Exploring the relationship between anemia in pregnancy and infant mortality: a narrative review

Anemia is a multivariate and highly prevalent health concern among the worldwide population. However, owing to the socioeconomic conditions of Pakistan and physiological changes that take place during pregnancy, an exceptionally high percentage of pregnant Pakistani females suffer from anemia with the most common cause being iron deficiency. Unsurprisingly, many complications for both mother and child have been recorded in association with this issue, such as postpartum hemorrhage, low birthweight, stunted development, and still birth. Given the situation, it is imperative to strengthen operational measures while introducing more effective strategies to improve health status among pregnant women.


Introduction
Anemia, as defined by the WHO, is a condition that leads to a decreased oxygen carrying capacity of the blood, presenting mainly as fatigue and weakness due to the lack of proper oxygenation of the body's tissues.The three main reasons for anemia comprise of blood loss, decreased/defected red blood cell (RBC) production, or increased RBC destruction.The probable causes vary according to the physiologic needs of a person depending upon age, sex, pregnancy status, and a few other factors such as economical status and cultural practices [1,2] .
According to WHO, around 40% of pregnant women are anemic worldwide, therefore it is considered to be a global public health problem in this specific population.The two most common types of anemia in pregnant women are iron deficiency anemia (IDA) and megaloblastic anemia.In pregnancy particularly, the body's nutritional requirements increase in order to provide optimal nourishment for the fetus.The daily iron intake for a normal adult female is estimated to be 14.8 mg, this goes up to around 30 mg/day during pregnancy.This is due to the fact that iron is not only needed for the regular bodily-functions, but is also required to increase RBC production and for plasma volume expansion, hence supporting the fetal-placental circuit to make up for the blood loss at delivery.In the mother, IDA is associated with multiple complications, including but not limited to a higher risk of maternal mortality, eclampsia, cardiovascular insufficiency, hemorrhagic shock, thermoregulation reduction, breast milk production disruption, on top of the regular anemic symptoms of pallor, fatigue, weakness, and irritability.In the fetus, it can result in placental abruptions, in-utero death, increased infection risks, preterm low-birth weight delivery, and can go onto disrupt their neurophysiological development [1,2] .
Similarly, the dietary allowance of folic acid goes from 400 mg in a normal adult to 600 mg during pregnancy.There is a huge probability of developing a megaloblastic anemia during pregnancy unless adequate supplementation is provided to the pregnant mother.Therefore, it is crucial to work toward preventing such a problem right from the time of conception planning, which can otherwise lead to detrimental effects on the fetus, such as increasing the risk of neural tube defects, and ultimately producing devastating outcomes [3,4] .
Worldwide, around 1.62 billion people were found to be anemic of which 56 million were pregnant women.In Pakistan, the prevalence of anemia in pregnant women varies between 29 and 50%, depending on the area (rural or urban) mainly due to the underlying socioeconomic disparities.Even though the data in such developing countries is very limited and unreliable, certain statistics went on to estimate the presence of IDA in some of the major cities in Pakistan to be around 64% in Karachi, 73% in Lahore, and 76% in Multan [5] .
This review aims to elaborate on various factors resulting in such high prevalence of anemia in Pakistan, it is consequences for both mother and child and strategies that can be applied to improve the situation in an effective manner [6] .
AND pregnancy', 'anemia AND pregnancy AND infant mortality', 'anemia AND pregnancy AND Pakistan'.Search results were then narrowed down by selecting relevant studies including crosssectional studies, meta-analyses, review articles, and randomized controlled trials where necessary.However, studies such as commentaries, LTEs, only abstracts, non-English text, and paid articles were excluded from this study.Statistics were also added from reliable sources, such as the official WHO website, wherever required to supplement points of discussion.All the articles included were screened by multiple authors to avoid bias.

