elemental iron per day; prescribed as 200mg ferrous sulphate three times a day (65mg elemental iron per tablet x 3\u0026thinsp;=\u0026thinsp;195mg).\u003c/p\u003e \u003cp\u003eAll women were offered a full blood count (FBC) to screen for IDA usually 8\u0026ndash;12 weeks\u0026rsquo; gestation and then 28 weeks\u0026rsquo; according to standard practice [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Women who consented to participate were started on oral iron no longer than 14 days from the point of diagnosis (Visit 1). Enrolled women were given verbal instructions, and written information on the correct way to take the tablets to maximise absorption.\u003c/p\u003e \u003cp\u003eWomen were asked to return for a follow up visit, between 2 and 4 weeks after initiating treatment, when a peripheral blood count was taken to assess the therapeutic response and assessments were made of side effects and adherence (Visit 2). The variation in follow up visits was to coincide with a woman\u0026rsquo;s obstetric appointments. Iron has a marketing authorisation (MA) in the UK and is being used in this study in its marketed presentation and packaging bearing the MA number.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eNon-response to therapy\u003c/h2\u003e \u003cp\u003eParticipants who didn\u0026rsquo;t have the expected rise in haemoglobin of 10g/L minimum, at Visit 2, were classified as non-responders and the reasons for not responding were explored with these women. If the non-response was due to side effects a modified regimen of twice daily iron administration was implemented along with further advice on how best to consume iron, symptomatic treatment for side effects was also given where necessary, e.g. laxative for constipation. Blood samples were also taken for vitamin B12 and folic acid estimation. Women were asked to continue with the modified treatment regimen and continue recording in their treatment diary. They were reviewed in a further 2 weeks (Visit 3), when the same process as in Visit 2 was followed. Women who had increased their haemoglobin into the normal range for pregnancy were maintained on oral iron. As per routine practice, women who continued to be non-responders, when assessed at visit 3, were offered intravenous iron to treat their anaemia.\u003c/p\u003e \u003cp\u003e Women, whose anaemia worsened between any of the visits, were offered intravenous iron as per standard care in local guidelines. All women who received intravenous iron were also asked to return to the clinic after a further 2 weeks for repeat blood sampling (including research blood samples) to ensure that they responded to treatment. Therefore, the total number of visits for each participant was dependent upon their clinical need according to the guidance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003e Baseline demographic, clinical and laboratory data were collected from the patient care record and laboratory information systems. Additional data were collected at each visit, and obstetric outcome data collected at the postnatal follow up visit 6 weeks after birth.\u003c/p\u003e \u003cp\u003eAt each visit, the frequency and severity of symptoms experienced by the participant and associated with IDA was assessed using an adapted version of a published pregnancy symptomatology tool [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The frequency of side effects was assessed by examining the pre-piloted tolerability and symptom tool adapted from a questionnaire developed to assess gastrointestinal symptoms after oral ferrous sulphate supplementation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Finally, participants were asked to complete a Well-being in Pregnancy (WiP) questionnaire [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eParticipants were also requested to keep a diary, recording the time at which they took their medication, the symptoms of anaemia experienced at the time and the side effects suffered since the last tablet was taken. The completed diary was returned at the follow up visits and supplemented the information gathered through questionnaires on adherence and side effects/symptoms suffered since the preceding visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBlood sampling\u003c/h2\u003e \u003cp\u003eRoutine blood samples were collected at baseline and follow up visits (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) for a peripheral venous blood count, iron studies and general biochemistry. An additional sample of blood was taken, processed, and stored at -80 degrees Celsius, for more specialist iron and inflammatory biomarker studies and will be the subject of a separate report.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe Primary outcome measure was the proportion of women with physiological recovery from anaemia defined as an increase in Hb by \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;10 g/L, 2-4weeks after the start of treatment. This was classified as a haematological response (HRes).\u003c/p\u003e \u003cp\u003eThe secondary outcome measures were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAn alternative obstetric definition of response (ORes), which was either an HRes and/or the normalization of the haemoglobin concentration, adjusted for gestational age. This was to recognize that the physiological changes of pregnancy result in haemodilution and thus a fall in the concentration of haemoglobin across gestation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ethe longitudinal changes in haemoglobin, red cell indices, iron, transferrin, ferritin, CRP.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ethe change in frequency and severity of symptoms associated with anaemia in pregnancy and assessed by the pregnancy symptomatology questionnaire [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e],\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ethe frequency and severity of side effects induced by iron therapy by an adapted published tolerability tool [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and general wellbeing [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eSample size\u003c/p\u003e \u003cp\u003eAs this was an exploratory cohort study and did not involve a novel intervention, we did not perform a sample size calculation and pragmatically proposed to recruit 120 women. This number was based on estimated numbers of anaemic women seen in the antenatal clinics and wards during the study and to support secondary and exploratory analyses to meet the objectives.