Lactoferrin or ferrous salts for iron deficiency anemia in pregnancy: a meta-analysis of randomized trials.

Studien Ziel:

Vergleich von Lactoferrin und Eisen(II)-Sulfat bei Eisenmangelanämie während der Schwangerschaft. Eine Meta-Analyse

Studien-Überblick:

• In Online-Datenbanken wurde nach Studien gesucht, bei denen schwangere Frauen mit Eisenmangel-Anämien durch Lactoferrin und/oder Eisen(II)-Sulfat (ferrous salts) behandelt wurden. 4 Studien mit insgesamt 600 Frauen kamen in Frage (siehe Zitate)
• Primäres Kriterium war eine Veränderung des Hämoglobin-Wertes innerhalb von 4 Wochen. Sekundäre Kriterien waren Veränderungen im Serum-Ferritin und Eisen-Wert, Nebenwirkungen, Frühgeburten und niedriges Geburtsgewicht, durchschnittliches Gewicht bei der Geburt und neonataler Tod.

Verwendete Studien:

• Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women.
• Efficacy and tolerability of oral bovine lactoferrin compared to ferrous sulfate in pregnant women with iron deficiency anemia: a prospective controlled randomized study.
• Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women.
• Lactoferrin versus ferrous sulphate for the treatment of iron deficiency anemia during pregnancy: a randomized clinical trial.

Keynotes

• Die Prävalenz einer Eisenmangel-Anämie ist weltweit ein bekanntes Problem (siehe Zitate)
• Zwei erwähnte Studien erhielten Sponsoren-Gelder via Industrie oder Regierung
• Verringertes Serum-Hämoglobin, Ferritin- und Eisenwerte wurden durch Lactoferrin mindestens so gut behandelt, wie durch Eisen(II)-Sulfat (binnen 4 Wochen Studiendauer) und zeigte weit weniger unerwünschte Nebenwirkungen
• Lactoferrin eignet sich sehr gut, um als Supplement bei Schwangeren mit Eisenmangelanämie zu dienen
• Weniger gastrointestinale Nebenwirkungen weisen auf eine möglicherweise geringere Interaktion mit Bakterien des Dickdarms hin. Eisen – wenn nicht resorbiert – landet ansonsten oft bei opportunistischen Bakterien des Dickdarms und kann damit zu unangenehmen Beschwerden führen
• Weniger Beschwerden sorgen ebenfalls für eine bessere Compliance der Patientinnen bei der Einnahme während dieser sensiblen Phase

Diskussion & Schlussfolgerungen

+: Kein Interessenkonflikt der Autoren

+: Aktueller Review (2017)

+: Obwohl nur 4 Studien ausgewählt wurden (aufgrund von strikten Kriterien) waren 600 Patientinnen beteiligt

+: Eine Reduktion gastrointestinaler Beschwerden bei Lactoferrin Gabe war signifikant positiv im Vergleich zu Eisen(II)-Sulfat und wurde ausführlich beschrieben

+: Klare Darstellung der Schwächen der Studie (Siehe Zitate)

-: 2 von 4 zitierten Stunden erhielten Sponsoring

+-: Kein Zusatzmaterial hinsichtlich mikrobieller Veränderungen durch Eisen(II)-Sulfat oder Lactoferrin. Jedoch nicht unbedingt Teil der ursprünglichen Fragestellung

Insgesamt eine sehr gute Übersichtsarbeit.

Details und weiterführende Informationen:

Zitate:

Ein- und Ausschlusskriterien:

Quasi-randomized, non- randomized or studies including other known cause of anemia, gestational or pre-existent maternal diseases were excluded. Accordingly, 4 eligible trials (600 women) were analyzed. Primary outcome was change in hemoglobin level at 4 weeks of treatment. Secondary outcomes were; change in serum ferritin and iron, rates of gastrointestinal side effects, preterm birth, low birthweight, neonatal death and mean birthweight. Quality assessment was performed by the Cochrane risk of bias tool. Odds ratio and mean difference were used to integrate dichotomous and continuous outcomes respectively. 

Relevanz der Eisenmangel-Anämie:

Globally, it affects 56.4 million pregnant women (41.8%). Higher prevalence rates are present in Africa, South East Asia and Eastern Mediterranean (57.1%, 48.2% and 44.2% respectively), meanwhile lower rates are in Europe and Americas (25.1% and 24.1% respectively) [1]. Hemoglobin (Hb) represents the most widely used indicator to assess anemia during pregnancy.

Details zu den Studien:

Of the four included studies; three were performed in Italy [13,24,25] and one in Egypt [26]. The four included studies enrolled 600 participants (297 women received treatment with oral bovine lactoferrin and 303 were treated with oral ferrous sulphate). The sample size varied across the trials and ranged from 75 to 300 participants. All the four studies were published between 2006 and 2016 in peer- reviewed indexed journals with an impact factor. All trials were single center and two [13,25] were funded through industry and governmental grants. The baseline of all trials was comparable. The duration of treatment was 4 weeks in 3 trials [13,24,25] and 8 weeks in 1 trial [26].

Limitationen der Studie:

On the other hand, this meta-analysis has several limitations. First, only 4 RCTs including 600 pregnant women with IDA are available in the literature. Another limitation is that in pregnant women with moderate IDA, there exists only one RCT [26] in which assessment of serum ferritin and iron levels had not been carried out. Third, the overall quality of the evidence was rated as moderate to low. The reasons for downgrading the evidence included unclear reporting of study methods in some trials (especially with respect to randomization, allocation concealment and blinding), high heterogeneity in hematological outcomes and there is lack of answer to some secondary outcomes, while others were included in only one or two studies (Table 2). Thereby, it could be argued that findings of this meta-analysis should be interpreted with caution. Another limitation is that funnel plot analysis to test for publication bias was not performed because of the relatively small number of included studies. Such analysis warrants the inclusion of 10 or more studies in the review to be performed. Finally, this review included 4 studies in which Hb levels were assessed at four weeks and only one study had 8 weeks assessment [26]. Thereby more long term-effects of treatment remain to be evaluated

Zusammenfassung:

For pregnant women with IDA, daily oral treatment with bovine lactoferrin is just as good as ferrous sulfate in increasing Hb and other hematological parameters with fewer gastrointestinal side effects. Considering the latter as a critical side effect causing lack of compliance of ferrous sulfate, lactoferrin should be the iron replacement agent of choice for treatment of IDA in pregnancy. The findings of our meta-analysis should fuel an in depth enthusiasm to obtain a high-quality evidence from adequately powered and blinded RCTs investigating different maternal, fetal, and neonatal outcomes of oral bovine lactoferrin treatment for pregnant women with IDA.