Prevalence, characteristics, and treatment outcome of congenital malaria in Nigeria: a systematic review

Abstract

Background

Congenital malaria remains a significant public health challenge in Nigeria, particularly in regions with high malaria endemicity. The increased vertical transmission of malaria is partly associated with the high susceptibility of women to malaria during pregnancy. This systematic review aimed to assess the prevalence, characteristics, and treatment outcomes of congenital malaria in Nigeria.

Methods

Twelve studies were included in this review. Studies were retrieved from multiple electronic databases such as PubMed, EMBASE, Google Scholar, Scopus, Web of Science, African Journals Online (AJOL), and Cochrane Library and subjected to a multistage screening per established eligibility criteria. The study was registered with PROSPERO and was conducted per PRSIMA-established guidelines. Quality assessment of included studies was done using the Critical Appraisal Skills Programme (CASP) framework, while a narrative synthesis synthesized and summarized extracted data.

Results

The prevalence of congenital malaria in Nigeria ranged from as low as 5.1% to as high as 96.3%. Clinical manifestations were often non-specific, with fever being the most common symptom. Treatment regimens included a variety of antimalarial drugs, such as chloroquine, sulfadoxine-pyrimethamine, amodiaquine, quinine, and artemisinin-based combination therapy. While treatment outcomes were generally positive, some studies reported complications and deaths.

Conclusions

The findings highlight the need for improved diagnostic tools, standardized treatment protocols, and targeted interventions in high-burden areas. Further research is required to investigate the long-term health outcomes of neonates with congenital malaria and to evaluate the effectiveness of different treatment strategies. By addressing these gaps, effective prevention and management strategies can be developed to reduce the burden of congenital malaria in Nigeria.

Background

Malaria remains a significant global health challenge, particularly in regions within the Global South. In 2023, an estimated 263 million cases of malaria and 597,000 deaths were reported across 83 countries, with the World Health Organization (WHO) African Region disproportionately bearing the burden—accounting for 94% of cases (246 million) and 95% of deaths (569,000) [1]. This burden predominantly affects vulnerable populations, including children under five and pregnant women, who face the highest risk of severe disease and mortality due to their relative immunosuppression [2]. Children under five years old accounted for 80% of malaria deaths globally in 2023 [1]. Pregnant women are also highly susceptible, as malaria in pregnancy (MiP) can result in complications such as maternal anemia, stillbirth, preterm delivery, and low birth weight, all of which increase neonatal and infant mortality rates [3]. Within this vulnerable cohort, congenital malaria represents a specific but often overlooked and misdiagnosed health challenge.

Congenital malaria presents unique diagnostic and therapeutic challenges [4]. This condition arises from transplacental transmission of Plasmodium, primarily Plasmodium falciparum, during pregnancy or delivery, leading to significant neonatal health consequences [1, 5]. Unlike the mosquito-borne transmission of malaria, congenital malaria occurs in utero or during labor, making it a distinctive yet under-recognized manifestation of the disease [6]. In neonates, the symptoms of congenital malaria often overlap with those of other serious illnesses, such as neonatal sepsis, bacterial meningitis, or metabolic disorders, contributing to diagnostic challenges and potential misdiagnosis [7]. Common clinical features include fever, anemia, hepatosplenomegaly, poor feeding, and irritability, but less specific signs like respiratory distress and cyanosis can also occur [8, 9]. Laboratory findings, including parasitaemia and thrombocytopenia, aid in diagnosis, typically through rapid diagnostic tests (RDTs), microscopy of stained blood smears, or polymerase chain reaction (PCR) testing [10]. However, the reliance on clinical presentation alone frequently leads to missed or delayed diagnoses, particularly in resource-limited settings where advanced diagnostic tools are unavailable [11].

Nigeria, with the highest global malaria burden, reports alarmingly high rates of congenital malaria, mirroring the widespread prevalence of MiP [12]. Contributing factors include poverty, inadequate healthcare access, pregnancy-related immunosuppression, and other socio-demographic determinants [12, 13]. Many cases remain undiagnosed or untreated, leading to significant maternal and neonatal complications [14]. Treatment of congenital malaria poses additional challenges, as anti-malarial regimens must balance efficacy with safety in this vulnerable age group. Historically, older anti-malarial drugs, such as chloroquine, quinine, and sulfadoxine-pyrimethamine (SP), were commonly used. However, widespread resistance to these agents has prompted the adoption of artemisinin-based combination therapy (ACT) as the gold standard for malaria treatment since 2005 [15, 16]. The use of ACT in neonates has demonstrated superior outcomes, although safety and efficacy studies remain limited in this population. Moreover, varying treatment practices and delays in administering effective therapies further compound the risks of poor neonatal outcomes [16].