\u003c/p\u003e \u003cp\u003eDifferences between responders and non-responders were explored by comparing baseline demographic data, haematological, and iron parameters. Distributions of haematological and iron parameters between responders and non-responders at V2 and V5 were compared and checked for equality using the Mann-Whitney U test. Statistical significance was defined as a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eThe primary outcome HRes was described as a percentage for the group. These data were also interrogated using the adjusted definition of response ORes, a secondary outcome described above. To calculate the response rate to oral treatment the results for visit 2 \u0026amp; 3 were combined and are shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. This was to mimic normal practice, which was to explore adherence and adjust the treatment plan before abandoning oral treatment.\u003c/p\u003e \u003cp\u003eCategorical variables were summarized using percentages and quantitative variables were summarized using mean, standard deviation, median, interquartile range.\u003c/p\u003e \u003cp\u003eThe proportion of women achieving HRes and ORes were estimated using the observed sample proportion and 95% confidence intervals were calculated using the Wilson-Score Method. Women who dropped out at V2 or V5 were considered as non-responders.\u003c/p\u003e \u003cp\u003eLogistic regression models were explored to identify predictors of HRes from the set of baseline demographic (index of deprivation quintile, ethnicity, marital status), obstetric (parity, trimester of recruitment), and routinely collected haematological and iron indices. Principal component analyses were further utilized to derive scores representing combinations of haematological and iron indices. Positive and negative predictive values were obtained to assess the predictive utility of the model and positive predictive values of at least 75% were considered useful for practice.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using statistical analysis software (SAS/STAT, Version 9 of the SAS System for Windows, SAS Institute, Inc., Cary, NC).\u003c/p\u003e \u003cp\u003e The report has been prepared using the STROBE guidelines for reporting observational cohort studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eBaseline Socio-Demographic and Clinical Characteristics\u003c/h2\u003e\n \u003cp\u003eThe flow diagram (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) shows the number of individuals at each stage of the study and the reasons for withdrawal.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003cp\u003eThe characteristics of enrolled pregnant women is shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and was representative of the general maternity population served by the hospital located in a central urban environment. Their mean age was 29.6 years and the proportions for body mass index and socio-economic deprivation were as expected, with 65.6% of the population being in the most deprived quintile when measured by the index of multiple deprivation score produced by the Office of National Statistics, UK. The ethnic diversity reflected that of the local population where around 62.5% are from ethnic minority groups.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Socio-Demographic and Clinical Characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAntenatal\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAntenatal with \u0026ge;\u0026thinsp;1 follow-up visit\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.6 (5.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.8 (5.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (Min \u0026ndash; Max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (19\u0026ndash;45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (19\u0026ndash;45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eEthnicity, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlack\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (17.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (16.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMixed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMarital status, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMarried\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (49.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (49.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eGestation at recruitment (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e170.0 (62.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e171.4 (62.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (Min \u0026ndash; Max)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e203.0 (51\u0026ndash;250)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e203 (51\u0026ndash;250)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGravida\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (31.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParity, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiparous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (65.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObesity Class\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-overweight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (49.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44 (50.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverweight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (27.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (24.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuper-morbid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedical comorbidities, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (21.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSickle Cell Trait\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGDM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMood Disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIndex of Multiple Deprivation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (65.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot reported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e98 women agreed to enter the study 2 were found to ineligible and so were excluded. 96 women were therefore included in the data analysis. 8 women were lost to follow up between entry into the study and the follow up visit. 1 woman suffered a miscarriage in the same period.