Comparative efficacy and safety of Chinese patent medicines of iron deficiency anemia during pregnancy: A network meta-analysis

Abstract

BACKGROUND

Iron deficiency anemia (IDA) is a prevalent nutritional disorder during pregnancy. Clinical studies indicate that incorporating Chinese patent medicines (CPMs) with oral iron (OI) in treating IDA in pregnancy can reduce adverse effects and improve clinical outcomes. Nonetheless, the comparative efficacy of different CPMs remains unclear.

AIM

To assess the safety and effectiveness of different CPMs for treating IDA during pregnancy using network meta-analysis.

METHODS

We conducted a search for randomized controlled trials (RCTs) that combined CPM and OI for IDA treatment in pregnancy, spanning from 2013 to the present. Data analysis was performed using Rev Man 5.3 and Stata 14.0 on literature that satisfied the quality criteria.

RESULTS

The analysis included 45 RCTs, encompassing 4422 pregnant patients with IDA. Six CPMs were examined, including Shengxuebao Mixture, Shengxuening Tablets (SXN), Yiqi Weixue CPMs (YQWX), Jianpi Shengxue CPMs (JPSX), Yiqi Buxue Tablets, and Compound Hongyi Buxue Oral Liquid (FFHY). Findings indicated that FFHY + OI significantly improved the clinical effective rate. SXN + OI was most effective in boosting red blood cells counts and hemoglobin levels. YQWX + OI showed superior results in improving serum ferritin, and SXN + OI was most effective in increasing serum iron levels. JPSX + OI was optimal in reducing adverse pregnancy outcomes, while YQBX + OI effectively minimized adverse events. A cluster analysis suggested that SXN + OI could be the potentially optimal therapeutic regimen for IDA in pregnancy.

CONCLUSION

This study demonstrates that the combination of OI with CPMs offers better outcomes than OI alone. Based on clinical efficacy and other measured outcomes, SXN + OI emerges as the most effective treatment modality for improving the health of pregnant patients with IDA.

Key Words: Chinese patent medicine, Network meta-analysis, Shengxuebao Mixture, Shengxuening Tablets, Yiqi Weixue Chinese patent medicines, Jianpi Shengxue Chinese patent medicines, Yiqi Buxue Tablets, Compound Hongyi Buxue Oral Liquid

Core Tip: The network meta-analysis demonstrated that combining Chinese proprietary medicines with oral iron (OI) for the treatment of iron-deficiency anaemia in pregnancy significantly improved clinical effective rate, improved red blood cell indicators and iron metabolism indicators, and reduced adverse pregnancy outcomes and adverse events. Based on the available evidence, it is recommended that the combination of Shengxuening Tablets with OI improve clinical efficacy and other outcome indicators. Further high-quality randomised controlled trials are needed to reassess or confirm this finding.

INTRODUCTION

Iron deficiency anemia (IDA) is one of the most common malnutritional diseases worldwide. Globally, 36% of pregnant women aged 15-49 suffer from anemia. It is estimated that 40% of anemias in pregnancy stem from iron deficiency, making it the leading cause of such conditions[1]. During pregnancy, the demand for iron escalates due to increased erythropoiesis, plasma volume expansion, and the development of the placenta and fetus[2,3]. Maternal anemia can lead to severe, potentially life-threatening complications for both mother and baby, and it may also result in long-term issues such as low birth weight and reduced iron stores in infancy, which could further lead to anemia and delayed development in children[4-6].

Treatment for IDA in pregnancy typically involves oral iron (OI) and intravenous (IV) iron. Guidelines from bodies such as the ACOG[7] and the CDC[8] advocate for the use of OI supplements during pregnancy. OI is known to cause gastrointestinal side effects in most pregnant women. There are a number of gastrointestinal side effects associated with different OIs, including constipation, abdominal pain, flatulence, nausea, vomiting, and diarrhea[9]. Many studies have shown that IV iron is safe and effective for pregnant women[10-12]. However, due to the lack of safety data in early gestation, the use of IV iron has been limited to the second and third trimesters of pregnancy. Despite less frequent and severe side effects, infusion therapy can still cause adverse events such as headaches, diarrhoea, and hypotension[13], as well as infection.

Clinical studies indicate that incorporating Chinese patent medicine (CPM) with OI can decrease adverse events and improve clinical efficacy in treating IDA during pregnancy[14]. Yet, a scarcity of comparative research on the efficacy of different CPMs complicates the selection of an optimal treatment regimen. This study employs network meta-analysis (NMA) to evaluate the effectiveness of various CPMs, including Shengxuebao Mixture (SXB), Shengxuening Tablets (SXN), Yiqi Weixue CPMs (YQWX), Jianpi Shengxue CPMs (JPSX), Yiqi Buxue Tablets, and Compound Hongyi Buxue Oral Liquid (FFHY) when combined with OI, specifically focusing on their impacts on pregnancy outcomes and adverse events.

