Introduction

The cellular discrepancy between the body's need for nutrients and energy and the available supply required for growth and maintenance, including the imbalance and excess in food consumption, is termed malnutrition. The significance of maintaining a regular, well-balanced diet is reiterated since it is critical in ensuring proper functioning, steady health, and body development throughout life. Survival, development of the body and mind, productivity and performance, health, and well-being are maintained well by balanced diet intake. Nevertheless, age, gender, and physiological changes like motherhood present distinct dietary needs. A woman's pregnancy is an important phase in her life, during which the growing fetus needs adequate nutrition. Malnutrition is a symptom that is impacted by several complex circumstances that affect the children's general health in the country. It is strongly linked to a poor diet and health issues in specific situations, like cultural beliefs and lack of access to necessary healthcare for individuals in low socioeconomic conditions, inappropriate childcare and feeding practices, a crisis in the home food supply, unhealthy housing, and a lack of education among parents, particularly among mothers. Pregnant women must ensure adequate nourishment to promote their own well-being and ensure a successful pregnancy outcome. The time when the body needs more macro- and micronutrients to meet its demands is crucial for pregnancy because of the increased nutritional needs. Thus, 53.8 million pregnant women worldwide suffer from vitamin A deficiency (VAD) and anaemia, two prevalent micronutrient deficiencies.

Intrauterine growth retardation (IUGR), low birth weight, and both mother and infant mortality and morbidity are frequently caused by poor nutrition during pregnancy when combined with infections. Since the impacts of malnutrition are pervasive and persistent, and prevention is the most significant course of action when eradicating it, it continues to rank among the world's most urgent health concerns. In addition to inadequate nutrition, psychological and social variables, mother’s comprehension of nutrition, and hormonal fluctuations that affect how they perceive their food choices while pregnant all have an impact on maternal malnutrition. A multitude of women experience impoverished micronutrient status, insufficient weight gain during pregnancy, and chronic energy deficiency. Maternal malnutrition is caused by low food intake, excessive energy expenditure, diets lacking in micronutrients, infections, and the demands of lactation and pregnancy (Figure 1).  There exists a correlation between maternal undernutrition and increased rates of maternal morbidity and mortality, as well as an intensified likelihood of adverse pregnancy outcomes, including preterm birth and low birth weight. Subsequently, these consequences contribute to an increased likelihood of morbidity and mortality among neonates. According to the United Nations Children's Fund (UNICEF), lack of correct nutrition when pregnant accounts for 50% of maternal fatalities annually, and it is the main factor causing unfavourable pregnancy outcomes, being among the world's most pressing reproductive health issues. During prenatal consultations, emphasizing the significance of maternal nutrition as a vital component of a healthy pregnancy is vital. Adequate nutrition is crucial for maintaining the health of the mother throughout pregnancy and for the growth and development of the fetus; it can also have enduring consequences for the health of the mother and her child. A frequent term used to describe pregnancy is "teachable moment," when women are inspired to adopt healthier behaviours for their overall well-being. This is especially beneficial in light of the growing body of evidence showing that nutrition from infancy might influence an infant's chronic health (Developmental Origins of Health and Disease) (García, Ortega, Peral-Suárez, Bermejo, & Rodríguez-Rodríguez, 2020). Some of the most well-known examples include insufficiency of folic acid causing neural tube anomalies, alcohol usage during pregnancy leading to fetal alcohol spectrum disorders, and deficiency of vitamin D causing rickets (Seymour, Beck, & Conlon, 2019).

The majority of the 178 million children under five who are stunted (i.e., have a height-for-age Z score of less than −2) reside in South-central Asia and sub-Saharan Africa. Only 36 countries have a population of 160 million stunted children, which accounts for 90% of all stunted children worldwide and represents 46% of the total number of children residing in those countries. Out of the estimated 55 million children who are wasted, meaning they have a weight-for-height Z score below -2, around 19 million have severe acute malnutrition, which is indicated by a weight-for-height Z score of -3 or below together with edema, or severe wasting, which is indicated by a weight-for-height Z score below -3. Fetal undernutrition, also known as intrauterine growth restriction, is a widespread condition, particularly prevalent in south-central Asia (Black, Morris, & Bryce, 2003). There is a strong correlation between undernutrition and child mortality but there is less compelling evidence regarding the contribution of intrauterine growth restriction to the mortality of neonates and children under the age of five.

The fetus intrauterine environment affects the genetic control of fetal growth, even though the program contained in its genome drives fetal growth and development. The provision of nutrients and oxygen to mother is one element that is essential for the life and well-being of the fetus. The mother's physical size, composition, metabolism, and nutritional status—all developed during her own fetal life, childhood, and adolescence—determine her capacity to nourish her unborn child. The fetus can grow to its full potential if sufficient nourishment is available, which would lead to the delivery of a healthy infant that is the right size. The development of the fetus may be negatively impacted by any anomaly in the intrauterine environment. Fetal undernourishment results from the insufficient supply of nutrients to fulfill fetal needs, which can be affected by several aspects example maternal malnutrition, insufficient placental function, or increasing nutritional demand. It is also harmful to the fetus to receive more nutrients. An increased flow of nutrients, including glucose, from the placenta of a diabetic mother to the fetus can cause fetal enlargement or macrosomia.