\u003c/p\u003e\n \u003cp\u003eTherefore, 87 women had 1 or more follow up visits. The 9 women withdrawn from the data set had no material impact on the data with no significant differences found between the whole group and the 87 with follow up data.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary outcome\u003c/h2\u003e\n \u003cp\u003eThe overall haematological response rate, (HRes), to antenatal oral iron treatment at follow up was 36.5%. For the adjusted obstetric definition, (ORes), the response rate was 55.2%. By the end of treatment, defined as 3 months following diagnosis, the HRes rate was 57.3% and for ORes 71.9%. When the rates are calculated for only the women with observed outcomes, n\u0026thinsp;=\u0026thinsp;87, then the HRes is 70.5% and ORes 88.5%. [Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e]. Of those who failed to respond after adjustments were made to oral iron treatment, 17 were offered intravenous iron.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResponse, Remission and Retention Rates according to BCSH 2012 guidelines\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eCategories\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003ePost oral iron therapy follow-up (V2\u0026amp;V3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eEnd of iron therapy follow-up (V5 end of treatment 3 months after the diagnosis)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIncidence \u003csup\u003e1\u003c/sup\u003e (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIncidence \u003csup\u003e1\u003c/sup\u003e (95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eOverall Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHRes\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e36.5 (27.6\u0026ndash;46.4)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e40.2 (30.4\u0026ndash;50.7) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e57.3 (47.3\u0026ndash;66.7)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e70.5 (59.8\u0026ndash;79.7) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOres\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e55.2 (45.3\u0026ndash;64.8)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e60.9 (50.4\u0026ndash;70.7) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e71.9 (62.2\u0026ndash;79.7)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e88.5 (80.0\u0026ndash;94.1) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttrition \u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.4 (5.0\u0026ndash;16.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18.7 (12.2\u0026ndash;27.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e35.4 (26.6\u0026ndash;45.4)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e39.1 (29.5\u0026ndash;49.6) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e9.4 (5.0\u0026ndash;16.0)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e11.5 (6.2\u0026ndash;20.5) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eTypes of Non-Response \u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsufficient Hb increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47.1 (31.1\u0026ndash;63.5) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0 (0.0\u0026ndash;23.8) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.8 (2.5\u0026ndash;21.7) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0 (0.0\u0026ndash;23.8) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorsening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.1 (28.5\u0026ndash;60.7) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100.0 (76.2\u0026ndash;100.0) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e46.9 (37.2\u0026ndash;56.8)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e51.7 (41.3\u0026ndash;62.0) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e71.9 (62.2\u0026ndash;79.7)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e88.5 (80.0\u0026ndash;94.1) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" align=\"left\"\u003e\n \u003cp\u003eRemission by severity \u003csup\u003e6\u003c/sup\u003e of baseline Hb deficit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-severe (n\u003csub\u003eV2V3\u003c/sub\u003e= 54; n\u003csub\u003eV5\u003c/sub\u003e = 47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.1 (47.8\u0026ndash;73.3) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83.0 (70.4\u0026ndash;91.6) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere (n\u003csub\u003eV2V3\u003c/sub\u003e = 33; n\u003csub\u003eV5\u003c/sub\u003e = 31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36.4 (21.6\u0026ndash;53.4) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.8 (85.9\u0026ndash;99.6) \u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e90.6 (83.6\u0026ndash;95.3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e81.3 (72.6\u0026ndash;88.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eRetention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsian (n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96.9 (86.3\u0026ndash;99.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.6 (77.0\u0026ndash;97.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlack (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.4 (60.0\u0026ndash;94.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.4 (60.0\u0026ndash;94.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMixed (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.9 (64.7\u0026ndash;99.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.9 (64.7\u0026ndash;99.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite (n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.9 (75.7\u0026ndash;96.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69.4 (53.3\u0026ndash;82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Incidence of response, attrition, remission and overall retention calculated based on total eligible antenatal population (N\u0026thinsp;=\u0026thinsp;96).\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e Incidence of response, non-response and remission calculated based on participants with observed outcomes, i.e., n\u0026thinsp;=\u0026thinsp;87 at V2/V3 and n\u0026thinsp;=\u0026thinsp;78 at V5.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003e HRes response is defined as attainment of \u0026ge;\u0026thinsp;10 increase in Hb from baseline.