MATERIALS AND METHODS

This study followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) Protocols guidelines[15] and the registration ID is CRD42023482561. The medical ethics committee approval is not required for this type of study.

Search strategy

Our study concentrated on utilizing electronic searches through various databases including PubMed, EMbase, Cochrane Library, CNKI, WanFang, VIP database, and CBMdisc. The search timeframe was restricted to articles published from 2013 to the present time. There were no limitations on publication year, language, or blinding. A comprehensive outline of the search methodology can be found in Supplementary Tables 1-7.

Inclusion and exclusion criteria

Eligible RCTs met the following criteria: (1) A randomized controlled trial (RCT) was conducted, with no language restrictions; (2) IDA in pregnancy patients diagnosed according to authoritative organization diagnostic criteria, without restriction on age or duration; and (3) The experimental group was administered CPMs in conjunction with OI, whereas the control group only received OI. All included CPMs are listed as national essential or protected drugs[16].

Exclusion criteria: (1) Repeatedly published literature; (2) Literature with incomplete data or inaccessible full texts inconsistent study subjects or inconsistent interventions; (3) reviews, observational studies, animal studies, conference papers, meta-analyses, etc; and (4) fewer than 30 participants.

Outcomes

The primary outcome was the clinical effective rate. Secondary outcomes focused on erythrocyte and iron metabolism indicators, such as red blood cells counts (RBC), hemoglobin levels (Hb), serum ferritin levels (SF), and serum iron levels (SI). Safety outcomes included adverse pregnancy outcomes and adverse events.

Study selection and data extraction

The two researchers screened the literature using NotExpress, reading the title and abstract, following the inclusion and exclusion criteria, and then reading the full text for screening. If there is a disagreement over whether the literature should be included, a decision should be reached after discussion or consultation with a third party. We extracted the following information from the literature: authors, year of publication, sample size, age, duration of pregnancy, intervention measures, intervention duration, outcomes indicators, outcome data, study design, and risks of bias investigation.

Assessment of literature quality

The quality of the literature included in the study was assessed independently by two researchers using the Cochrane Risk of Bias Assessment Tool[17]. Seven aspects were evaluated, which included methods of random assignment, concealment of allocation, blinding of patients and implementers, blinding of outcome assessment personnel, handling of incomplete outcome data, selective reporting, and identification of other biases. Each aspect was judged on three levels of risk: "high risk", "low risk", or "uncertain risk". The researchers made assessments and judgments for each item in the evaluation entries.

Statistical analysis

Using the frequency science model, statistical analyses were conducted to assess bias risk and conduct NMA, employing Rev Man 5.3 and Stata 14.0. ORs and corresponding 95%CIs were computed for dichotomous outcomes, while MDs and corresponding 95%CIs were calculated for continuous outcomes. Multi-arm studies were partitioned into two-arm trials whenever feasible. An adjusted funnel plot was utilized to evaluate small sample effects in the NMA. Treatment rankings were determined by the surface under the cumulative ranking curve (SUCRA) probability values, with a 100% value denoting maximum efficacy. Due to the absence of a closed loop in the evidence network, the consistency test to compare direct and indirect comparison results was not valid in this analysis.

RESULTS

Literature screening result

After an initial search, NoteExpress imported 784 relevant papers, leaving 498 after deduplication. A total of 48 full-text evaluations were screened based on titles and abstracts, with 45 being included after further reading. Figure 1 shows The PRISMA flowchart in Figure 1 outlines the literature search process. All included trials were published as full-text articles.

Figure 1 Flow diagram of study inclusion.

Included study characteristics

Our analysis covered 45 trials[18-62] involving 4422 patients, split evenly with 2215 in the experimental group and 2207 in the control group. The breakdown of trials included six on SXB + OI vs OI, seventeen on SXN + OI vs OI, four on YQWX + OI vs OI, thirteen on JPSX + OI vs OI, three on YQBX + OI vs OI, and two on FFHY + OI vs OI. As for outcome indicators, there were 36 trials focusing on clinical effective rate, 34 on RBC counts, 41 on Hb levels, 27 on SF, and 27 on SI. There were also 21 trials examining adverse pregnancy outcomes and 30 addressing adverse events. Table 1 provides detailed characteristics of these studies. Figure 2 displays a network graph illustrating the relationships between different interventions, where node size indicates the total number of patients treated and line width represents the number of medical records reported.