Poverty and poor nutritional status
Anemia is a major public health concern among women specially those of reproductive age.In Pakistan, National Nutrition Survey 2018 reveals that 41.7% of Women of Reproductive age (WRA) are anemic, the burden being slightly higher in Rural areas (44.3%) compared to urban areas (40.2%).It also reveals that every one in seven WRA is undernourished making them susceptible to anemia [7] .
Recent developmental updates have shown that up to 30 million women in Pakistan live in poverty, not only exposing them to food shortages but also to limited healthcare facilities during pregnancy, with a low doctor to patient ratio in Basic Health Units (BHU) and Rural Health Centers (RHC) [8] .Apart from that, only 1% of the women have health insurance, while a large number of the working women are in the informal sector where proper protocol is not laid down for such incentives, therefore, depriving them of health protection from employers [8] .
It is known that women with poor nutritional status have worse outcomes including low immunity, poor growth, and poor mental development and it can also be an underlying cause of anemia during pregnancy [8] .National Nutrition Survey of 2011 revealed that pregnant women in Pakistan are deficient in multiple macro and micronutrients including iron, zinc, and vitamin A [9] .Iron and folic acid are two micronutrients that are required by the body to form functional RBCs and therefore prevent anemia [10] .WHO recommends daily oral iron (30-60 mg) and folic acid supplementation (0.4 mg) for pregnant women [11] .In Pakistan, these supplements are provided to women during antenatal care by BHU/ RHC or they are prescribed to them in private clinics.Barriers to supplementation include low adherence to antenatal care, lack of education, lack of counseling, low compliance, and at times lack of availability of these supplements [12] .Lack of nutrition coupled with inadequate supplementation during pregnancy thus increases the prevalence of anemia especially since deficiency of micronutrient iron remains to be the most common cause of anemia [13,14] .

Lack of education
Besides poverty, a study conducted in the Khyber Pakhtunkhwa (KPK) province of Pakistan established the relation that the incidence of anemia decreases with a higher level of education, according to the study the rate of anemia was 88% in the pregnant women who had received no formal education [15] .Another research conducted in Thatta revealed that the majority of the women were not aware of what anemia was, and would consider it a blood deficiency.Lack of knowledge combined with limited access to health in lower socioeconomic conditions made anemia prevalent in pregnant women of rural areas [16] .In Urban areas, lack of nutritional education, lack of a balanced diet with lower intake of red meat, egg, and fruit, low iron levels prior to pregnancy, and increased consumption of tea were found to be a cause of high rates of anemia [17] .

Lack of reproductive autonomy and societal norms
A study assessing maternal health in the Punjab province of Pakistan revealed factors that contribute to poor maternal health outcomes.These include early marriages and the low status of women where they are considered subordinates to men in a highly patriarchal society with no say in decision-making leading to lack of reproductive autonomy [18] .Early marriages mean that due to immaturity, these women will less likely be able to make health decisions for themselves as seen by the high rates of multiparity in young women of Pakistan and low contraception rate.The slowgrowing Contraceptive Prevalence Rate also confirms this struggle of Pakistan where only 15% of WRA receive family planning services [19,20] .Women are expected to have multiple close-spaced pregnancies due to religious, societal, and economic reasons where family planning is considered a sin, while the birth of a female child is looked down upon and hence conceive multiple times.Without family planning and reproductive autonomy, large families in an already low socioeconomic background would also lead to food insecurity where females would be more likely to be ignored and not have their dietary needs met [21] .Multiple pregnancies would also lead to a further decrease in micronutrients as a women's body loses its iron stores during pregnancy and childbirth, in case of a subsequent close-spaced pregnancy the body will be unable to recover and form adequate stores hence resulting in exacerbation of anemia [22] .

Contribution of prevalent diseases
Another factor that could contribute to anemia in pregnant women is the prevalence of gastrointestinal diseases.In Pakistan, the most common intestinal parasites that prevail are Ascaris Lumbricoides, Hookworm, and Giardia Lamblia [23] .These parasites attach to the host mucosa and feed on blood and tissues leading to chronic blood loss and malnutrition [24] .Infections from these organisms prevail are more common in lower socioeconomic societies, where tap water is consumed, poor personal hygiene is maintained and there is a lack of a clean environment [23] .Another common gastrointestinal condition that extra intestinally presents with iron deficiency anemia is celiac disease [25] , which is an immune-mediated disorder triggered by foods containing gluten and is associated with the development of malabsorption in individuals [26] .Approximately 10-20% of celiac disease patients develop iron deficiency anemia therefore adding to the list of above-mentioned factors increasing the risk of anemia in pregnancy [25] .