In order to mitigate the likelihood of adverse consequences, such as gestational diabetes mellitus (GDM), pre-eclampsia, stillbirth, macrosomia, miscarriage, and caesarean section for the mother, as well as abnormal birth weight and an elevated susceptibility to childhood obesity, it is imperative for mothers to uphold a state of optimal health. Given the advantages this can have for the health of both the fetus and the mother, pregnant women have long been advised to abstain from alcohol and tobacco use in addition to engaging in regular physical exercise. The optimum outcome for both the mother and the newborn during pregnancy can be achieved by optimising the nutritional condition of the mother both before and throughout the pregnancy. Dietary recommendations for the best possible health during pregnancy have traditionally centred on eating a balanced diet and making sure that both macro- and micronutrient intakes are adequate. The way that woman's diets are viewed should centre on taking more thorough steps to safeguard and prepare the female population against triple nutritional and dietary issues. The early stages of life are a critical period of adaptability, extending from the moment of conception until around two years of age. During this period, developing cells and organs undergo modifications in response to environmental factors that impact the mother, such as stress, infections, alcohol consumption, smoking, chronic diseases, obesity, and malnutrition. These factors eventually dictate an individual vulnerability to a specific illness risk in adulthood. During gestation, the developing fetus is very susceptible to environmental factors, including energy balance and the availability of nourishment, which are crucial for optimal growth and development. Gestation not only involves increased nutritional and energy needs for the developing fetus, especially during the later stages of pregnancy, but also serves as a time of preparation for an even higher energy demand.

Considering that pregnancy is a period of heightened susceptibility to nutritional deficiencies and has a substantial impact on the growing fetus, it is essential to acknowledge the significance and complexity of nutrition during this period (García et al., 2020). Due to the fact that these conditions will fluctuate in response to the arduous demands of two years of breastfeeding and nine months of pregnancy, there is cause for concern regarding the nutritional status of pregnant women during gestation. This raises questions about the significance of nutrition for pregnant women throughout the pregestational, gestational, and breastfeeding periods (Castillo-Matamoros & Poveda, 2021). Essential components of balanced food during pregnancy incorporate eating foods that are high in macro- and micronutrients and energy, gaining the right amount of weight, following general and pregnancy-specific food safety guidelines, and abstaining from dangerous substances (Forbes, Graham, Berglund, & Bell, 2018). According to earlier research, Failure to adhere to these behaviours increases the likelihood of adverse pregnancy outcomes, including but not limited to preterm delivery, hypertension, low birth weight, and neurodevelopmental complications like fetal alcohol spectrum discord (García et al., 2020). The time between conception and the age of two is a formative one, during which the body undergoes remarkable plasticity. Cells and organs in development adjust to the mother's internal and external environments throughout this time in response to stress, infections, alcohol and tobacco use, chronic disease, obesity, and starvation. Whether an adult is at risk for a certain disease is ultimately determined by these criteria. Environmental factors, including as energy balance and nutrition availability, are especially important during gestation because they affect the fetus capacity to grow and develop normally. During the course of a pregnancy, the growing fetus has substantial nutritional and energy needs, especially in the later trimesters, and the body also prepares for even greater energy demands in the future (Castillo-Matamoros & Poveda, 2021).

During the first half of gestation, by utilizing increases in insulin sensitivity, the woman's body can adapt and store large amounts of energy as fatty acids and protein. During this stage of anabolism, insulin sensitivity changes are prominent. The next step, known as the catabolic phase, involves the mobilisation of maternal resources to ensure that the fetus receives enough nutrition through the placenta. In this early stage, micronutrients are also in high demand. Some examples of these elements are calcium, which is necessary for building bones and for intracellular communication, iron, which is necessary for building a number of proteins (including haemoglobin, which is vital for transporting oxygen and, by extension, for cellular respiration), and folic acid, which is essential for "one-carbon metabolism," the building block of the nucleic acids needed for cell replication (Mousa, Naqash, & Lim, 2019). Crucially, other intermediate vitamins and minerals are needed to facilitate metabolic processes in the biochemical pathways in which these three micronutrients engage. Since there is a strong correlation between poor pregnancy outcomes and neglecting nutritional care, nutritional care must be prioritized or integrated into core interventions during gestational care. This is because increased anabolic activity is largely responsible for the increased demands for nutrients during gestation (Herreño & M, 2016). As a result of the intensified physiological demands associated with human gestation, it is critical to maintain a healthy diet and nutrition throughout pregnancy to supply the energy reserves and macronutrient and micronutrient pools that support the numerous cell replication and differentiation reactions. This entails the suitable addition of the aforementioned three micronutrients. These ensure optimal fetal development and growth when combined with the physiological substrates. Obstetric complications that are significantly impacted by the nutritional status of the expectant mother and child, including intrauterine growth retardation, preterm birth, low birthweight, neonatal and maternal morbidity and mortality, and delivery complications, can be avoided with the aid of a nutritious diet (Castillo-Matamoros & Poveda, 2021).

Diet and Nutrition Supplementation During Pregnancy

Women must manage their diets before becoming pregnant, during pregnancy, and after giving birth. Instead of concentrating on specific nutrients or foods, dietary patterns are a developing field of study that encompasses the complete diet. Adhering to a nutritious diet prior to and throughout pregnancy has been associated with a reduced likelihood of developing pregnancy-related complications, including gestational diabetes mellitus (GDM), preterm birth, complications arising from obesity, preeclampsia, and gestational hypertension in specific instances. Particularly for expectant women who are obese, have undergone bariatric surgery, or have pre-existing diabetes mellitus (DM), nutrition therapy is the cornerstone of GDM treatment. A diet that promotes good perinatal outcomes and ensures a secure pregnancy is one that promotes a balanced intake of macronutrients. Considered healthful are diets that are abundant in fruits, vegetables, whole grains, seeds, legumes, seafood, monounsaturated fat-rich oils, and fibre, while being low in refined grains and fatty red meat. Additionally, processed foods, saturated and trans fats, and basic carbohydrates should be avoided in healthy diets (Marshall et al., 2022).