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003e ORes response is defined as attainment of \u0026ge;\u0026thinsp;10 increase in Hb from baseline or remission, i.e., normalisation of Hb (based on trimester-specific thresholds).\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003e Attrition due to loss to follow-up or miscarriage: at V2/V3, 8 were lost to follow-up and 1 miscarried; at V5, 9 more participants were lost to follow-up.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e5\u003c/sup\u003e Non response with respect to standard definition; 34 of 87 participants (at V2/V3) and 9 of 78 (at V5) failed to respond to iron therapy.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e6\u003c/sup\u003e Non severe baseline Hb is defined as Hb requiring\u0026thinsp;\u0026lt;\u0026thinsp;10 g/dL units to normalise; Severe baseline Hb is defined as Hb requiring\u0026thinsp;\u0026ge;\u0026thinsp;10 g/dL to normalise\u003c/p\u003e\n \u003cp\u003eThe scatter plot (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) shows haemoglobin of the group of women, (represented by the orange dots), who failed to increase their haemoglobin by 10g/L at visit 2, but normalized their haemoglobin based upon the gestation specific levels used for pregnancy. Their median baseline haemoglobin was higher than the group as a whole and those who demonstrated the HRes.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003cp\u003eThe women who responded (HRes) to oral iron therapy had lower median levels of haemoglobin at diagnosis than those who did not respond, median Hb at baseline 95g/L versus 100g/L. After treatment, the median Hb level in the responder group (HRes) was higher than the non-responders, at V2, 113 g/L versus 103 g/L and this difference persisted throughout pregnancy. At the final assessment visit, 3 months after the original diagnosis had been made, the median Hb for those who responded to oral treatment was 122 g/L and for the non-responders 111g/L. When the ORes definition was applied then the same pattern emerged, although the median baseline haemoglobin was the same in both groups, the increase in the responders (ORes) was also maintained throughout the period of treatment and follow up and above that of non-responders. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows responses of haemoglobin at V2. The change in haemoglobin was compared between the baseline visit, the initial and final follow up visits. At both time points there was a significant difference in the change in haemoglobin concentration between responders and non-responders. By the final visit (V5) all women had given birth and there were no statistical differences between the responders and non-responders. Nevertheless, the maintenance of a higher haemoglobin concentration implies a greater improvement in iron stores in women who responded to oral iron.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003cp\u003eAll women who met the HRes response criteria also normalized their gestationally adjusted haemoglobin concentration. Of the 37 women who did not meet the HRes definition of a response, 22 increased their haemoglobin concentration above the gestationally adjusted threshold to no longer fall into the defined criteria as being anaemic for a pregnant woman. The response rates to oral iron for both definitions have been mapped against each other and are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. The pattern of changes in haemoglobin was mirrored by the changes in haematocrit (see supplementary Table\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe numbers of responders and non-responders by each definition showing that 41.6% of women failed to respond to treatment by either definition and 33.7% responded by both definitions. The difference in final response rates between the definitions were the 24.7% of women who normalised their Hb for the gestation of pregnancy but failed to obtain a 10g/L increase in haemoglobin concentration in the required time frame for follow up.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth colspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eORes\u003c/p\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;10g/L and/or normalisation for gestation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth rowspan=\"2\" align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHRes \u0026gt;10g/L only\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37 (41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22 (24.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59 (66.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (33.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37 (41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52 (58.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eOther outcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\n \u003ch2\u003eAdherence\u003c/h2\u003e\n \u003cp\u003eTo assess adherence, we used the Ores response. Pragmatically, women who did not reach the threshold for HRes, but normalized their haemoglobin concentration for pregnancy continued their original dose rather than have it increased or be offered intravenous iron. Thus, reflecting clinical practice. Self-reported adherence was similar in both groups, with 71% of responders and 67.7% of non-responders stating they had taken their medication as instructed. Women who reported being adherent were less likely to suffer from nausea, p\u0026thinsp;=\u0026thinsp;0.032. But for the other symptoms associated with iron there were no statistically significant differences between women who were adherent and those that were not. There were no differences noted for the total number of side effects (Supplementary Table\u0026nbsp;6).\u003c/p\u003e\n \u003cp\u003eNinety five percent (95%) of non-responders reported one or more side effect attributed to the medication compared to 85% of participants who were recorded as responding. Of the women who reported a high number of side effects 4 or 5 out of a possible 5, 18.6% were in the group of non- responders and 12.5% in the group of responders. The incidence of black stools in the non-responder group was 23% higher than responders to treatment. But there were no statistically significant differences between the groups for each of the side effects and for the side effects in total (Supplementary Table\u0026nbsp;7).