Figure 2 Network graph of the different outcomes. In each study, the size of the point is determined by the total number of participants and the width of the edge is determined by the standard error. A: Clinical effective rate; B: Red blood cell counts; C: Hemoglobin levels; D: Serum ferritin levels; E: Serum iron levels; F: Adverse pregnancy outcomes; G: Adverse events. OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid.

Table 1 Basic characteristics of the included studies.

Ref.	Sample size T/C	Age (yr)		Duration of pregnancy (wk)		Intervention measures		Course	Outcome indicators
		T	C	T	C	T	C
Peng et al[18]	40/40	27.8 ± 5.3	27.1 ± 4.4	21.2 ± 4.3	20.6 ± 4.0	SXB + OI	OI	3 months	①②③④⑥⑦
Hu et al[19]	40/40	33.15 ± 3.15	33.37 ± 3.42	24.26 ± 2.11	24.52 ± 2.23	SXB + OI	OI	8 wk	①②③④⑦
Bi et al[20]	50/50	29.15 ± 2.46	29.64 ± 2.37	22.34 ± 0.87	22.56 ± 0.93	SXB + OI	OI	1 month	①②③④⑤⑥⑦
Zhang[21]	60/60	30.7 ± 5.0	31.6 ± 4.5	22.2 ± 3.8	21.2 ± 3.1	SXB + OI	OI	4 wk	①③④⑥⑦
Wang et al[22]	60/60	28.4 ± 3.6	28.5 ± 3.5	24.6 ± 1.3	24.5 ± 1.2	SXB + OI	OI	4 wk	②③④⑤⑥⑦
Ke et al[23]	40/40	29.74 ± 1.99	30.26 ± 2.08	22.37 ± 2.14	22.56 ± 2.03	SXB + OI	OI	3 months	①②③④⑤⑦
Yang et al[24]	56/56	28.52 ± 3.46	28.69 ± 3.81	27.53 ± 3.62	27.59 ± 3.31	SXN + OI	OI	4 wk	①②③④⑤⑥⑦
Wu[25]	40/40	30.25 ± 5.36	31.16 ± 5.48	-		SXN + OI	OI	1 month	①②③⑤⑥⑦
Peng[26]	40/40	29.44 ± 3.18	30.25 ± 3.11	28.71 ± 4.12	27.63 ± 4.19	SXN + OI	OI	4 wk	④⑤⑦
Yang[27]	80/80	29.0 ± 4.5	28.7 ± 4.1	22.6 ± 2.4	22.7 ± 2.6	SXN + OI	OI	4 wk	①②③④⑤
Chen et al[28]	44/44	27.51 ± 3.69	27.59 ± 3.75	29.58 ± 1.27	29.64 ± 1.32	SXN + OI	OI	4 wk	②③⑤
Sun et al[29]	33/34	28.93 ± 3.86	29.01 ± 3.92	23.53 ± 3.47	23.61 ± 3.51	SXN + OI	OI	4 wk	①②③⑤⑥⑦
Liu et al[30]	60/61	26.85 ± 3.35	27.12 ± 3.51	22.91 ± 2.37	23.07 ± 2.49	SXN + OI	OI	4 wk	②③⑤⑥
Fu et al[31]	39/39	25.3 ± 5.9	25.8 ± 5.2	21.0 ± 4.8	21.3 ± 4.4	SXN + OI	OI	30 d	②③⑤⑥⑦
Jiao[32]	50/50	26.74 ± 2.59	26.52 ± 2.78	33.41 ± 2.77	31.82 ± 2.23	SXN + OI	OI	28 d	①②③⑤
Gu[33]	50/50	30.1 ± 2.3		28.3 ± 1.5		SXN + OI	OI	4 wk	①②③
Ruan et al[34]	100/100	26.52 ± 2.74	26.14 ± 2.76	32.41 ± 2.61	31.86 ± 2.17	SXN + OI	OI	28 d	①②③⑤⑥
Li et al[35]	40/40	27.5 ± 2.8	27.9 ± 3.1	22.4 ± 6.3	22.0 ± 5.9	SXN + OI	OI	1 month	③⑦
Ji[36]	64/56	28.56 ± 1.58	28.13 ± 2.17	-		SXN + OI	OI	4 wk	①⑦
Zhao[37]	40/40	29.0 ± 2.0	9.54 ± 1.5	21.0 ± 1.5	20.5 ± 2.0	SXN + OI	OI	1 month	①②③⑤
Liu et al[38]	50/48	26.44 ± 4.58	26.89 ± 4.62	22.86 ± 3.88	23.03 ± 3.94	SXN + OI	OI	4 wk	①②③④⑤⑥⑦