The extra energy needs of 300 kcal per day during pregnancy are classified as such. Calorie intake is not as crucial as nutritional quality. The amount of protein, vitamins, and minerals in food per 100 kcal is known as nutrient density. Many women, especially those in their teens, eat a diet high in low-density foods poor in nutrients. Pregnant women need 60 g of protein per day, which is around 15 g more than they would need otherwise. Certain vegetable oils and fish oils include omega-3 fatty acids, which are regarded to be vital for the development of brain and visual function in fetuses. Dairy-based vegetarian diets can offer a well-balanced food intake during pregnancy.  As long as there is additional monitoring and counseling, as well as vitamin B12 and D intake along with some crucial amino acid supplements, vegan diets, which omit all animal products, are also safe to follow while pregnant. The US Public Health Service recommends that women of reproductive age take a daily dosage of folate (0.4 mg) before getting pregnant to reduce the risk of non-transformed disorders. To ensure enough iron intake during pregnancy, it is recommended to supplement with 30 mg of elemental iron daily, as diet alone may not be sufficient. Women following supplemental diets should incorporate 2 mg of copper and 15 mg of zinc, in addition to iron supplementation. The recommended daily intake of calcium during pregnancy is same to that outside of pregnancy: 1000 mg per day for women aged 19 to 50, and 1300 mg per day for those under the age of 18. Supplementing with calcium has not been associated with a decrease in hypertensive diseases or preeclampsia, according to randomised research (Bucher et al., 1997). Recent randomized controlled studies assessing the effectiveness of vitamin C and E supplementation in lowering preeclampsia rates have not shown a decrease in preeclampsia, growth restriction, or fetal/neonatal mortality rates.

Fiber, different minerals, vitamins A, C, and Bs, and other nutrients all rise, albeit to a lesser degree. Certain dietary guidelines do not become any better throughout pregnancy. Fluoride and vitamins D, E, and K remain unchanged. Using fluoride supplements during pregnancy is not recommended. However, it is important to advise the mother that bottled water cannot be relied upon as a supply of fluoride. While it is common for individuals to have inadequate calcium consumption before pregnancy. The Dietary Reference consumption (DRI) for calcium does not increase during pregnancy. Women in their childbearing years also exhibited inadequate consumption of vitamin E, magnesium, potassium, and fibre. This issue can be resolved by increasing the intake of fruits, vegetables, and whole grains. While not explicitly mentioned, it is assumed that the Dietary Reference Intakes (DRIs) for nutrients are higher in twin pregnancies. There are currently no set guidelines for prenatal weight growth recommendations or Dietary Reference Intakes (DRIs) for triplets and higher-order multiples; nevertheless, best practice information is accessible. Weight gain that occurs early (before 20-24 weeks) seems to be crucial. Eating properly becomes much more important with all the multiples because of the increasing requirements and even less room available. In conclusion, while calorie requirements rise, they do so at a slower rate than nutritional demands. The emphasis should be on smaller, more frequent meals and higher-nutrient foods, particularly as the pregnancy goes on and physical space becomes more of a concern. Patients should prioritise consuming whole grains instead of juice, opt for whole milk or yoghurt first (then transition to low-fat, followed by skim), favour red meats over white meats, select leaner cuts of meat, and opt for water instead of sports drinks. In order to maximise the nutritional value while minimising calorie intake, it is advisable to give preference to fresh or frozen fruits and vegetables, avoid fried meals, and restrict the consumption of additional fats and sugars. Women with elevated requirements, such as those carrying multiple fetuses, those with HIV, those who smoke, consume alcohol, or use drugs, or those who have a limited intake of animal products, are advised to take prenatal vitamins (multivitamin/multimineral). Some individuals utilise them as a form of protection rather than as a substitute for a nutritious diet (Cox & Phelan, 2008) (Table 1).

Current themes of concern include the consumption of liver and its potential hazards, the need of avoiding raw cheese, and the potential problems associated with consuming excessive amounts of tuna and other oil-rich seafood (beyond two meals per week). According to the National Institute of Health and Care Excellence (NICE), alcohol use should be severely limited during the remaining weeks of pregnancy since it may harm the fetus health during the first trimester of pregnancy (Aquino, Edge, & Smith, 2015). Moreover, alcohol is regarded as a concentrated source of energy, providing 7 kcal/g. As such, moderate drinking may raise energy intake and promote excessive weight gain during pregnancy. Maternal caffeine intake has drawn a lot of attention, as it is believed that higher intakes limit fetal development. Retrospective measurements of caffeine intake were made in one enormous prospective observational study conducted in two UK maternity units. The findings demonstrated that while small amounts of caffeine (up to 100 mg daily) are safe, larger amounts (over 200 mg daily) raise the risk of miscarriage, early delivery, and low birth weight in children. Two cups of tea or coffee provide about 200 milligrams of caffeine, but there are other rich sources as well, including caffeinated beverages. These beverages' decaffeinated equivalents could be worthwhile. Recognising the importance and intricacy of nutrition during pregnancy is crucial due to the heightened nutritional vulnerability of pregnant women compared to other stages of their lives. Additionally, pregnancy has a substantial impact on the future health and nutritional status of the fetus, which in turn affects the woman's health as an adult. Due to the physical demands of nine months of pregnancy and two years of breastfeeding, the nutritional needs of women during this period vary. Therefore, it is important to carefully consider the health and significance of nutrition for pregnant women throughout the stages of pre-pregnancy, pregnancy, and breastfeeding.