Complications
The onset of Anemia during pregnancy has many health complications in mothers and developing fetus during all trimesters and after birth.Mahmood et al. have mentioned in their retrospective study that the prevalence of maternal complications such as gestational hypertension, pre-eclampsia, antepartum hemorrhage, postpartum hemorrhage (PPH), transfusions, prolonged/ obstructed labor, urgent induction of labor, and urgent cesarean section were statistically more significant among women with anemia compared to nonanemics [27] .Neonatal complications such as low birth weight (LBW), small-for-gestational-age, preterm, stillbirth and early neonatal death were also associated with maternal anemia [27] .Anemia can increase risk of severe maternal morbidities (SMM) such as poor cardiac function and chances of hemorrhage [28] .Daru et al. have analyzed that out of n = 312 281, 4687 women had severe anemia among which there were 341 (7%) maternal deaths giving a P < 0.0001 making the correlation highly statistically significant [29] .

Postpartum hemorrhage
The most common cause of maternal death among pregnant women is PPH according to the National Institute of Child Health and Human Development (NICHD) [30] .PPH is highly associated with severe anemia, which is caused due to the lack of oxygen and hemoglobin supply to muscular structures such as uterus during delivery.Muscles of uterus lose their tone and fail to contract blood vessels during pregnancy leading to a significant blood loss [31] .Anemic mothers cannot bear large amounts of blood loss, which also causes cardiogenic shock and leads to death [28] .One intervention to overcome this issue is to provide immediate blood transfusion; however, it has multiple adverse effects on its own.Ehsan et al. mentioned in their systematic review that blood transfusions in Pakistan have been associated with the risk for infections, leading to prenatal and antenatal sepsis [32] .This further leads to complications such as prenatal and antenatal sepsis.In Pakistan, the risk for congenital rubella infection has been rising among pregnant women that causes cardiac, auditory, ophthalmologic, neural, and blood defects in infants [33] .Rubella in other parts of the world has been eradicated through immunization vaccines, whereas in Pakistan, rubella immunization programs are yet to be introduced [33] .

Pre-eclampsia/eclampsia
In severe maternal anemia, there is a higher risk for developing hypertensive disorders and pre-eclampsia, which can progress to eclampsia.While it is secondary to hemolytic anemia during Hemolysis, Elevated Liver enzymes and Low Platelet (HELLP) Syndrome, pre-eclampsia and hypertension is associated with multiple micronutrient deficiencies among pregnant women, which prevail in low to middle income countries (LMICs) where micronutrients such as zinc, calcium, and magnesium are absent in the diets of pregnant women [34] .

Hampered fetal growth and still births
During the prenatal phase, the complications for Anemia in fetus include high risk for prenatal morality, still births, and spontaneous abortion [35] .Other complications include premature births, intrauterine growth restriction and LBW.These complications occur when the nutrients and iron levels in mother's blood do not meet the needs of a developing fetus.Parks et al. have stated in their prospective cohort study that fetal and neonatal mortality is statistically significant with severe maternal anemia [36] .While there are chances of survival, the future implications for these children include weak immunity, poor physical, and mental development, and susceptibility to many comorbidities [37] .
In Pakistan, the healthcare system aims to provide efficient maternity care; however, many shortcomings prevent progress.
These include low number of healthcare centers, short number of professional staff, lack of equipment, lack of incubators and ventilators, unhygienic working environment, and miscommunication between patient and doctor [38] .Additionally, families from rural areas travel long distances to reach certified healthcare centers, they find many treatments and tests unaffordable, making it difficult to access care in emergency situations.Many uneducated patients tend to approach unskilled individuals for deliveries where they perform unhygienic procedures and use traditional methods for operations (using herbs to reduce pain and prevent infection) that are not medically approved [39] .These practices in Pakistan make it challenging for maternity care from stabilizing and being satisfactory.