Yin[39]	85/85	28.03 ± 5.68	27.91 ± 5.73	22.74 ± 7.05	22.58 ± 6.37	SXN + OI	OI	4 wk	①②③⑤
Chen[40]	42/42	26.1 ± 3.2	25.2 ± 2.1	20.5 ± 2.5	19.4 ± 2.2	SXN + OI	OI	1 month	①②③⑤⑥⑦
Sheng[41]	45/45	30.66 ± 4.06	30.85 ± 4.11	20.15 ± 1.25	20.98 ± 1.22	YQWX + OI	OI	12 wk	①③④⑤⑥⑦
Yu et al[42]	45/45	29.34 ± 6.84	30.20 ± 7.21	21.16 ± 1.20	21.42 ± 1.26	YQWX + OI	OI	3 months	①②③④⑤⑥
He[43]	40/40	29.64 ± 7.84	30.11 ± 7.68	21.46 ± 1.39	21.52 ± 1.37	YQWX + OI	OI	3 months	①②③④⑤⑥⑦
Ren et al[44]	43/43	32.12 ± 4.06	32.54 ± 4.17	22.45 ± 10.24	22.14 ± 10.14	YQWX+OI	OI	12 wk	①②③④⑥⑦
Zhang[45]	35/35	27.73 ± 3.78	27.25 ± 3.21	22.24 ± 1.89	22.31 ± 1.42	JPSX + OI	OI	4 wk	①③⑦
Yi[46]	30/30	29.01 ± 6.65	29.45 ± 6.71	24.51 ± 5.09	24.65 ± 5.13	JPSX + OI	OI	4 wk	①⑦
Wu et al[47]	50/50	29.4 ± 6.2	29.2 ± 4.6	19.8 ± 3.5	20.2 ± 3.9	JPSX + OI	OI	4 wk	①②③④⑤⑥⑦
Wu[48]	43/43	32.56 ± 4.29	31.96 ± 4.32	23.52 ± 3.18	23.40 ± 3.30	JPSX + OI	OI	1 month	①②③⑥⑦
Liu et al[49]	45/45	30.41 ± 7.43	30.29 ± 7.54	25.13 ± 8.70	25.21 ± 8.64	JPSX + OI	OI	4 wk	①③⑤⑦
Li[50]	40/40	33.4 ± 6.6	31.2 ± 6.5	20.4 ± 1.4	20.2 ± 1.5	JPSX + OI	OI	30 d	①②③④⑥
Xu[51]	53/53	23.15 ± 2.68	23.12 ± 2.82	23～34	22～33	JPSX + OI	OI	1 month	①②③④⑦
Wu[52]	35/35	28.03 ± 2.36	27.12 ± 5.16	24.03 ± 2.60	23.42 ± 3.22	JPSX + OI	OI	1 month	④⑤
Sun et al[53]	82/82	26.84 ± 3.57	27.35 ± 3.03	18.43 ± 2.06	17.87 ± 1.59	JPSX + OI	OI	3 months	①②③④⑤⑦
Shi et al[54]	65/64	27.38 ± 6.02	26.87 ± 5.14	23.02 ± 2.40	22.41 ± 3.12	JPSX + OI	OI	4 wk	①②③④⑤
Xiang et al[55]	32/33	24.2 ± 3.3	25.1 ± 3.4	22.9 ± 1.8	22.0 ± 1.3	JPSX + OI	OI	4 wk	①②③④⑦
Su et al[56]	30/30	26.8 ± 3.7	27.4 ± 4.2	22.6 ± 6.6	21.6 ± 6.0	JPSX + OI	OI	2 months	①②③④
Li et al[57]	48/48	27.36 ± 1.23	27.38 ± 1.26	18.53 ± 1.35	18.57 ± 1.38	JPSX + OI	OI	4 wk	①②③④
Wen et al[58]	60/60	26.6 ± 4.5	29.3 ± 2.6	22.8 ± 4.1	21.4 ± 3.1	YQBX + OI	OI	4 wk	③④⑤⑥
Liu et al[59]	40/40	28.6 ± 4.3	27.4 ± 3.2	23.8 ± 2.2	24.2 ± 2.1	YQBX + OI	OI	8 wk	①②③④⑥⑦
Luo et al[60]	50/50	28.3 ± 12.5	28.5 ± 12.4	21 ± 5	22 ± 4	YQBX + OI	OI	1 month	②③⑦
Jiang et al[61]	54/54	27.65 ± 5.92	26.85 ± 5.65	23.46 ± 5.58	24.37 ± 5.66	FFHY + OI	OI	4 wk	①③④⑤⑦
Zhang et al[62]	47/47	28.49 ± 3.20	28.15 ± 2.98	19.52 ± 2.19	19.12 ± 2.13	FFHY + OI	OI	4 wk	②③④⑦

T: Test group; C: Control group; OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid; ① Clinical effective rate; ② Red blood cell level; ③ Hemoglobin level; ④ Serum ferritin level; ⑤ Serum iron level; ⑥ Adverse pregnancy outcomes; ⑦ Adverse events.