The Role of Essential Nutrients During Pregnancy

Pregnancy depends heavily on nutrition, which may also be a modifiable risk factor since it determines a person's lifetime risk of disease. The World Health Organization (WHO) has standards for prenatal care, but there are no thorough guidelines that describe the dietary requirements of women throughout the whole reproductive cycle, from conception to nursing and beyond. Considerable discourse has ensued regarding the criticality of sufficient and essential nutrition across the entire developmental continuum, encompassing preconception, pregnancy, delivery, infancy, and adolescence (Marshall et al., 2022).

Gut microbiome

The adult human intestine harbours an estimated 15,000 to 36,000 species of bacteria, representing more than 1800 genera. A bacterial classification is utilised to classify 94–98% of the isolated microorganisms: Actinobacteria (3%), Firmicutes (64%), Bacteroidetes (23%), and Proteobacteria (8%). The remaining 2% of taxa, while less prevalent, comprise an exceptionally heterogeneous assortment, thereby augmenting the intricacy of the gastrointestinal microbiota (Frank et al., 2007). Women tended to have a greater proportion of Proteobacteria strains, which are associated with inflammation, in their intestinal microflora during the third trimester of pregnancy. During the third trimester, there is an increase in the population of Bifidobacteria, Proteobacteria, and lactic acid-producing bacteria, and a decrease in the population of butyrate-producing bacteria. There is a substantial increase in the total quantity of bacteria and notable changes in the composition of the gastrointestinal microbiota during pregnancy, especially in the latter stages. An increase in the abundance of Actinobacteria and Proteobacteria phyla strains and a reduction in the diversity of individual bacteria characterise this evolution (Table 2).

Dietary fiber is crucial in establishing the human microbiome, as are lipid and protein sources that supply essential amino acids. Insufficiency of upper gastrointestinal tract enzymes that catalyse carbohydrate metabolism dictates the fermentation processes that occur in the lower intestine (Vojinovic et al., 2019). It has been demonstrated that pregnancy affects the mother's gut microbiome, which varies in the first and third trimesters. Carbohydrates from dietary fiber travel undigested through the upper gastrointestinal tract and into the large intestine, during which the anaerobic microorganisms undergo fermentation. Intestinal microbiota during the initial trimester of pregnancy resembles that of non-pregnant, healthy individuals. Nevertheless, a substantial transformation occurs in the intestinal microflora composition between the initial and third trimesters (Table 4; Table 3). Studies involving rodents incubated with intestinal microflora from pregnant women during the third trimester of gestation observed an increase in body weight and insulin resistance, which mirrored the diabetogenic changes observed in pregnant women. The aforementioned findings could suggest that modifications to the gut microbiota during gestation play a role in developing pregnancy-specific metabolic alterations, including elevated levels of inflammatory markers and energy content. Intestinal microflora increases adipocyte-stimulating factor secretion during fasting, stimulates catabolic reactions, and strengthens the immune system; these functions may contribute to the way in which the microflora influences the weight gain of expectant hosts. Long-term detrimental consequences for the host organism and its offspring may result from dysbiosis, which refers to the continued alteration of various factor compositions induced by the microbiota. Such consequences may include obesity, enteritis, diabetes, and metabolic syndrome. Microflora in the human intestine may influence the regulation of nutrient metabolism, and dysbiosis may be associated with an increased uptake of energy resources.

Along the gut-brain axis, which connects the central, enteric, and autonomic nervous systems, bidirectional communication occurs via the hypothalamic-pituitary-adrenal (HPA) axis. The microbiota-gut-brain axis is comprised of gut microorganisms (including bacteria, viruses, fungi, and archaea), as well as their metabolites and by-products. These components also contribute to this bidirectional communication. The vagus nerve, which connects the brain to the abdomen and controls internal organ functions such as respiration, digestion, and pulse rate, is the tenth cranial nerve. Comprised of efferent and afferent neurons, it facilitates communication between the brain and various organs, including the intestines, where the impact of the gastrointestinal microbiota can be felt. The brain is thereby able to sense the gastrointestinal environment via this physical connection. A growing body of research suggests that there is a reciprocal relationship between the immune system and gut-brain signalling, demonstrating an interdependence (Salvo-Romero, Stokes, & Gareau, 2020). Low-grade systemic inflammation is linked to a variety of neurological disorders, including autism spectrum disorders, Alzheimer's disease, Parkinson's disease, epilepsy, and cerebrovascular diseases. This suggests that the immune system is compromised and that the gastrointestinal microbiota is unbalanced. Research on germ-free mice and mice that were administered broad-spectrum antibiotics has demonstrated that the gut microbiota has an impact on intestinal immunity, thereby influencing both systemic and local immune reactions within the organism (Fung, 2020). Recent studies have established a correlation between gut hormones and the modulation of mood, anxiety, depression, and obesity. Moreover, the gut microbiota may have an impact on these hormones and mood maintenance (Sun, Li, & Nie, 2020). An increasing body of evidence suggests that the gut microbiota and neuroendocrine system, both of which are linked to conditions such as irritable bowel syndrome and depression, engage in bidirectional communication. The hypothalamic-pituitary-adrenal (HPA) axis, which regulates mood, stress response, and immune function, can be stimulated by the intestinal microbiota (Bao & Swaab, 2019). Additionally, neurotransmitters like dopamine and serotonin, which have hormonal properties, may be influenced by the gut microbiota (Figure 2).