Congenital malaria presents in two distinct forms: a milder, asymptomatic variant with transient parasitemia that resolves spontaneously, and a severe form characterized by persistent parasitaemia and life-threatening complications [14]. Historically considered rare in Africa, congenital malaria is now increasingly recognized due to heightened awareness and improved diagnostic capabilities [15]. Nonetheless, gaps persist in understanding the nationwide prevalence, clinical characteristics, and outcomes of different treatment regimens for congenital malaria in Nigeria. This review aims to address these gaps by synthesizing available data on the prevalence, clinical manifestations, and treatment outcomes of congenital malaria in Nigeria.

Methods

Study protocol and registration

This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and adhered to a protocol registered with PROSPERO (International Prospective Register of Systematic Reviews) under registration number CRD42024565939 [17]. The protocol detailed the research question, objectives, inclusion and exclusion criteria, and the methodological approach for this review.

Search strategy

A search of PubMed, EMBASE, Google Scholar, Scopus, Web of Science, African Journals Online (AJOL), and Cochrane Library were conducted. Keywords and Medical Subject Headings (MeSH) related to "congenital malaria," "malaria in the newborn," "congenital cerebral malaria," "neonatal malaria," "prevalence," "characteristics," "treatment outcomes," and "Nigeria" were used. The search was limited to English-language articles published from the inception of each database (e.g., PubMed from 1940, Scopus from 2004) to June 2024. The inclusion criteria included:

Study design

• Observational studies (cohort, case–control, cross-sectional)

• Intervention studies (randomized controlled trials, controlled clinical trials)

Study population

• Pregnant women and their newborns up to 7 days old

• Studies conducted in Nigeria

Exposure

• Malaria infection during pregnancy

Outcome

• Prevalence of congenital malaria

• Clinical characteristics of congenital malaria

• Treatment outcomes of congenital malaria

Data

• Studies reporting data on prevalence, characteristics, and treatment outcomes of congenital malaria

The following exclusion criteria were applied:

Study design

• Review articles

• Editorials

• Letters to the editor

• Conference abstracts without full-text availability

Study selection

Titles and abstracts were independently screened by two reviewers (NA & GO) to determine eligibility based on the inclusion and exclusion criteria outlined in the PROSPERO protocol. Full-text articles of potentially eligible studies were then reviewed. Any discrepancies between reviewers were resolved through discussion or by consulting a third reviewer (EK). Data extraction included study details (authors, publication year, design, location, duration), demographics (age in days or months), diagnostic criteria, prevalence, clinical characteristics, treatment outcomes, and regional variations.

Quality assessment

The quality of the included studies was evaluated using the Critical Appraisal Skills Programme (CASP) framework. This assessment tool was applied to systematically review each study's design, population representativeness, data collection methods, data analysis, results, and conclusions. The CASP appraisal provided a structured approach to assessing the methodological rigor and overall reliability of the research. Supplementary file 1.

Data synthesis

A narrative synthesis was used to summarize key findings, including prevalence, clinical characteristics, and treatment outcomes. The findings were interpreted in the context of study quality, potential biases, and implications for clinical practice, public health, and future research.

Results

Study characteristics

A total of 162 studies were identified through the search. After applying the inclusion and exclusion criteria, 12 studies [18,19,20,21,22,23,24,25,26,27,28,29] were retained for the final analysis (Fig. 1). The total sample size across all the studies is 4,510 (see Table 1). The geographic scope of the studies spans multiple regions across Nigeria. The Southwest region (highest number of studies) includes Ogun State (Sagamu), Lagos State, and Osun State (Ile-Ife). The Northwest region is represented by Sokoto and Kaduna State (Zaria), while the North Central region features Abuja (FCT) and Plateau State (Jos). Additionally, the Southeast region includes Anambra State (Awka) and Delta State (Eku).