Comparing Pakistan with other South Asian countries
Afghanistan Afghanistan, like Pakistan, is also considered a LMIC and has multiple research literature that updates on maternal and fetal health for its prevalence of anemia.During the years 2018-19, the prevalence of anemia among the total population of pregnant women in Afghanistan was 36.5%, according to WHO, which is considered a moderate health problem [40] .This prevalence is comparatively lower than that of Pakistan's, which happened to be 57% during the same time frame [40] .An observational study by Ahmadi et al. in 2022 at Qarabagh District, Ghazani province, Afghanistan was conducted to evaluate the prevalence of anemia among 625 pregnant women receiving antenatal care.This study reported that factors such as household income, husband's employment status, menstruation cycle, previous pregnancy complications and education impacted prevalence on anemia in Afghanistan [41] .Compared to Pakistan, the same factors do apply, which affect the incidence of anemia among pregnant women.Anwary et al. states further in their cross-sectional data analysis that among 787 pregnant women in Bost Hospital, Afghanistan, the women's employment status and birth interval too plays a statistically significant role in incidence of anemia [40] .These factors; however, are not seen to affect women and their hemoglobin levels in Pakistan.

Bangladesh
Bangladesh is a country that recently upgraded from a lowincome country to a lower-middle income status with a highdensity of the population in rural areas similar to Pakistan.Studies have revealed that the total prevalence of anemia in pregnant women in these areas is 57% [42] where Thalassemia and groundwater intake are among the few common reasons contributing to it [43] .Similarly, in Pakistan Thalassemia trait is also known to be highly prevalent in pregnant anemic patients.In Bangladesh micronutrient deficiencies including iron, Vitamin B12, and zinc were very prevalent contributing to anemia, Ascaris infections were also noted to be causing an increase in anemia cases during pregnancy [44] .Comparing it to Pakistan, micronutrient deficiencies were also noted where a study conducted by Soofi et al. revealed prevalence of Vitamin B12 and Folate to be 52.4 and 50.8% [45] .
A facility-based cross-sectional study conducted in Jashore, Bangladesh, by Ahmed et al. concluded a high prevalence of anemia (58.9%) in women presenting to the facility for antenatal care.This study classified the anemia to be of the moderate type as described by WHO [46] .A cross-sectional study conducted in Dhaka city of Bangladesh described factors contributing to maternal anemia, which included younger age, no education, and lower socioeconomic status.Furthermore, women in urban areas were less affected by anemia compared to those living in rural areas, 33 and 58%, respectively [47] .These factors also seemed to be common when compared to Pakistan.Similarly, the anemia burden was higher in women of reproductive age living in rural areas compared to those living in urban areas [7] .

India
India, a LMIC has similar socioeconomical status as Pakistan has reported numerous research articles on the effect of anemia on maternal health hence ultimately on fetal mortality.It serves as a reference for particular methods that can be implemented depending on the socioeconomic status of the country.Anemia is extremely common amongst pregnant women residing in Northwest India's rural farming population, it has been estimated that the prevalence rate is about 90%, which is greater than the national average of 65-70% [48] .Additionally, other contributors to maternal anemia include plant-based diets, hemoglobinopathies, helminths infections, malaria, and large quantities of tea consumption.Tea consumption is a common practice within both Pakistan and India, there has been a strong correlation between tea consumption and decrease dietary iron absorption [48] .Similarly, like in Pakistan, iron deficiency anemia is one of the main causes of maternal anemia, which is typically prevalent in rural and backward tribal areas, these regions have a high prevalence of micronutrient deficiency [49] .Moreover, there are a multitude of reasons for high rates of anemia amongst pregnant women, like poor coverage of iron supplementation programs and suboptimal adherence to iron supplementations during pregnancy for many reasons.These include side effects, forgetting the correct doses of iron supplements and misconceptions about the importance of anemia in pregnancy [49] .According to a retrospective cohort study, a strong association has been made between anemia during pregnancy (especially in the third trimester) and low fetal birth weight [50] .According to the NFHS-4 report, anemia in pregnancy affects 50.3% of pregnant women in India (45.7% in urban areas and 52.1% in rural areas).Furthermore, UNICEF, 2014, reported 28% LBW babies in India and 22.6% in West Bengal.Anemia during pregnancy is a risk factor for LBW as there is a direct relation between low Hb levels during pregnancy (Hb < 11.0 g/dl, according to WHO) with LBW [50] .