The intestinal mucosa interacts with microorganisms along with micro- and macronutrients that act as substrates for host and microbe cells. As a result, hormonal cascade and signal transduction is triggered, leading to absorption and transport to other body tissues. Various pathways digest nutrients in the gut; they may either be immediately broken down by the host cells like fatty acids, which activate receptors that produce hormones like GLP1, promoting insulin release. They may also be the metabolic products of the microbes, leading to the release of secondary molecules that regulate important body processes. For instance, insoluble dietary fibres fermented to acetate (for appetite regulation) (Silva, Bernardi, & Frozza, 2020), butyrate (for memory, mood, cognition) and propionate (preventing diabetes mellitus, obesity and stress) short-chain fatty acids (SCFAs) (Silva et al., 2020). After being absorbed in the intestine, they modulate the CNS by crossing the blood-brain barrier, while supporting its integrity and prevent leakage, whose depletion can adversely lead to Alzheimer’s (Dinan & F, 2017; Ratsika, Codagnone, O’mahony, Stanton, & Cryan, 2021). Dendritic and T-cell functioning is regulated, boosting the immune system and inhibiting cytokine production. These directly impact early fetal brain development and neurulation, mediated by nutrient-microbiota crosstalk (Mcdonald & Mccoy, 2019). Several nutrients and microbial metabolites, such as B complex vitamins, SCFAs, and polyphenols, have epigenetic potential and can influence fetal programming during sensitive developmental periods. Developmentally sensitive times are crucial windows of opportunity where changes may cause permanent adjustments to the way the body grows and functions. Preconception, pregnancy, and the perinatal and early postnatal phases are among them (Robertson, R, B, & J, 2019). Neuronal, immune, endocrine, and metabolic processes mature at a rapid rate during this period. Weight gain, metabolism regulation, brain development, microbiota composition, and immune system priming—all of which have a lifelong impact on an individual's health—are all significantly influenced by the type and quantity of food ingested during these periods (Huus et al., 2020). In order to mitigate the risk of neural tube defects and other malformations, it is recommended that expectant or intending women incorporate micronutrients, including folate, into their diet. Nevertheless, several variables, including vitamin kinetics, drug-microbiota-nutrient interactions, and drug use, may impact the availability of folate and raise the possibility of congenital abnormalities. According to research, factors in the environment that affect parents' health can affect their children's behaviour in later life. Fathers' immune system activation from infection, for instance, may have an impact on the behaviour of their offspring for at least two generations through the epigenetic regulation of reproductive cells (Tyebji, Hannan, & Tonkin, 2020). Environmental factors can exert an impact on the maternal immune system both prior to and throughout pregnancy, potentially resulting in enduring modifications to the well-being of her children from infancy to maturity. During pregnancy, the brain undergoes significant structural and functional changes, including axonal growth, synapse formation, and neuronal connections. These changes are essential for later-life cognitive development and behaviour. Brain function may be negatively impacted for some time after disturbances during these time-specific events. In addition to environmental factors including smoking, air pollution, infections, and radiation exposure, maternal factors including nutrition, lifestyle, mental health, and antibiotic use can influence the development of the fetus and the health of the expectant mother. Prenatal nutrition by the mother can influence structural and functional changes in the brain of the progeny during the perinatal period. The impact of nutrient intake on neurotransmitter pathways, synaptic transmission, and signal-transduction pathways ultimately determines the structural characteristics of the brain at both the microscopic and macroscopic levels Hung et al., 2021. For instance, by controlling hippocampus BDNF in rodents, omega-3 polyunsaturated fatty acids (PUFAs) are known to influence brain plasticity, cognition, and health. Omega-3 fatty acid intake during the formative years is linked to better cognition in humans, while lower levels are linked to mental health issues and neurodegenerative diseases. Maternal malnutrition whilst pregnant may cause abnormal neurodevelopment in the fetus, which may result in related problems in the adult offspring. The development of the nervous system in progeny may be influenced epigenetically by molecules associated with one-carbon metabolism, such as betaine, choline, and folate (Ars et al., 2019). Obtaining these nutrients is beneficial when consuming green leafy vegetables, beets, wheat, or seafood (Craig, 2004). Folate can be produced by specific gastrointestinal bacteria as well. A macronutrient and micronutrient profile that is optimally nourished is necessary for the brain to operate at its optimum capacity (Table 5). The microbiota composition of the progeny may be influenced, potentially impacting social behaviour and overall health, according to preclinical investigations conducted on rodents utilising maternal dietary manipulations (e.g., high-fat or high-fiber diets) during pregnancy (Buffington et al., 2016).