Risk of bias assessment

Of the 45 studies assessed, 25 were deemed low-risk using the random number table method for bias. Twelve studies employed randomized methods but did not specify these methods and were therefore classified as unknown risk. Eight studies were categorized as high risk due to their use of treatment allocation, computerized odd-even, envelope methods, or unspecified methods. Allocation concealment and blinding were not mentioned in any of the studies, both rated as unknown risks. Outcome reporting was comprehensive across all studies, though two studies were considered high-risk due to data loss. The absence of access to study protocols prevented the evaluation of potential selective reporting, which was assumed to be a low risk. The risk of bias assessments are detailed in Figure 3 and Supplementary Figure 1.

Figure 3 Results of risk of bias graphs.

Primary outcome

The clinical effective rate: NMA results indicated that combining the six CPMs with OI significantly improved the clinical effective rate compared to OI alone (P < 0.05). An indirect comparison among the six CPMs revealed no statistically significant differences in clinical effective rates. For detailed data, refer to Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): FFHY + OI > JPSX + OI > SXB + OI > YQWX + OI > SXN + OI > YQBX + OI > OI.

Figure 4 The surface under the cumulative ranking curve plot for all different outcomes. A: Clinical effective rate; B: Red blood cell counts; C: Hemoglobin levels; D: Serum ferritin levels; E: Serum iron levels; F: adverse pregnancy outcomes; G: Adverse events. OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid.

Table 2 Odds ratio/mean difference (95% credible interval) results of the network meta-analysis.