\u003c/p\u003e\n \u003cp\u003eWhen we examined these differences by ethnic group, we discovered that black women (women of African / Caribbean heritage) and women of mixed racial heritage were less likely to respond to treatment, OR 0.15 (ci 0.017,0.949) and OR 0.11 (ci 0.005, 0.93) respectively. There was no difference in response rates between Asian and White women OR 0.92 (ci 0.22, 3.98). The differences between the ethnic groups remained even after adjustment for side effects.\u003c/p\u003e\n \u003cp\u003eWe found no statistical difference between those that responded to oral iron and those that did not for general wellbeing.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eModelling\u003c/h2\u003e\n \u003cp\u003eWe used logistic regression modelling to test if these data could identify women who were more likely to respond to oral iron treatment. Model 1 using the haemoglobin at diagnosis and the variables, ethnicity, trimester at recruitment, marital status and parity had a predictive accuracy of 75%. The specificity was high at 89.8% but the sensitivity low at 42.9%. We then tested to see how much baseline laboratory data improved the predictability of the model. Using principal component analysis (PCA), two models were constructed, PC1, which included alkaline phosphatase, Albumin, Transferrin, calculated total iron binding capacity (TIBC), iron saturation and iron, and PC2, which included mean cell volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC). The laboratory models showed a marginal gain in the specificity to 92.3% but a reduction in the sensitivities to 30.8% and 34.6% (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe overall predictive accuracy fell slightly from 74.7% with Model 1 to 71.8% and 73% when laboratory measures were included in the models. The overall predictive accuracy was not adjusted and so the differences could be due to random chance.\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePrinciple component models used to predict most likely to respond.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eModels\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTrue positive rate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTrue negative rate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePositive predictive value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNegative predictive value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOverall predictive accuracy**\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModel 1 (Baseline) n\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e74.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModel 2* n\u0026thinsp;=\u0026thinsp;77\u003c/p\u003e\n \u003cp\u003e(Model 1\u0026thinsp;+\u0026thinsp;PC1 and PC2),\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e88.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e74.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModel 3 n\u0026thinsp;=\u0026thinsp;78\u003c/p\u003e\n \u003cp\u003ePC1\u0026thinsp;+\u0026thinsp;PC2,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModel 4 n\u0026thinsp;=\u0026thinsp;78\u003c/p\u003e\n \u003cp\u003eHb1\u0026thinsp;+\u0026thinsp;PC1,\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e69.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cem\u003eSummary of (crude) predictive ability: Model 1 Baseline\u0026thinsp;=\u0026thinsp;haemoglobin at diagnosis, ethnicity, trimester at recruitment, support staus, and parity. PC1\u0026thinsp;=\u0026thinsp;alkaline phosphatase, albumin, transferrin, total iron binding capacity iron saturation and iron. PC2\u0026thinsp;=\u0026thinsp;mean cell volume, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration.\u003c/em\u003e\u003c/p\u003e\n \u003cdiv class=\"BlockQuote\"\u003e\n \u003cp\u003e*In Model 2, Hb at recruitment was dropped because Hb is already in PC2.\u003c/p\u003e\n \u003cp\u003e**Not corrected for chance\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eWe also examined the impact of socio-economic deprivation on the predictive ability of the models. Using the index of multiple deprivation (IMD), as a single measure and then each of its component parts were included in the models. There were no material changes to the results (Supplementary Table\u0026nbsp;8).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e We successfully followed up a cohort of women with anaemia during pregnancy in the setting of a dedicated maternity anaemia clinic and on a background of a challenging period of delivery of maternity services in the NHS during COVID19. In this study, we focused on following best practice guidance as closely as possible to evaluate the success of iron treatment for anaemia. Our study findings suggest that even after optimising the management pathway for treating iron deficiency anaemia, closely following national guidelines, a significant proportion of women identified (and labelled) as iron deficient failed to demonstrate a haematological response according to recognised criteria [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This study was started prior to updated guidance which promotes lower daily doses of oral iron, but we believe our findings have value as an evaluation of practice and in the context of implementing guidelines. It should also be noted that evidence for lower doses has largely been derived from studies of iron absorption in health volunteers and not pregnancy. Key findings of our study are that 1) around two thirds of affected women failed to increase their haemoglobin concentration by the criteria of 10g/L 2 to 4 weeks following the start of treatment with oral iron and educational support. Even when the definition of response to treatment was adjusted to account for the physiological changes in pregnancy, around a half of women still appeared to fail to respond to oral iron therapy. 2) Self-reported levels of adherence were similar between responders and non-responders. No significant differences for each specific side effect were identified between the two groups, although being a pragmatic study we were not specifically powered to show any differences. 4) Factors that may predict positive response to therapy suggested that haemoglobin at the time of diagnosis, ethnicity, trimester at recruitment, marital/support status and parity are positively associated with response. But the models have a low predictive ability and cannot be improved with the addition of routinely collected haematological and iron studies.