Hormonal intervention 

Gut microorganisms produce neurotransmitters such as gamma-aminobutyric acid (GABA), serotonin, dopamine, noradrenaline, and tyramine, in addition to the neuroactive amino acids tyramine and tryptophan and short chain fatty acids (SCFAs) (Chakrabarti et al., 2022). Mood, thought, sleep, and appetite regulation are all influenced by serotonin. Since they raise the amount of serotonin that is available in the brain, selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed therapies for depressive symptoms. Research also emphasizes that tryptophan is the only amino acid that functions as serotonin precursor. It has been suggested that the gut microbiota may affect the absorption of tryptophan and, consequently, the synthesis of serotonin. In the enteric system, 90% of total tryptophan is produced via the kynurenine pathway, which also generates kynurenic and quinolinic acids that are essential for the operation of the enteric and central nervous systems, respectively (Gheorghe et al., 2019). A study on fetal mice by Xin Ye et al. depicted that perturbed maternal diet affects the fetal brain, predisposing to postnatal autism spectrum disorders. Serotonin and oxytocin which are vital in the development of neural connectivity, are fuelled by glucose transporters GLUT3, whose sufficiency is crucial (Ye et al., 2021). Beyond the peripartum period, oxytocin is also required to induce labour and for a healthy, and safe delivery (Monks & Palanisamy, 2021). Dopamine, a crucial neurotransmitter involved in the reward systems of the brain, functions as a norepinephrine initiator - which influences behaviour and cognition, and adrenaline- which is also known as arousal and alertness. Parkinson's disease, schizophrenia, and addiction are disorders linked to dopamine deficiency, which are either synthesized or metabolized by certain bacteria (Rekdal et al., 2020). GABA, synthesized mainly by Bifidobacterium and Lactobacilli, significantly impacts cognition, behavior, and the body’s response to anxiety, fear, and stress (Jewett & Sharma, 2020). A deficit, however, causes depression, autism, and schizophrenia.

Miscarriage

A miscarriage occurs when a pregnancy unexpectedly ends between the twelfth and twenty-fourth week of gestation, which is recorded to occur in at least 1 of 5 pregnancies. With significant physical and emotional effects on the individual, it is additionally linked to substantial healthcare expenses. Nearly 50% of the cases are attributed to chromosomal aberrations, nevertheless, there is further evidence linking substantially higher rates of miscarriage to factors involving ethnic origin, the mother's psychological state, extremely high or low BMI pre-pregnancy, stress, smoking, use of non-steroidal anti-inflammatory drugs, and alcohol consumption. In a study conducted in Pakistan, it was found that 23% of the population that suffered a miscarriage were having a poor diet, while 20% was due to hypertension, and 6% due to depression. 8% of the population miscarried having a history of C-section due to improper or incomplete healing or uterine involution. In another research as well, it was found that alongside socioeconomic factors and poverty, malnutrition was a driving force in occurrences of miscarriage, abortion and preterm labour (Malik et al., 2022). Micronutrients with antioxidants such as Vitamin A, B9, E, C, and iron have been suggested as interventions in severe cases of recurrent miscarriages, to normalise metabolism and defend a normal pregnancy (Coomarasamy et al., 2021).

Supplementation and Dietary Modification

In certain cases, a prolonged administration of broad-spectrum antibiotics to treat infections, end up depleting the enteric flora, which can impair the immunity and digestion in neonates and new mothers. Severe consequences like diminished absorption of nutrients, synthesis of vitamins and non-essential amino acids, and accelerated risk of obesity, asthma, diabetes, and infections. The simplest solution to this would be an oral supplementation of prebiotics and probiotics, which either stimulate the growth of, or supply living microbes to the system which confer good health. They compete to adhere to the mucosal epithelium, thereby strengthening the barrier, increasing its IgA and antimicrobial substance turnover to improve immunity. Pro-inflammatory pathways are downregulated and anti-inflammatory cytokines are produced. These protect against obstetric and paediatric disorders, including obesity, hypersensitivity, gastrointestinal complications, and upper-respiratory difficulties. Studies have also found that polyphenols, omega-3 fatty acids (Swanson et al., 2020), inulin, fructo- and galacto-oligosaccharides can be used as prebiotics (Quigley, 2019). Probiotics include Lactobacillus spp., Bifidobacterium spp., Streptococcus thermophiles etc (Quigley, 2019).

The ancient proverb goes something like, "let food be thy medicine, and not medicine thy food." In a nut, it emphasises on the fact that a good diet can indeed preserve the body's equilibrium and health, as well as stop or lessen the onset of certain illnesses (Zhuang, H, S, J, & Q, 2019). The microorganisms that inhabit the gut, especially of fetus and neonates perform a multitude of vital roles, including but not limited to immune system development and function and vitamin B and K synthesis. A healthy titre of native bacteria possesses the capability to compete against pathogenic organisms wanting to colonise the gastrointestinal tract and also affect the metabolism and functioning (Ansaldo, Farley, & Belkaid, 2021). Gestational age, prenatal factors, genetics, method of delivery, maternal health and nutrition, and postpartum feeding regimen are all influential in determining the composition and development of the intestinal microbiota in the progeny.

Fetal programming

British physician and epidemiologist David Barker created the concept nutritional programming, sometimes known as the ‘Barker hypothesis’. It holds that critical fetal development phases determine metabolic and hormonal changes that may affect health later in life. According to fetal programming (Parrettini, Caroli, & Torlone, 2020), unfavourable factors such maternal starvation during early organogenesis can permanently change organ and organ system anatomy. Epidemiological causes include environmental triggers including dietary excess or deficiency and chronic structural, metabolic, and functional organ damage in children (Alemany, 2024). It is linked to ‘civilization diseases’ such type 2 diabetes (T2D), hyperlipidemia, obesity, osteoporosis, high blood pressure, cancer, and cardiovascular disease (Stolarczyk, 2022). Maternal body composition and malnutrition-related energy extremes (ingestion and assimilation) usually affect fetal life (Ma et al., 2020).