Clinical effective rate	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	0.78 (0.38, 1.60)	0.97 (0.37, 2.58)	1.03 (0.49, 2.18)	0.70 (0.20, 2.45)	1.76 (0.28, 11.22)	0.23 (0.12, 0.43)
SXN + OI		1.24 (0.55, 2.83)	1.31 (0.77, 2.25)	0.90 (0.29, 2.80)	2.25 (0.38, 13.29)	0.29 (0.21, 0.42)
YQWX + OI			1.06 (0.45, 2.48)	0.72 (0.19, 2.69)	1.81 (0.27, 12.04)	0.24 (0.11, 0.50)
JPSX + OI				0.68 (0.21, 2.17)	1.71 (0.29, 10.26)	0.22 (0.15, 0.34)
YQBX + OI					2.51 (0.32, 19.55)	0.33 (0.11, 0.97)
FFHY + OI						0.13 (0.02, 0.74)
Red blood cell level	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	0.84 (0.34, 1.35)	0.32 (-0.38, 1.01)	-0.08 (-0.62, 0.45)	0.05 (-0.78, 0.89)	-0.27 (-1.32, 0.77)	-0.67 (-1.10, -0.25)
SXN + OI		-0.52 (-1.13, 0.08)	-0.93 (-1.34, -0.51)	-0.79 (-1.55, -0.03)	-1.12 (-2.10, -0.13)	-1.52 (-1.78, -1.26)
YQWX + OI			-0.40 (-1.04, 0.23)	-0.26 (-1.16, 0.64)	-0.59 (-1.69, 0.50)	-0.99 (-1.54, -0.45)
JPSX + OI				0.14 (-0.65, 0.92)	-0.19 (-1.20, 0.81)	-0.59 (-0.91, -0.27)
YQBX + OI					-0.33 (-1.52, 0.86)	-0.73 (-1.44, -0.01)
FFHY + OI						-0.40 (-1.35, 0.55)
Hemoglobin level	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	17.40 (8.27, 26.54)	5.34 (-7.00, 17.68)	4.55 (-4.99, 14.09)	12.87 (-0.40, 26.14)	-1.66 (-17.20, 13.88)	-11.25 (-18.94, -3.56)
SXN + OI		-12.06 (-22.90, -1.22)	-12.85 (-20.35, -5.35)	-4.53 (-16.43, 7.36)	-19.06 (-33.45, -4.68)	-28.66 (-33.59, -23.72)
YQWX + OI			-0.79 (-11.97, 10.40)	7.53 (-6.97, 22.03)	-7.00 (-23.60, 9.60)	-16.59 (-26.25, -6.94)
JPSX + OI				8.32 (-3.89, 20.53)	-6.21 (-20.85, 8.43)	-15.81 (-21.45, -10.16)
YQBX + OI					-14.53 (-31.84, 2.78)	-24.12 (-34.94, -13.30)
FFHY + OI						-9.59 (-23.10, 3.92)
Serum ferritin level	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	0.71 (-5.99, 7.41)	8.16 (1.27, 15.05)	-0.59 (-6.14, 4.96)	1.29 (-7.20, 9.79)	6.34 (-2.39, 15.08)	-5.41 (-9.68, -1.15)
SXN + OI		7.45 (-0.04, 14.94)	-1.30 (-7.57, 4.98)	0.59 (-8.39, 9.57)	5.64 (-3.58, 14.85)	-6.12 (-11.28, -0.95)
YQWX + OI			-8.74 (-15.21, -2.28)	-6.86 (-15.99, 2.26)	-1.81 (-11.16, 7.53)	-13.57 (-18.99, -8.15)
JPSX + OI				1.88 (-6.28, 10.04)	6.93 (-1.48, 15.34)	-4.82 (-8.38, -1.26)
YQBX + OI					5.05 (-5.54, 15.64)	-6.71 (-14.05, 0.64)
FFHY + OI						-11.75 (-19.38, -4.13)
Serum iron level	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	4.31 (-0.28, 8.90)	1.83 (-4.09, 7.74)	3.48 (-1.79, 8.76)	3.34 (-5.01, 11.68)	0.64 (-7.85, 9.12)	-3.03 (-7.19, 1.12)
SXN + OI		-2.48 (-7.11, 2.15)	-0.83 (-4.61, 2.95)	-0.97 (-8.46, 6.52)	-3.67 (-11.31, 3.97)	-7.34 (-9.28, -5.40)
YQWX + OI			1.65 (-3.65, 6.96)	1.51 (-6.85, 9.87)	-1.19 (-9.69, 7.31)	-4.86 (-9.06, -0.66)
JPSX + OI				-0.14 (-8.07, 7.78)	-2.84 (-10.92, 5.23)	-6.51 (-9.76, -3.27)
YQBX + OI					-2.70 (-13.04, 7.64)	-6.37 (-13.60, 0.86)
FFHY + OI						-3.67 (-11.06, 3.72)
Adverse pregnancy outcomes	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	OI
SXB + OI	0.79 (0.29, 2.12)	1.33 (0.45, 3.92)	0.72 (0.19, 2.63)	1.41 (0.35, 5.63)	3.04 (1.43, 6.48)
SXN + OI		1.69 (0.62, 4.63)	0.91 (0.26, 3.13)	1.80 (0.48, 6.77)	3.87 (2.03, 7.40)
YQWX + OI			0.54 (0.15, 2.00)	1.06 (0.26, 4.28)	2.29 (1.05, 4.97)
JPSX + OI				1.97 (0.41, 9.47)	4.25 (1.47, 12.28)
YQBX + OI					2.16 (0.68, 6.88)
Adverse events	SXN + OI	YQWX + OI	JPSX + OI	YQBX + OI	FFHY + OI	OI
SXB + OI	0.46 (0.19, 1.10)	1.03 (0.40, 2.68)	0.93 (0.41, 2.13)	0.29 (0.07, 1.11)	2.32 (0.75, 7.20)	1.47 (0.76, 2.86)
SXN + OI		2.23 (0.89, 5.56)	2.01 (0.92, 4.41)	0.62 (0.16, 2.31)	5.01 (1.71, 14.62)	3.18 (1.84, 5.51)
YQWX + OI			0.90 (0.36, 2.23)	0.28 (0.07, 1.12)	2.24 (0.69, 7.25)	1.43 (0.69, 2.96)
JPSX + OI				0.31 (0.08, 1.15)	2.49 (0.85, 7.31)	1.58 (0.91, 2.77)
YQBX + OI					8.11 (1.79, 36.78)	5.16 (1.55, 17.11)
FFHY + OI						0.64 (0.25, 1.60)

OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid.

Table 3 The surface under the cumulative ranking curve for outcomes.

	Clinical effective rate (%)	RBC (%)	Hb (%)	SF (%)	SI (%)	Incidence of adverse pregnancy outcomes (%)	Adverse events (%)
SXB + OI	62.2	49.5	33.2	40.9	33.3	60.6	47.4
SXN + OI	41.4	98.7	96	46.8	81.9	75.3	85.3
YQWX + OI	59.1	71.9	54.9	92.3	51.4	43.3	45.1
JPSX + OI	66	41.7	52.9	35.6	71	77.1	52.2
YQBX + OI	40.5	52.5	81.7	51.1	65.5	41.4	94
FFHY + OI	80.2	32.1	30.1	82.2	42	-	6.3
OI	0.5	3.7	1.4	1	4.8	2.4	19.7

OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid; RBC: Red blood cells counts; Hb: Hemoglobin; SF: Serum ferritin; SI: Serum iron.