Fig. 1

Flowchart

Table 1 Study characteristics

The prevalence of congenital malaria in Nigeria varies significantly across different studies, ranging from as low as 5.1% in a multi-centre study spanning Oyo, Kwara, and Kaduna states [19] to as high as 96.3% in Sokoto [23]. Treatment approaches across the studies included the use of Chloroquine, SP, Amodiaquine, Quinine (both oral and intravenous), and artemether-lumefantrine. Chloroquine was the most commonly used drug. However, it is important to contextualize these findings within the studied periods, as the treatment of malaria in Nigeria has evolved over time. Notably, ACT was officially introduced as first-line treatment for malaria in Nigeria in 2005, following global recommendations due to widespread resistance to chloroquine and other older anti-malarial drugs. The studies that predominantly reported the use of Chloroquine and other non-ACT were likely conducted before or during the early phases of ACT implementation.

Prevalence of congenital malaria

The prevalence of congenital malaria in Nigeria varies significantly across different studies, reflecting regional differences and methodological approaches. Studies have reported a wide range of prevalence rates, which highlight the impact of local malaria endemicity and diagnostic practices. Falade et al. [19] documented an average prevalence rate of 5.1% in a multi-centre study conducted across three Nigerian states: Oyo, Kwara, and Kaduna, which represent different geopolitical zones. However, given the substantial variation in prevalence rates observed in individual states, it is important to note that this figure should be interpreted as an average for the combined states and not as a uniform rate across the regions. In contrast, Runsewe-Abiodun et al. [18] found a much higher prevalence rate of 17.4% in Sagamu, Ogun State. Obiajunwa et al. [20] reported an even higher prevalence of 46.7% in Ile-Ife, Osun State. Similarly, a study by Okechukwu et al. [22] observed a prevalence of 28.6% in Abuja, in the Northcentral region.

Studies from the northern regions of Nigeria also show varying prevalence rates. Onankpa et al. [23] recorded a striking prevalence of 96.3% in Sokoto. Additionally, Diala et al. [27] reported a prevalence of 5.3% in Jos, Plateau State. Other studies, such as Mukhtar et al. [21] in Lagos and Hyacinth et al. [26] in Jos, Plateau State, reported lower prevalence rates of 13.4% and 58.5%, respectively.

Characteristics of congenital malaria cases

The gender distribution of congenital malaria cases revealed a slight male predominance across most studies. However, Hyacinth et al. [23] reported an equal number of male and female participants, unlike the other studies, which documented unequal male-to-female ratios. This variability highlights demographic differences across study populations. The clinical presentations of congenital malaria were largely non-specific, but certain patterns emerged. Fever was the most consistently reported symptom, appearing in every case reported [19, 23, 28]. Across the studies that documented clinical features, fever was universally observed. Poor feeding was another common clinical feature, identified in 75% of the reviewed studies [18,19,20, 18,19,20].

Jaundice and hepatomegaly were reported in 25% of the studies [25, 27, 28], while respiratory issues, such as respiratory distress, difficulty breathing, or rapid breathing, were documented in 33% [18, 24, 25, 27]. Convulsions and cyanosis were each observed in 17% of the studies [18, 24, 26, 27], and hypothermia was similarly noted in 17% [20, 28]. Excessive crying was also reported in 17% of the studies [24, 27]. Less common symptoms included umbilical cord discharge, skin rashes, and oliguria, which were sporadically noted across the studies. It is worth mentioning that Mukhtar et al. and Okonkwo et al. did not provide details about the clinical symptoms observed in their neonatal subjects [22, 29].

Treatment options

The treatment options for congenital malaria in Nigeria have evolved over time, reflecting changes in malaria treatment guidelines and the availability of newer therapies. Across the studies reviewed, a variety of antimalarial drugs were used, including SP, chloroquine, quinine, amodiaquine, ACT, and intravenous artesunate. The choice of treatment was influenced by both the timing of the studies and the prevailing malaria treatment protocols.

Earlier treatment protocols (before the widespread adoption of ACT and artesunate)

In the earlier studies, prior to the universal recommendation of ACT, SP, chloroquine, quinine, and amodiaquine were commonly used. For example, SP was employed in studies performed during a period when ACT had not yet been universally adopted [19, 20, 29]. Chloroquine remained a popular choice for treating malaria [19,20,21, 24, 29], despite its declining effectiveness due to the emergence of chloroquine-resistant strains of Plasmodium falciparum.