Up to 70% of adult gut microbiota is stable and identical to that of a child's first three years, but the rest can be affected by nutrition, lifestyle, pet exposure, and antibiotics. Proper nutrition is important throughout life, including during pregnancy (Kim et al., 2019). Recent investigations have found maternal bacteria in umbilical cord blood, placenta, amniotic fluid, membranes, and newborn meconium, which may have entered via maternal circulation (Raspini et al., 2020). The mother's microbiome changes during gestation, post-partum weight, GDM prevalence, nutrition before and during conception, and intergenerational antibiotic use (Chu, Valentine, Seferovic, & Aagaard, 2019).

Effects of malnutrition

Enhancing a woman's dietary habits and general well-being prior to, during, and subsequent to pregnancy may potentially yield favourable results for obstetrical operations, perinatal survival, fetal development, and even the long-term health of the mother and child (Marshall et al., 2022). Numerous adolescent mothers encounter intricate socioeconomic and lifestyle obstacles that necessitate expert and communal assistance to assist them in optimising their nutrition and other facets of health and social care prior to, during, and subsequent to their pregnancies. Researchers and clinicians of the 20th century held the belief that the fetus, barring acute famine, was "a perfect parasite" (Almond & Currie, 2011) capable of fulfilling its nutritional requirements. During the middle of the 20th century, pregnant women were advised to restrict their mercury consumption and minimize their exposure to the element. Infants diagnosed with LBW were considered thin and relatively unproblematic. Recent research, on the other hand, indicates that a mother's body mass, dietary patterns, and nutritional status have a substantial influence on the fetus health, both prior to and during pregnancy. Overemphasis on weight gain and undernutrition prior to and throughout pregnancy contribute to adverse pregnancy outcomes for both the mother and the fetus. Additionally, complications associated with conception, placenta, embryo, and fetus development, fetal size, and perinatal complications are influenced by these factors (Bodnar et al., 2017).

Conditions during pregnancy

The parents and healthcare providers might be more inclined to synchronise new born nutrition and intake with weight gain goals rather than with maintaining normal fetal in utero growth trajectories. This is especially true if the existing postnatal strategy, which primarily relies on infant weight as the determinant for neonatal intensive care unit or hospital discharge, accelerates catch-up growth for body fat mass excessively quickly. On the other hand, macrosomia or LGA (Large for gestational age) may occur from fetal overnutrition brought on by maternal obesity, diabetes, and excessive fat and sugar intake. These disorders, which give the fetus an excessive amount of glucose and fat, are becoming more prevalent and are linked to several problems. Fasting and pulsatile postprandial hyperglycaemia stimulate the production of fetal insulin, which in turn causes the fetus to store extra glycogen and accumulate fat. This phenomenon is more common in pregnancies complicated by type 1 diabetes (T1DM), GDM, and T2DM, especially when obesity is present (Barbour & Hernandez, 2018). While macrosomia and/or LGA are frequently linked to pregnancies complicated by diabetes mellitus (DM), the majority of these children are delivered to moms who are obese alone, a condition that now affects up to one in three women. When maternal plasma glucose and lipid contents are high, even more fetal fat mass accumulates (Barbour & Hernandez, 2018). According to recent research, fetal fat mass growth in obese pregnancies is primarily driven by maternal triglycerides, which are made available to the fetus by placental lipases that hydrolyse them to free fatty acids (FFAs) and accelerate the fetus accumulation of fat mass (Adank et al., 2020).  Although they may retain fat, fetuses have a restricted ability for fatty acid (FA) oxidation. Being overweight during pregnancy may contribute to obesity in later life, but postnatal fat gain, particularly in the first year or two of life, may continue into adulthood and result in childhood obesity (Marshall et al., 2022).

Complications during pregnancy

Recovery period

The postpartum period lasts for 6-8 weeks, which begins following the delivery of the fetus, and persists until uterine involution (Frilasari et al., 2020). Post-delivery, healing and recovery are just as important for the new mother as breastfeeding is for the newborn, as she will have to resume normal life while also catering to its various needs. The postpartum period poses new trials and tribulations such as emotional weakness and loneliness- risen from new responsibilities- leading to depression, extended bleeding in both caesarean-section or episiotomy, and natural deliveries, fatigue, and physical stress. In such time, being nutritionally deficit will only cause more harm and slow down internal healing. A perineal wound occurs between the vulva and the anus, between the two thighs, as a result of an episiotomy or rupture that occurs during childbirth. Whilst the puerperium, this will heal in a week if there is no prevailing infection (Gustirini, Pratama, Maya, & Mardalena, 2019). A high intake of calories, vitamins, fluids, and especially protein, are recommended during the puerperium to attain the right nutritional status, on the other hand, insufficient treatment often results in inflammation or infection. A study in Indonesia by Frilasari et al. revealed that a higher level of nutrition and education or awareness meant quicker healing among a group of antenatal women. Adequate protein intake in postpartum mothers enhances cell regeneration, leading to faster healing of perineal wounds. A well-nourished mother can speed up scar tissue formation and the development of fibrin threads, promoting quicker wound healing and accelerated breast milk production (Frilasari et al., 2020).