RBC counts: The NMA demonstrated that combinations of SXB, SXN, YQWX, JPSX, and YQBX with OI significantly improved RBC counts compared with OI alone (P < 0.05). Indirect comparisons between the six CPMs showed that SXN was superior to SXB, JPSX, YQBX, and FFHY in terms of RBC recovery (P < 0.05). For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. For detailed data, refer to Table 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): SXN + OI > YQWX + OI > YQBX + OI > SXB + OI > JPSX + OI >FFHY + OI > OI.

Hb levels: The NMA demonstrated that combinations of SXB, SXN, YQWX, JPSX, and YQBX with OI significantly improved Hb levels compared with OI alone (P < 0.05). Indirect comparisons between the six CPMs showed that SXN was superior to SXB, YQWX, JPSX, and FFHY in terms of Hb recovery (P < 0.05). For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): SXN + OI > YQBX + OI > YQWX + OI > JPSX + OI > SXB + OI > FFHY + OI > OI.

SF levels: The NMA demonstrated that combinations of SXB, SXN, YQWX, JPSX, and FFHY with OI significantly improved SF levels compared with OI alone (P < 0.05). Indirect comparisons between the six CPMs showed that YQWX was superior to SXB and JPSX in terms of SF recovery (P < 0.05). For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): YQWX + OI > FFHY + OI > YQBX + OI > SXN + OI > SXB + OI > JPSX + OI > OI.

SI levels: The NMA demonstrated that combinations of SXB, SXN, YQWX, JPSX, and FFHY with OI significantly improved SI levels compared with OI alone (P < 0.05). An indirect comparison among the six CPMs revealed no statistically significant differences in terms of SI recovery. For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): SXN + OI > JPSX + OI > YQBX + OI > YQWX + OI > FFHY + OI > SXB + OI > OI.

Incidence of adverse pregnancy outcomes: The NMA demonstrated that combinations of SXB, SXN, YQWX, and JPSX with OI significantly reduced the incidence of adverse pregnancy outcomes compared with OI alone (P < 0.05). An indirect comparison among the six CPMs revealed no statistically significant differences in terms of reducing the incidence of adverse pregnancy outcomes. For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): JPSX + OI > SXN + OI > SXB + OI > YQWX + OI > YQBX + OI > OI.

Adverse effects: The NMA demonstrated that combinations of SXN and YQBX with OI significantly reduced the incidence of adverse events compared with OI alone (P < 0.05). Indirect comparisons between the six CPMs showed that SXN and YQBX was superior to FFHY in terms of reducing the incidence of adverse events (P < 0.05). For further details, see Table 2. The result is plotted as forest plots shown in Supplementary Figure 2. The rankings according to the SUCRA probabilities are as follows (Table 3; Figure 4): YQBX + OI > SXN + OI > JPSX + OI > SXB + OI > YQWX + OI > OI > FFHY + OI.

Cluster analysis

In three dimensions, clustering was performed on different indicators for various drugs to identify the most effective interventions. Interventions belonging to the same group were highlighted with the same color. Figure 5 displays the results of the three-dimensional clustering analysis for the clinical effective rate, RBC, and Hb. The analysis revealed that the combination of SXN and OI yielded superior efficacy.

Figure 5 Cluster analysis plot. OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid.

Funnel plot characteristics

By utilizing the total clinical effectiveness rate as a parameter, comparison-corrected Funnel plots were generated to analyze the included literature containing all six CPMs. The plots indicated a symmetrical distribution around the zero line for the majority of the literature. However, a subset of the distribution, as illustrated in Figure 6, exhibited dispersion and slopes, indicating the presence of publication bias and a small-sample effect.

Figure 6 Funnel plot of clinical effective rate. OI: Oral iron; SXB: Shengxuebao Mixture; SXN: Shengxianning Tablet; YQWX: Yiqi Weixue Chinese patent medicines; JPSX: Jianpi Shengxue Chinese patent medicines; YQBX: Yiqi Buxue Tablets; FFHY: Compound Hongyi Buxue Oral Liquid.