Use of amodiaquine and quinine

Amodiaquine, often used in combination with artesunate, was frequently used [26, 27, 29]. Quinine, administered through various routes, was used in the treatment of severe malaria cases. It was still employed particularly before intravenous artesunate became more widely available [25, 26, 28].

Introduction of intravenous artesunate and artemether-lumefantrine (ACT)

The introduction of intravenous artesunate and the adoption of ACT marked a significant shift in the treatment of severe and uncomplicated malaria cases. In the study by Nwaneli et al. [18], intravenous artesunate was exclusively used, reflecting the later introduction of this therapy as a response to growing resistance to older antimalarial drugs. ACT was also used in the study by Onankpa et al. [23], consistent with the more recent guidelines from the WHO, which recommended ACT as the first-line treatment for uncomplicated malaria.

Inconsistent treatment regimens and routes of administration

One of the challenges in interpreting treatment approaches across studies was the inconsistency in the reported treatment regimens and routes of drug administration. For instance, in the studies by Runsewe-Abiodun et al. [20] and Obiajunwa et al. [21], some patients did not receive any treatment, with 6 and 10 untreated patients, respectively. The study by Mukhtar et al. [22] also involved patients who were monitored without therapeutic intervention, with follow-up extending to 28 days. These instances highlight gaps in treatment delivery, which were not aligned with malaria treatment guidelines at the time.

Notable treatment approaches

In some cases, the treatment regimens were tailored to specific age groups or clinical conditions. For example, in the study by Falade et al. [19], symptomatic infants with parasitaemia were first treated with chloroquine before the age of 3 days, and SP was used for those who did not respond to chloroquine by day 3. Although this approach reflected earlier treatment protocols, it likely led to suboptimal outcomes due to the development of chloroquine resistance. In contrast, Orogade employed a treatment regimen starting with a subcutaneous dose of chloroquine (5 mg/kg), followed by daily oral doses (10 mg/kg) for two additional days [24].

In more recent studies, including that of Nwaneli et al. [18], a more contemporary treatment approach was employed, where intravenous artesunate (3 mg/kg for 5 days) was given, followed by a 3-day course of oral artesunate-amodiaquine combination therapy.

Treatment success rates

An analysis of all twelve studies reveals notably high success rates for the antimalarial treatments administered to neonates with congenital malaria. The overall effectiveness of the therapies employed consistently reflects positive outcomes, although the success rates are closely tied to how well the treatment approaches adhered to the prevailing malaria treatment guidelines during each study period. In studies that followed the most current guidelines at the time, such as those that incorporated ACT, treatment success was particularly high. For example, the study by Onankpa et al. [23] demonstrated significant success with ACT in treating congenital malaria, with a high cure rate that aligns with the recommendations of the WHO for the treatment of P. falciparum malaria. This is consistent with the broader adoption of ACT as a first-line treatment for uncomplicated malaria in line with updated guidelines. In earlier studies that adhered to older treatment protocols, chloroquine was still widely used, with studies by Falade et al. [19] and Obiajunwa et al. [20] showing high rates of parasitological cure and clinical improvement. However, the effectiveness of chloroquine has been compromised over time due to the emergence of chloroquine-resistant strains of P. falciparum. Despite this, chloroquine still showed positive outcomes in these studies, likely reflecting cases involving non-resistant strains or early periods prior to widespread resistance.

In instances where chloroquine was insufficient, other medications such as SP and quinine were successfully employed, ensuring positive outcomes. For example, the studies by Runsewe-Abiodun et al. [18] and Okechukwu et al. [22] reported favourable results with SP and quinine, indicating that these treatments were still effective in managing congenital malaria, even as newer therapies, such as ACT, gained prominence. Amodiaquine, a drug often used in combination with artesunate, also demonstrated high effectiveness, achieving a 94% cure rate in the study by Diala et al. [27]. The success of amodiaquine can be attributed to its adherence to treatment guidelines during its use, particularly in areas with limited access to ACT. Quinine, whether administered intravenously or orally, was well-tolerated and effective in treating severe malaria, as evidenced by the findings of Anyanwu et al. [24] and Okechukwu et al. [22]. Although quinine is now considered second-line therapy, it showed high success rates in these studies, likely due to its timely administration in severe cases of congenital malaria and its continued inclusion in national treatment guidelines during the periods of the studies.