Efforts
There are numerous programs working in Pakistan to prevent diet-related anemia.These programs are centered around providing micronutrients like zinc, folic acid, iodine, iron, vitamin A, etc. through many interventions.These include supplementation, improving diet diversity and food security through nutrition availability, agricultural practice, and education.The most widely used program nationwide is the prenatal program, which provides four basic nutrients: iron, folic acid, ascorbic acid, and vitamin A [51] .
Collaboration between local and international organizations has proven to be effective in reducing anemia during pregnancy across Pakistan.This includes the launch of Right start program in Pakistan by Nutritional international organization, supported by the Canadian government [52] .With the support of the World Food Program (WFP), Nutrition International (NI) conducted a wheat flour fortification project in Azad Jammu and Kashmir (AJ&K) to improve the level of anemia in the population, especially amongst pregnant women.As part of the project, NI provides technical support to the private sectors, the AJ&K government, and the Food ministry to ensure effective control and appropriate fortification.Additionally, support for repair and maintenance of the micro-feeders installed at the mills and the purchase of internal quality control iron test kits is also provided [53] .
Moreover, Pakistan has less qualified healthcare professionals and low service coverage resulting in 48% of all births not being attended by trained attendants and 50% of pregnant women not receiving at least four prenatal screenings [52] .To address this issue, NI assists the Pakistani government by implementing comprehensive capacity-building programs for health workers to provide integrated nutrition and health education to low-income and ethnically diverse communities, with a focus of promoting increased iron and folic acid intake, timely prenatal care by qualified maternity healthcare professionals [52] .Thus, these efforts have proven to be effective as Right Start Pakistan has prevented 315 577 cases of anemia in pregnant women, children, and 2892 neonatal and child deaths through maternal and child health and nutrition measures including exclusive breastfeeding, timely breastfeeding onset, and childbirth package [52] .
Under the provision of NI, Maternal Newborn health, and nutrition program (MNHN) made efforts to enforce multiple intervention through Pakistan in order to improve both maternal and neonatal outcomes.These include providing iron and folic acid supplements for pregnant women to reduce anemia, managing the needs of malnourished pregnant women and children (6-23 months) and making antenatal care quality more accessible with trained professional to ensure that best care and needs are being provided for the mother and neonate during and after the gestation period [54] .Moreover, in 2020, it was estimated 1 in every 10 babies are born preterm, currently there are 5-18% of prenatal births globally [55] .Consequently, UNICEF, in collaboration with the Ministry of National Health Services, Regulations, and Coordination and provincial health departments, has supported the establishment of 17 Kangaroo Mother Care Centers across the Pakistan (11 in Punjab, 3 in Sindh, 1 in Khyber Pakhtunkhwa, 1 in AJ&K, and 1 in Islamabad Capital Territory) [55] .They have provided all the essential equipment and materials to train the staff of the Gynecology/Obstetrics and Neonatology departments in the method of mother kangaroo care.KMC is one of the best options for preterm care in lowincome countries [55] .

