Pregnancy and Bariatric Surgery: Very Different and Very Similar

The organizational guidelines on treatment for these two clinical conditions are remarkably similar: “oral iron is frontline therapy” 1, 2 despite a litany of high-quality evidence informing on its near ubiquitous intolerability, and the US Preventive Services Task Force concluding that in pregnant individuals there is insufficient evidence to recommend routine testing for iron deficiency in the absence of anemia 3. During pregnancy, oral iron is frequently associated with worsening constipation, present due to the high progesterone levels which slow bowel transit and the enlarging uterus pressing posteriorly on the rectum. Oral iron, particularly after bariatric surgery, has little or no absorption due to the need for conjugation to vitamin C, amino acids, or sugar in the presence of gastric acid to maintain iron in the soluble ferrous (Fe2+) form rather than the insoluble, unabsorbable ferric form (Fe 3+) in the alkaline milieu of the proximal duodenum 4, 5. In the second and third trimester, oral iron is too poorly and too slowly absorbed to get to the developing fetus, exposing the fetus to the risk of developmental abnormality 6. These data are supported by published evidence reporting that intravenous, much more than oral iron, when administered to iron deficient mothers in the second or third trimester, improves the infants' ferritin at birth 7. Two manuscripts in this issue of the American Journal of Hematology reporting on completely different clinical scenarios arrive at similar conclusions: iron deficiency is underdiagnosed, undertreated and, when treated, is done so inefficiently and ineffectively. In the Benotti study 8, from a clinical registry that had 5713 patients who underwent a bariatric surgical procedure between 2005 and 2023, 4079 had iron parameters performed preoperatively. 35% were deficient. Virtually none received preoperative iron therapy, especially with intravenous iron. The authors reported that those with serum ferritin concentrations < 30 ng/mL or percent transferrin saturations < 15, not routinely measured as a standard, were at much higher risk for the development of severe post-operative iron deficiency made worse by the lack of clinical evidence of benefit for oral iron replacement. The authors concluded these data support aggressive iron repletion preoperatively with intravenous iron. This conclusion is supported by an earlier publication on 61 post bariatric surgery patients who received oral iron supplementation 9. By 5 years, 75% were reported to have clinically significant iron deficiency. In the Benson study 10, a prospective single-arm evaluation of safety and efficacy of a single infusion of ferric derisomaltose was undertaken. 75/78 enrolled received 1000 mg over an average time of 24 min. The overwhelming majority had an excellent response with observed increments in hemoglobin from 10.3 to 11.6 at delivery (64.3%) and then 12.8 at 6 weeks post-partum (92.6%). Equally dramatic improvements in iron parameters were observed. Both of these clinical trials, one retrospective and the other prospective observational, clearly inform on a need for felicitous iron repletion in two distinct ambulatory patient populations. We have already explained why oral iron is inappropriate in both situations. Intravenous iron has historically been used as frequent doses of the iron salts, ferric gluconate and iron sucrose. These formulations are limited in single doses to 200–300 mg because of the smaller carbohydrate carriers (gluconate and sucrose), which result in a significantly larger release of labile free iron, the putative cause of minor infusion reactions 11. Higher doses of these formulations are simply not tolerated. Four formulations (low molecular weight iron dextran, ferumoxytol, ferric carboxymaltose and ferric derisomaltose, the formulation used in the Benson study) allow complete replacement doses in a brief 20–60 min single visit, obviating non-completion, markedly improving convenience and with improved efficacy 12. This point was dramatically corroborated in a cohort of 309 pregnant individuals who received either iron sucrose or one of the formulations allowing a total dose infusion, with low molecular weight iron dextran being the predominant formulation 13. The authors concluded that the use of iron sucrose resulted in less complete repletion and more anemia than those administered a total dose infusion. Earlier administration of intravenous iron, irrespective of the presence or absence of anemia, was associated with less anemia at delivery, fewer blood transfusions, and less pre-eclampsia and gestational hypertension. The newer formulations are similar in structure, with an iron core surrounded by a carbohydrate shell, excluding ferric derisomaltose which is a matrix structure. The release of labile free iron is much reduced within the nanoparticle and is readily mobilized by chemical reactions or proteins over time. As was so clearly elucidated by Benson et al. 10, in a population of iron deficient gravidas, a complete replacement dose of 1000 mg was administered in an average of 24 min. It does not require a great deal of imagination to see the similar benefit of such an intervention in an ambulatory bariatric population, who so desperately need to be iron replete for the rigors of ongoing weight loss after a decision to re-route the gut. Anemia, according to the World Health Organization, is a leading cause of Years Lived with Disability worldwide, clearly deserving of a degree of respect considering the enormous clinical and economic impact it has on multiple populations. In these two trials, the populations studied represent two distinct groups that for all intents and purposes are normalized and marginalized by current organizational guidelines which ignore the common-sense advocacy to routinely search for and subsequently treat this ubiquitous condition. This was made abundantly clear in a prospective study of asymptomatic primiparous women without anemia tested for iron deficiency at 15, 20, and 33 weeks gestation 14. In this population, none of whom would have been tested if the current recommended standard was followed, rates of iron deficiency of 21, 47 and a staggering 84% respectively were reported. To reiterate, all of these individuals were non-anemic and would have been missed under current guidelines. These data became all the more dramatic by a recent publication by the same group 15 which reported a 42.3 μg/L difference in cord ferritin concentrations in infants born to iron deficient mothers compared with those iron replete. Using Bayley scales of infant and toddler language and motor development, the iron deficient babies had statistically significant lower scores at 2 years of age. If this doesn't disturb you, it should! The two manuscripts in this issue highlight the need for early diagnosis and intervention. The Benotti study calls into question the current guidelines of the American Bariatric Association, which recommends oral iron therapy as frontline treatment for iron deficiency after bariatric surgery, fomenting a cohort of significantly symptomatic post-operative patients who have chosen surgery to achieve weight loss. The Benson study, while not addressing early diagnosis, informs on a therapy which continues to be underutilized and has been shown to be enormously superior to the time-honored intervention with ineffective and toxic oral iron supplements. We have the ability and resources to effect a change. Iron deficiency is effectively ubiquitous in both populations, both of whom need to be iron replete to avoid the morbidity which we so frequently observe. While we await evidence from year-long randomized controlled trials demonstrating the advantages of preventing severe post-operative anemia, maternal fatigue, maternal depression, and poor neonatal iron loading, it seems unconscionable not to act. Our informed recommendation is to detect iron deficiency in similar patients as early as clinically possible and to treat with your preferred intravenous iron formulation. Ideally, one that is able to be administered in a single visit. The authors declare no conflicts of interest. The authors have nothing to report.