Complications and adverse outcomes

Out of the twelve studies analysed, three [20, 21, 26] reported deaths attributable to congenital malaria. Notably, in the study by Runsewe-Abiodun et al., the deaths occurred in neonates whose fever persisted beyond five days despite appropriate malaria treatment, suggesting potential unidentified contributing factors. The treatments administered included chloroquine for 50 infants, SP) for 1 infant, and 6 neonates received no treatment at all. Similarly, in the study by Hyacinth et al., congenital malaria was directly linked to neonatal deaths, though details on other potential contributing conditions were not specified [26]. The treatment regimens used included amodiaquine for 20 infants, quinine for 3, and a combination of amodiaquine and quinine for 1 infant. Onankpa et al. [23] highlighted a more complex scenario. Although congenital malaria was confirmed in six cases, these were accompanied by septicaemia, and five additional infants died despite negative malaria tests and appropriate treatment. These infants exhibited persistent fever and worsening clinical signs, indicating possible underlying or co-existing conditions that contributed to their deaths. In contrast, the remaining studies reported no complications or fatalities directly attributable to congenital malaria. Studies did not document any severe adverse outcomes [19, 21, 22, 24, 25, 27, 28, 29]. Even in the case documented by Nwaneli et al., where the infant initially experienced seizures and opisthotonic posture, follow-up after one year revealed no lasting neurologic deficits [29].

Discussion

This review provides an analysis of congenital malaria in neonates, examining 12 studies across various regions in Nigeria. The findings highlight important patterns and outcomes in the management of this condition, revealing both commonalities and variations in clinical presentations, treatment regimens, success rates, and complications. The prevalence of congenital malaria in Nigeria exhibits notable regional variability, reflecting differences in local malaria transmission rates and diagnostic practices. This variability is consistent with findings from global literature, which underscores how endemicity influences the prevalence of congenital malaria in different settings [30].

In Nigeria, prevalence rates have ranged from as low as 5.1% in a multi-center study across Oyo, Kwara, and Kaduna states [19] to as high as 96.3% in Sokoto, reflecting the severe endemicity of malaria in this region [23]. These discrepancies mirror the regional malaria transmission intensity, which is a common pattern observed worldwide. For instance, in highly endemic areas like Sokoto, where malaria transmission is intense, the prevalence of congenital malaria is correspondingly high. This is consistent with findings from other malaria-endemic regions, such as sub-Saharan Africa, where areas with high malaria burden report higher rates of congenital malaria [1, 2].

The prevalence rate of 28.6% in Abuja [22] suggests that even in regions with better healthcare facilities, congenital malaria remains a significant concern. This highlights the need for continued vigilance and targeted interventions, especially in urban areas where healthcare accessibility might be higher but malaria remains a persistent threat. The findings also underscore the need for context-specific healthcare strategies, with regions experiencing higher prevalence requiring intensified malaria control measures, such as widespread antenatal screening and access to anti-malarial medications. On the other hand, regions with lower prevalence should focus on maintaining and enhancing existing malaria control programmes.

The variability in prevalence rates also emphasizes the diagnostic challenges of congenital malaria. The non-specific nature of congenital malaria symptoms, which often overlap with those of other neonatal conditions, complicates early diagnosis. Fever emerged as the most consistently reported symptom, corroborating previous studies [31, 32]. The frequent occurrence of poor feeding, jaundice, and hepatomegaly further highlights the complex clinical spectrum of the disease. Respiratory symptoms, while less prevalent, should not be overlooked, as they could indicate underlying congenital malaria, especially in malaria-endemic regions. This underscores the need for heightened clinical suspicion and early recognition, which can lead to prompt management and better outcomes [33, 34].

Early and accurate diagnosis of congenital malaria is crucial, as it allows for timely intervention that can prevent severe complications. Standardized case definitions and diagnostic algorithms, tailored to the local malaria burden, could enhance the accuracy of congenital malaria diagnosis. Furthermore, public health interventions aimed at reducing malaria transmission during pregnancy, such as insecticide-treated nets (ITNs) and intermittent preventive treatment, are essential for preventing congenital malaria and potential outbreaks.