DISCUSSION

IDA, a deficiency disease arising from prolonged iron imbalance, affects Hb production and leads to anemia. It is a common complication during pregnancy, driven by several etiological factors. Notably, plasma and erythrocyte volumes increase during pregnancy, but the rise in plasma volume is relatively higher, causing blood dilution and decreased SF. Due to the developmental needs of the fetus, pregnant women require more iron and produce less gastric acid, which reduces iron absorption efficiency. As the fetus utilizes SF preferentially, pregnant women are more prone to iron deficiency, and inadequate iron supplementation can trigger anemia[63,64]. Research links anemia during pregnancy not only to conditions such as anemic heart disease, hemorrhagic shock, and perinatal infections but also to adverse fetal outcomes[13]. The primary clinical treatment for IDA in pregnancy is OI supplementation. The main OIs used clinically include Ferrous Iron Salts, Heme Iron, Carbonyl Iron, Iron Protein Succinylate, and Polysaccharide-Iron Complex. However, using OI alone often leads to gastrointestinal side effects. A meta-analysis of 20 trials indicated that oral ferrous sulfate significantly increased gastrointestinal side effects compared to placebo (P < 0.001), causing a 30%-70% reduction in treatment adherence among symptomatic patients[9,65]. Thus, the exploration of combination therapy using iron is also of interest.

Traditional Chinese Medicine (TCM) characterizes IDA as a "blood deficiency" and "fatigue" in pregnancy, occurring when the spleen and stomach are deficient or overexerted due to congenital endowment deficiencies. Anemia in this context results from a deficiency of Qi and Blood, leading to fatigue, dizziness, and palpitations. The primary treatment approach in TCM is to replenish Qi, nourish blood, and strengthen the spleen and stomach. Numerous studies have demonstrated that CPMs are comparable to OI in treating IDA, offering fewer side effects, and have thus gained significant attention as an adjunctive or alternative treatment. Iron supplementation remains effective, and it also improves the body’s ability to absorb and utilize iron effectively[66,67].

Using NMA, we assessed the efficacy and safety of CPMs as adjuvant treatments for IDA in pregnancy across seven indicators. The CPMs evaluated include SXB, SXN, YQWX, JPSX, YQBX, and FFHY, with the assessed indicators being clinical effective rate, RBC, Hb, SF, SI, adverse pregnancy outcomes, and adverse events. According to the results, FFHY + OI emerged as the most effective intervention in improving the clinical effective rate. RBC, which reflects the body's capacity to transport oxygen, saw the greatest improvement with SXN + OI. Hb, crucial for the oxygen transport function of erythrocytes[68], also improved most notably with SXN + OI. SF, a sensitive marker of iron storage[64], showed the greatest improvement with YQWX + OI. In the context of blood components, SI represents iron bound to transferrin, crucial for Hb synthesis and hematopoiesis[69], and SXN + OI was the top performer in improving SI levels. IDA reduces the supply of blood and nutrients to the fetus, which can adversely impact the fetus' growth and development.In reducing adverse pregnancy outcomes, JPSX + OI was the best intervention. Iron supplementation alone is associated with an increased risk of gastrointestinal adverse events. In reducing adverse events, YQBX + OI was the best intervention.

NMA results indicated that SXN + OI had higher SUCRA values for increasing RBC, Hb, SI, and reducing adverse pregnancy outcomes and events. Cluster analysis identified SXN + OI as the most effective intervention for improving treatment effects. The core ingredient of SXN tablets is silkworm sand, known for its mild nature and benefits to qi and blood. Modern pharmacology has demonstrated that SXN supplements iron and supports bone marrow hematopoietic functions, promoting the rapid recovery of erythrocytes and Hb, and effectively alleviating symptoms of anemia. The active elements in SXN, including sodium iron chlorophyllate and chlorophyllin derivatives, form porphyrin complex vesicles. These vesicles are absorbed through the Hb receptor by small intestinal mucosal cells. This absorption process is unaffected by dietary components such as oxalic acid, proteins, and plant fibers, ensuring high absorption efficiency. Furthermore, these components cause mild gastrointestinal stimulation, thereby reducing gastrointestinal adverse reactions and improving the drug's safety[70].

Limitations and future directions

This study has notable limitations: The low quality of the included studies and the lack of allocation concealment or blinding might introduce bias, potentially compromising the authenticity and reliability of the findings. Moreover, the absence of a closed-loop analysis and direct comparisons in the literature review could not establish heterogeneity, possibly leading to biased results. It is advisable to adhere strictly to the CONSORT standards for rigorous implementation and reporting of RCTs to minimize risk bias. To strengthen the evidence, further multicenter, large-sample, double-blind RCTs are recommended.

CONCLUSION

As a result, conventional treatment coupled with the use of CPMs as an adjunct to IDA was superior to OI alone. Furthermore, a comprehensive analysis by cluster analysis led us to conclude that SXN + OI was the most effective intervention to improve clinical efficacy and other outcome indicators. Nevertheless, due to the subpar quality of the studies included, it remains essential to carry out high-caliber RCTs for a direct comparison of CPMs to establish a more accurate foundation for clinical application.

ACKNOWLEDGEMENTS

We would like to thank the researchers and study participants for their contributions.