Recommendations
Anemia is a multifactorial problem, which needs to be addressed from multiple angles so that proper management and measures can be implemented during pregnancy to reduce rates of child mortality.
According to USAIDS (United States agency for international development), anemia often stems from diet-related and diseaserelated causes, such as malaria or intestinal helminth infections, along with iron deficiency during pregnancy hence multiple interventions are implemented to reduce neonatal and maternal adverse outcomes [56] .International organizations like MCHIP (mother and child health integrated program) can collaborate with local government with the aim to formulate effective distribution strategies for maternal anemia response packages (consist of iron, folic acid, antimalarial, and helminths drugs) in healthcare facilities, thereby ensuring that such packages reach where they are most needed instead of saturating a certain target area [56] .
According to Pakistan's national nutrition survey of 2012-2013, it was found that amongst various micronutrient deficiencies, IDA (50.4%) is most prevalent in pregnant women [8] .Furthermore, anemia during pregnancy causes serious complication in both the mother and child, for this reason, WHO recommends weekly dose of 120 mg elemental iron and 2.8 mg folic acid throughout pregnancy to reduce gestation complications [57] .New guidelines from the WHO on using ferritin concentrations to assess iron status in individuals and populations will help healthcare professionals identify iron deficiency early and avoid its most severe effects.Accurate measurements of this protein, along with clinical and laboratory assessment, can guide appropriate interventions both in pregnant females and individuals at the population level [58] .
Better promotional activities can be implemented including posters, slogans, and radio/TV advertisements [59] , which will help to educate anemic pregnant females regarding the management options.Additionally, most countries have common practices and cultures like daily consumption of large quantities of tea in Pakistan [60] .This effects iron absorption ultimately contributing to anemia.Hence, it is vital to promote regular weekly educational nutrition related PowerPoints led by healthcare professionals in collaboration with community figures (religious leaders) to promote awareness of importance of dietary intake and its effects on the developing neonate during pregnancy.Family members should be encouraged to attend educational events as they can play a critical role in persuading uncompliant anemic pregnant females in the importance of regular antenatal visits and taking supplements [59] .Furthermore, Health Information programs have been implemented in Indonesia, India, Saudi Arabia, and African countries to educate anemic pregnant women about the importance of proper nutritious diet and management of anemia during pregnancy.Strategies implemented included educating individuals through a PowerPoint presentation, handouts, and follow-ups [61,62] .Moreover, health education messages and reminders were sent via social media platforms such as WhatsApp, which significantly helped pregnant women to make better and more beneficial food choices, and comply with iron supplements, this as a result decreased rates of anemia in turn reducing child mortality [61,62] .Hence, all the aforementioned strategies can be effectively implemented by healthcare facilities in Pakistan to help educate and increase awareness, collectively, helping to reduce anemia in pregnancy and its complications.
Furthermore, many pregnant females living in rural areas do not regularly attend their antenatal clinic mainly because the clinics setting are too far.Telemedicine services can be set up with the assistance of local and international organizations.Through this intervention, management, and check-ups of anemic pregnant women can be made much easier and proper treatment can be implemented without delay as antenatal professional would have daily reports on patients' condition [59] .
Lastly, specific training, such as WHO training on Life Saving Skills for health workers, could improve the clinical skills of local health workers.Although the training focuses on basic midwifery skills, it could be expanded to include maternal CPR, which can be applied in anemia-related emergencies; additionally, local health workers must be given access to cutting-edge equipment.Although laboratories in developing countries generally lack the capacity to perform high-quality blood tests, they may be able to provide reliable estimates of RBC indices.To reduce partial implementation of preventive treatment, local health workers should be encouraged to follow the Package Prenatal Care Guidelines at each prenatal visit [63] .

Limitations
This study, despite the authors' best efforts to provide a wellrounded and accurate review, suffers from a few mentionable limitations.Our work may be slightly skewed to support the main objective due to authors' bias.Due to a lack of funding, paid articles were inaccessible and therefore not included.Even though the literature search was thorough, there is a possibility of missed content that may supplement or contradict data.Additionally, equivalent data was not available for South Asian countries, mentioned or otherwise, providing a very limited comparison of them with Pakistan with regard to our topic.

Conclusion
The alarmingly high prevalence of anemia and associated complications is reflected through various studies conducted in different parts of the country.Similar trends have been noted in regional counterparts such as Afghanistan, Bangladesh, and India, further emphasizing on the role of various causative factors.The key to reducing this particular presenting complain lies with better surveillance, nutritional counseling, and supplementation bearing in mind internationally accepted guidelines.

Ethical approval
Ethical approval was not required for this short communication article.

Research registration unique identifying number (UIN)
Not applicable.