The use of ACT, such as artemether-lumefantrine, aligns with current WHO guidelines, which recommend ACT as the first-line treatment for uncomplicated P. falciparum malaria [35]. This is consistent with broader research literature, which recognizes ACT for its high efficacy, particularly in areas where resistance to older drugs like chloroquine is prevalent [36]. However, the recurring use of chloroquine in several studies points to its historical prominence as a frontline anti-malarial drug. Despite its diminished effectiveness in many regions due to widespread resistance, chloroquine continues to be used in some areas, reflecting the slow transition to newer therapies.

The use of other drugs, such as amodiaquine and quinine, in various studies also reflects the ongoing efforts to find effective treatment regimens, particularly in cases where resistance to first-line treatments is a concern. The varying treatment regimens, including different routes of administration and combination therapies, underscore the complexities of managing congenital malaria, especially across diverse demographic and geographic settings.

The diverse treatment approaches observed across these studies have significant clinical implications. The variation in treatment regimens suggests the need for standardized guidelines that can be adapted to local contexts, ensuring the efficacy of treatments. The successful use of ACT in some studies aligns with current best practices, suggesting that these treatments should be more widely adopted, particularly in regions with known resistance to other antimalarials [37]. However, the continued use of older therapies like chloroquine, despite known resistance patterns, points to gaps in the implementation of updated treatment protocols. This indicates the need for ongoing education and resources to support healthcare providers in transitioning to more effective treatment options.

The findings also highlight the importance of developing and adhering to standardized treatment protocols that consider drug resistance, comorbidities, and other factors influencing treatment success. While chloroquine remains effective in some contexts, the increasing prevalence of resistance necessitates a more widespread adoption of ACT. Additionally, quinine and other drugs, while useful in some cases, should be evaluated against current resistance patterns and safety profiles.

Although treatment success rates were generally high across the studies, some did report complications and adverse outcomes, including fatalities. Three of the twelve studies reviewed reported deaths attributable to congenital malaria, which underscores the severity of the condition in neonates. The variability in outcomes across studies further suggests that clinicians should remain vigilant in assessing the full clinical picture, including the possibility of comorbidities or complications that may complicate treatment. This reinforces the need for comprehensive care that addresses both the malaria and its potential complications.

In the future, larger-scale, multi-center investigations are required to validate and generalize the findings across diverse regions and populations in Nigeria, and potentially in other African countries. These studies should employ rigorous methodologies, such as randomized controlled trials, to provide stronger evidence on the efficacy of various therapies, including preventive measures and lifestyle interventions. Additionally, future research should focus on the impact of adherence-enhancing interventions, which could be critical in ensuring optimal malaria therapy, especially in resource-limited settings.

Limitations of review

The studies used various methodologies, including different diagnostic criteria and treatment approaches. This variability makes it difficult to directly compare results and draw definitive conclusions. Moreover, the review primarily focused on treatment success rates and immediate complications. It would be beneficial to understand the long-term health outcomes of neonates who had congenital malaria.

Conclusion

This systematic review analysed the prevalence, characteristics, and treatment outcomes of congenital malaria in Nigeria. The findings revealed significant regional variations in congenital malaria prevalence, with some states reporting relatively low rates, while others, particularly those with intense malaria transmission, experienced alarmingly high figures. Sokoto recorded a prevalence rate as high as 96.3%, while Oyo, Kwara, and Kaduna states reported a lower rate of 5.1%. These disparities shows the need for targeted interventions in high-burden areas. The clinical presentation of congenital malaria was complex and often non-specific, with fever being the most common symptom. This highlights the challenge of early diagnosis and the importance of a high index of suspicion among healthcare providers. A variety of antimalarial drugs were employed in treatment, with varying degrees of success. While some older drugs like chloroquine were still used, the increasing recognition of drug resistance emphasizes the need for wider adoption of more effective treatments, such as ACT. Future research should focus on larger-scale studies to strengthen the generalizability of findings, explore long-term health outcomes, and conduct randomized controlled trials to evaluate treatment efficacy. Additionally, investigating adherence-enhancing interventions is crucial for optimizing malaria treatment. It is important to note that the studies included in this review employed diverse methodologies, making direct comparisons challenging. Moreover, the focus on treatment success rates and immediate complications limits the understanding of long-term health outcomes.