\u003c/p\u003e \u003cp\u003ePublished quality improvement projects show that it is possible to improve the processes of management of iron deficiency anaemia and iron deficiency resulting in a reduction in the use of blood transfusion [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. But they have not addressed the issue of expected response from treatment and the reasons why many women fail to respond. It is possible that non-responders may be less adherent with their medication. When we examined the side effect profile 15% of responders did not report any side effects whereas the rate was 5% for non-responders. Overall, the trend in the incidence of side effects namely, black stools, constipation, diarrhoea, heartburn, and nausea, was consistently lower among responders compared to non-responders, although the uncertainty surrounding estimates of the differences was high.\u003c/p\u003e \u003cp\u003eIt is widely reported that the troublesome gastrointestinal side effects caused by oral iron result in problems with adherence [19\u0026ndash;22]. However, in this study, self-reported levels of adherence were similar between responders and non-responders. Those women who responded had, on average, lower levels of haemoglobin at diagnosis when compared to non-responders. Also, responders had at the follow up visit, increased their haemoglobin more significantly than the non-responders, who tended to show a much smaller increment in the level of Hb. At the end of follow up post birth, the responders still had a higher level of Hb than the non-responders. This pattern was replicated by the level of haematocrit, suggesting that the haemodilution effect seen in pregnancy was not influencing the findings.\u003c/p\u003e \u003cp\u003eThe differences between the women who responded to treatment and those who failed to respond might be accounted for in several ways. Non-responders may have been more severely affected by the side effects leading to a reduction in adherence. Although we were unable to measure the severity of the side effect profiles, these data show that the percentage reporting each side effect was consistently higher in the non-responder group. But self-reported adherence was similar between the groups. It is possible that the women who did not respond to treatment were not as iron depleted. As a group, their Hb concentration at the time of diagnosis was higher than women who did respond, a state that was mirrored in their haematocrit. This highlights the difficulties that are encountered with the diagnosis of IDA in pregnancy. The physiological haemodilution lowers the haemoglobin threshold for diagnosis in the second and third trimesters and it is possible that a group of women labelled as having IDA are in fact simply showing the normal changes of a healthy pregnancy [23]. This would be consistent with the finding that \u0026ldquo;mild anaemia\u0026rdquo; improves some obstetric outcomes [24,25]. It has been suggested that a measured ferritin level is used to improve the diagnosis. However, this approach has problems too. While ferritin is a good marker of iron stores the cut-off point in pregnancy is disputed and it is not a measure of functional iron [26\u0026ndash;30]. Therefore, we cannot exclude the possibility that some women diagnosed with IDA are in fact iron replete and have haemoglobin concentrations lower than the gestational threshold because of the haemodilution. Attempts have been made to utilize other haematological and iron indices to improve the accuracy of the diagnosis of IDA during pregnancy and predict response [23]. Using PCA, we derived scores, combining haematological and iron biomarkers and clinical features, in our logistic regression models. None of our models reached acceptable thresholds to be recommended for clinical practice.\u003c/p\u003e \u003cp\u003eStrengths and Limitations of the study\u003c/p\u003e \u003cp\u003eThe guidance on management of iron deficiency anaemia in pregnancy was applied in the anaemia clinic with a high level of follow-up, supporting full assessments of the rates of response and non-response. However, in addition to being a single centre evaluation, one limitation was the change in guidance for oral iron treatment during the study period. The recommendations for dosing with ferrous sulphate 200mg three times a day were changed, reducing it to 65mg (one 200mg tablet) of elemental iron per day. This was because of the finding that even one tablet of iron triggers Hepcidin release from the liver and as a result the amount of iron absorbed in subsequent oral doses is reduced [31,32]. Recent evidence also shows that alternate day compared to consecutive day dosing does not result in higher levels of ferritin but does have reduced numbers of gastrointestinal side effects [35]. It remains possible that some of our results were affected by the dosing frequency, but this has yet to be shown in clinical studies of pregnant women.\u003c/p\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eImplications for practice and research\u003c/h2\u003e \u003cp\u003eIn our maternity centre we adopted a model of anaemia care based on well-established pre-operative anaemia clinics, but our findings suggest this model may not support better anaemia care in maternity services. The attrition rate at the follow up visits 2 and 3 was 10%, and at the end of treatment (V5), the attrition was 20%. Since women who dropped out were automatically considered as \u0026lsquo;non-responders\u0026rsquo; this means that the estimate of overall response at the end of treatment which is 57.3% is a lower bound or the worst-case scenario estimate of the proportion of responders. Further research on the value of a dedicated anemia clinic including economic impact needs to be undertaken. Research continues to be required into the diagnosis and optimal management of IDA, including the role of iv iron, so that future guidelines and their recommendations can be made with a stronger evidence base [34].\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate.\u003c/strong\u003e Ethics approval was granted by the West Midlands \u0026ndash; Black Country Ethics committee. Ref number 18/WM/0090. All participants provided informed consent to participate in the study in writing using the ethically approved consent form.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication.\u0026nbsp;\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials.\u003c/strong\u003e Data is provided with the manuscript or supplementary information files. All source dta can be obtained by request from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests.\u0026nbsp;\u003c/strong\u003eD Churchill was formerly a member of the Multi-disciplinary Iron Deficiency Anaemia Steering (MIDAS) committee supported by Pharmacosmos. All other authors do not have any competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e D Churchill designed the project over saw its execution analysed the data and authored the manuscript prior to comments from the study team. S Stanworth assisted with the design of the project, analysis of the data and co-wrote the final draft of the paper. H Ali and M Moussa assisted with the design of the project, recruited, and collected data and commented on the final draft of the paper. D Bautista carried out the statistical analysis while working at NHS Blood and Transplant and co-authored the final draft of the paper. S Sweity coordinated the study set up assisted with the study design and co-authored the final paper, L Devison and J Icke assisted with recruitment, data collection and co-authored the final draft of the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The project was supported by a grant from the Rotha Abraham Trust a charitable fund at New Cross Hospital, Wolverhampton.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Rotha Abraham Charitable Trust for funding the project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy numbers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIRAS 244013\u003c/p\u003e\n\u003cp\u003eISRCTN 13007439\u003c/p\u003e\n\u003cp\u003eORCID:\u003c/p\u003e\n\u003cp\u003eDavid Churchill - https://orcid.org/0000-0003-0548-2953\u003c/p\u003e\n\u003cp\u003eSimon J Stanworth - https://orcid.org/0000-0002-7414-4950\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRoyal College of Obstetricians and Gynaecologists. Blood Transfusions in Obstetrics. Green-top Guideline No. 47. 2015. Available from: https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/blood-transfusions-in-obstetrics-green-top-guideline-no-47/\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence. Antenatal Care. NICE guideline [NG201]. Available from: https://www.nice.org.uk/guidance/ng201\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Available from: https://www.who.int/publications/i/item/WHO-NMH-NHD-MNM-11.1\u003c/li\u003e\n\u003cli\u003ePavord S, Myers B, Robinson S, Allard S, Strong J, Oppenheimer C, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2012;156(5):588-600.\u003c/li\u003e\n\u003cli\u003ePavord S, Daru J, Prasannan N, Robinson S, Stanworth SJ, Girling J, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2020;188(6):819-830.\u003c/li\u003e\n\u003cli\u003eChurchill D, Ali H, Moussa M, Donohue C, Pavord S, Robinson SE, et al. Maternal iron deficiency anaemia in pregnancy: Lessions from a national audit. Br J Haematol. 2022;199(2):277-284.\u003c/li\u003e\n\u003cli\u003eNair M, Churchill D, Robinson S, Nelson-Piercy C, Stanworth SJ, Knight M. Association between maternal haemoglobin and stillbirth: a cohort study among a multi-ethnic population in England. Br J Haematol. 2017;179(5):829-837.\u003c/li\u003e\n\u003cli\u003eNair M, Choudhury MK, Choudhury SS, Kakoty SD, Sarma UC, Webster P, et al. Association between maternal anaemia and pregnancy outcomes: a cohort study in Assam, India. BMJ Glob Health. 2016;1(1):e000026.\u003c/li\u003e\n\u003cli\u003eHaider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. 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Development and validation of a pregnancy symptoms inventory. BMC Pregnancy Childbirth 2013;13:3.\u003c/li\u003e\n\u003cli\u003ePereira DAI, Couto Irving SS, Lomer MCE, Powell JJ. A rapid, simple questionnaire to assess gastrointestinal symptoms after oral ferrous sulphate supplementation. BMC Gastroenterology 2014;14:103.\u003c/li\u003e\n\u003cli\u003eAlderdice F, McNeill J, Gargan P, Oliver P. Preliminary evaluation of the Well-being in Pregnancy (WiP) questionnaire. J Psychosom Obstet Gynaecol. 2017;38(2):133-142.\u003c/li\u003e\n\u003cli\u003eAbdulrehman J, Lausman A, Tang GH, Nisenbaum R, Petrucci J, Pavenski K, et al. Development and implementation of a quality improvement toolkit, iron deficiency in pregnancy with maternal iron optimization (IRON MOM): A before-and-after study. PLoS Med. 2019;16(8):e1002867.\u003c/li\u003e\n\u003cli\u003eFlores\u0026nbsp;CJ,\u0026nbsp;Sethna\u0026nbsp;F,\u0026nbsp;Stephens\u0026nbsp;B, Saxon B, Hong FS, Roberts T, et al. Improving patient blood management in obstetrics: snapshots of a practice improvement partnership. BMJ Qual Improv Rep.\u0026nbsp;2017; 23;6(1):e000009.\u003c/li\u003e\n\u003cli\u003eCamaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372(19):1832-1843.\u003c/li\u003e\n\u003cli\u003ePena-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev. 2015;2015(7):CD004736.\u003c/li\u003e\n\u003cli\u003eHyder SM, Persson LA, Chowdhury AM, Ekstr\u0026ouml;m EC. Do side-effects reduce compliance to iron supplementation? A study of daily-and weekly-dose regimens in pregnancy. J Health Popul Nutr. 2002;20(2):175-179.\u003c/li\u003e\n\u003cli\u003eMakrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. Am J Nutr. 2003;78(1):145-153.\u003c/li\u003e\n\u003cli\u003eBresani CC, Braga MC, Felisberto DF, Tavares-de-Melo CE, Salvi DB, Batista-Filho M. Accuracy of erythrogram and serum ferritin for the maternal anemia diagnosis (AMA): a phase 3 diagnostic study on prediction of the therapeutic responsiveness to oral iron in pregnancy. BMC Pregnancy Childbirth. 2013;13:13.\u003c/li\u003e\n\u003cli\u003eSteer P, Alam MA, Wadsworth J, Welch A.\u0026nbsp;Relation between maternal haemoglobin concentration and birth weight in different ethnic groups.\u0026nbsp;BMJ.\u0026nbsp;1995;310:489-491.\u003c/li\u003e\n\u003cli\u003eDewey KG, Oaks BM. U-shaped curve for risk associated with maternal hemoglobin, iron status, or iron supplementation. Am J Clin Nutr. 2017;106(Suppl 6):1694S-1702S.\u003c/li\u003e\n\u003cli\u003evan den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in pregnant women: which measurements are valid? Br J Haematol. 1998;103(3):817-824.\u003c/li\u003e\n\u003cli\u003eVolpi E, De Grandis T, Alba E, Mangione M, Dall\u0026rsquo;Amico D, Bollati C. [Variations in ferritin levels in blood during physiological pregnancy] Minerva Ginecol. 1991;43(9):387-391.\u003c/li\u003e\n\u003cli\u003eMilman N: Iron and pregnancy - a delicate balance. Ann Hematol. 2006;85:559-565.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Iron deficiency anaemia: assessment, prevention and control. A guide for program managers. 2001. Available from: https://www.who.int/publications/m/item/iron-children-6to23--archived-iron-deficiency-anaemia-assessment-prevention-and-control\u003c/li\u003e\n\u003cli\u003eNair M, Choudhury SS, Rani A, V. SC, Kakoty SD, Medhi R, Rao S, Mahanta P, Zahir F, Roy I, Chhabra S, Deka G, Minz, B, Deka R, Opondo C, Churchill D, Lakhal-Littleton S, Nemeth E, on behalf of the MaatHRI coolaboration. American Journal of Haematology. 2023; 98:1721-1731.\u003c/li\u003e\n\u003cli\u003eMoretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126(17):1981-1989.\u003c/li\u003e\n\u003cli\u003eShinar,S. Skornick-Rapaport,A, Maslovitz S. Iron supplementation in singleton pregnancy: is there a benefit to doubling the dose of elemental iron in iron-deficient pregnant women? A randomized controlled trial. J Perinatol. 2017;37(7):782-786.\u003c/li\u003e\n\u003cli\u003eStoffel NU, Zeder C, Brittenham GM, Moretti D, Zimmerman MB. Iron absorption from supplements is greater with alternate day dosing in iron deficiency anaemic women. Haematologica. 2020;105(5):1232-1239.\u003c/li\u003e\n\u003cli\u003eShand AW. Iron preparations for iron deficiency anaemia in pregnancy: which treatment is best? Lancet Haematol. 2021;8(7):e471-e472.\u003c/li\u003e\n\u003cli\u003evon Siebenthal HK, Nessler S, Vallelian F, Steinwender J, Kuenzi U-M, Moretti D, et al. Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomised double-blind placebo-controlled study. EClinicalMedicine. 2023;65:102286.\u003c/li\u003e\n\u003cli\u003eRoberts I, Phyllis Jones C. Structural racism and iron deficiency anaemia. Lancet. 2023;402(10405):834-835.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anaemia, Response, Iron, Diagnosis, Adherence, Prediction","lastPublishedDoi":"10.21203/rs.3.rs-3933791/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3933791/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIron deficiency anaemia is a common disorder affecting up to 30% of pregnant women. Treatment guidelines for iron deficiency anaemia in pregnancy exist, which if adopted, can reduce the associated risks of maternal and fetal morbidity and mortality.\u003c/p\u003e \u003cp\u003e Objective: To optimise the implementation of the British Society of Haematology (BSH) guidelines, for the treatment of iron deficiency anaemia (IDA) in pregnancy, assessing response rates and predictability of response.\u003c/p\u003e \u003cp\u003eStudy population: A prospective cohort study of pregnant women with IDA at a single site.\u003c/p\u003e \u003cp\u003eMethods: Women with anaemia were offered follow-up through a dedicated anaemia clinic. First line treatment was with ferrous sulphate 200mg three time a day as per earlier BSH guidelines. The response was assessed 2 to 4 weeks later by measuring the haemoglobin (Hb) concentration. A response was defined in 2 ways; i) a haematological response (HRes), a 10g/L increase in Hb and ii) adjusted obstetric response (ORes), a 10g/L increase in Hb and/or gestationally adjusted normalisation of the Hb. Education and advice were provided to women, with on-going follow-up at clinic appointments including an assessment of side effects. Continuing non-response led to an offer of intravenous iron infusion (IVI). Following a response with oral iron, treatment was continued for a further 3 months when the women were again reviewed.\u003c/p\u003e \u003cp\u003eResults: The initial rate of HRes to a first course of oral iron was 36.5% and for ORES at 55.2%. At the end of all follow up, post-delivery, the HRes rate was 70.5% and ORes 88.5% (excluding 9 women lost to follow up). Responders (HRes) to oral iron had lower median Hb at diagnosis 95g/L compared to non-responders 100g/L. The responders median Hb was 113g/l versus 103g/L for non-responders at first follow-up and was Hb 122g/L versus 110 g/L, respectively, at the end of the study. The same pattern was seen for ORes. Non-responders reported more side effects than responders 15% versus 5% respectively. Logistic modelling suggested Hb at diagnosis, ethnicity, trimester at recruitment, marital status and parity had a predictive accuracy for a response of 75%. The specificity was high 89.8% but sensitivity low 42.9%.\u003c/p\u003e \u003cp\u003e Conclusion: Oral iron treatment for IDA in pregnancy is challenging to deliver due to side effects and poor adherence, despite national guidelines. High rates of non-response were seen even in the setting of a specialist anaemia clinic. Alternative strategies such as prevention of IDA need to be evaluated.\u003c/p\u003e","manuscriptTitle":"Treatment of Iron Deficiency Anaemmia in Pregnancy Study. The Clinical Impact of Treatment for Iron Deficiency Anaemia using an Optimized Care Pathway in accordance with national guidelines","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-16 16:02:52","doi":"10.21203/rs.3.rs-3933791/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-20T14:14:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-15T19:24:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38400010716381689499364870277476534147","date":"2024-08-01T21:30:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-29T09:10:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64122221145308567259636938356398726722","date":"2024-07-25T09:56:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-08T18:48:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"443b68a4-3c65-4fd9-be47-9232167a96a3","date":"2024-02-26T15:05:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-16T07:45:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-16T07:35:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-02-15T05:47:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-15T05:35:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-02-06T11:48:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"01b64909-4708-4775-9f89-ee9c08c66732","owner":[],"postedDate":"February 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-25T16:31:13+00:00","versionOfRecord":{"articleIdentity":"rs-3933791","link":"https://doi.org/10.1186/s12884-025-07938-w","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2025-08-19 16:12:59","publishedOnDateReadable":"August 19th, 2025"},"versionCreatedAt":"2024-02-16 16:02:52","video":"","vorDoi":"10.1186/s12884-025-07938-w","vorDoiUrl":"https://doi.org/10.1186/s12884-025-07938-w","workflowStages":[]},"version":"v1","identity":"rs-3933791","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3933791","identity":"rs-3933791","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}