For lactating mothers, 1000mg/day of calcium is recommended for the maintenance and production of breast milk. In studies done across populations of various ethnic groups, it was seen that consumption of animal milk and calcium supplements improved bone mineral density which sustained post-delivery, while also keeping pre-eclampsia at bay (Gomes et al., 2022). During pregnancy, the intestinal calcium absorption efficiency doubles, while the mother's skeleton reabsorbs calcium during lactation to supply it for the milk. Women who have high calcium demands during lactation and pregnancy are more likely to experience osteoporosis as a result of bone resorption and calcium loss, which are increased by hormonal changes. These can be detrimental to the physical strength of the woman (Miedany, 2022). Osteopenia is a condition of low bone area and mass, while osteomalacia is related to the deficiency of calcium and vitamin D, and invariably to rickets, seen more times than often in pregnant women (Shlisky et al., 2022). Individuals suffering from osteomalacia may experience fragility fractures, muscle weakness, diffuse bone pain and tenderness (Minisola et al., 2021). Among Japanese school-going children, those born to underweight mothers were found to have abnormal bone mass, which implies a threat of osteoporosis and arthritis later in life (Fujita, Kouda, Ohara, Nakamura, & Iki, 2020). In states of high physiological demands like infancy, pregnancy, lactation, and old age, multiple reasons including malabsorption, dietary restrictions, lactose intolerance, food allergies, or cultural limitations forestall the uptake of the required amount of calcium. As for vitamin D, excessive sunscreen use, high-altitude or indoor living can limit its uptake (Uday & Högler, 2020). Hence, resorting to fortification and supplementation are feasible options, with higher bioavailability of nutrients (Horvath, 2021).

Figure 1

The factors that affect mother during lactation.

Mothers overall mental health

During a period of four to ten days immediately after childbirth, women may face an episode of depression, which is known as postpartum depression (PPD). When there is an onset of PPD, the mother, child, and family will be impacted. It can affect the pattern of sleep and lactation and can affect parenting (Kroska & N, 2020). Lowered happiness, a noticeable shift in eating and sleep patterns, anxiety, exhaustion, feeling worthless, difficulty focusing, and repeated thoughts of suicide or death are among the symptoms that describe PPD medically. A drop in parenting abilities, characterized by increased aggression, unfavourable interactions, less attentiveness, and hampered communication, might result from failing to treat maternal depression. This might make it more difficult to carry out responsibilities as a parent (Opie, Uldrich, & Ball, 2020). 

There hasn’t been much exploration on the correlation of PPD with nutritional deficiency. Recent studies have shown that plasma riboflavin levels and erythrocyte fatty acid composition play a significant role in the development of PPD. Women who consume moderate quantities of vitamin-B2 and n-3 fatty acids have lesser chances of PPD (Lin et al., 2019). It has been observed that socio-economic status of women can influence their chances of developing PPD, as women with low affordability, face more struggles, leading to stress, which can eventually trigger depression. Mothers who do not get access to enough food fail to produce enough breast-milk and this notably bears a huge impact on infants. Reducing the risk and development of PPD may be possible with a balanced maternal diet incorporating fruits, vegetables, fish, grains, legumes, and herbs (Opie et al., 2020).

Maternal morbidity and mortality can be significantly increased by complications during the postpartum period, which expose women to serious risks. In contrast to pregnancy and childbirth, postpartum care receives far less attention. The physical and mental health of mothers after childbirth is very crucial. PPD, anxiety, and traumatic stress disorder, all of which are prevalent at this time, are recognized by women as mental health issues. A major drawback in many cases is that it may be stigmatizing to discuss the intensity and experiences of mental health issues. Even though women who have postpartum depression symptoms frequently have thoughts of suicide, due to various reasons they may strongly oppose discussions about suicidal ideas. Therefore, educating the society about the importance of mental health of mothers soon of childbirth, is essential (Adams et al., 2023). Over the course of time, PPD might increase the likelihood of mental health issues and jeopardize their general wellbeing. Maternal behaviours and the relationship between a mother and her child can be significantly impacted by PPD. PPD-affected mothers may find it difficult to identify and react to their baby's requirements, which can cause delays or irregularities in providing the comfort, feeding, and interaction requirements of their child. The mother and child may become less connected as a result of this diminished responsiveness, which might have an impact on the child's social and emotional growth. PPD-affected mothers may not give their babies as much physical affection, such as hugs, cuddles, and soft strokes. In order to foster a mother's and her child's emotional attachment, a tender touch is essential (Saharoy, Potdukhe, Wanjari, & Taksande, 2023).

Three maternal behavioural lifestyle factors—stress, nutritional deficiency, and physical inactivity—can affect the functioning of the immune system and the central nervous system (CNS) in both the mother and the fetus. As a result, they may raise the risk of neurodevelopmental and mental health disorders. Lowering stress, eating well, and exercising frequently throughout pregnancy and after giving birth may be successful measures to mitigate the detrimental effects of maternal stress and malnutrition/obesity on the growing fetus.

Figure 2

The gut-brain axis of a pregnant female.

Various factors affect the gut-brain axis of the mother and, subsequently, the offspring. They may be 1a. Immune response; 1b. Maternal microbiome and mode of delivery; 1c. Feeding patterns (breastfeeding the infant and maintaining a balanced diet); 1d. Gut microbiota. Nutrition mainly impacts 2a. Neuro-sensory development; 2b. Motor skills; 2c. Cognition; Chronic effects of malnutrition may be 3. Ill mental health; 4. Diseases like Parkinson’s and Alzheimer's

Prevention strategies

Existing research has established a correlation between malnutrition and an increased prevalence of maternal complications, including preeclampsia, gestational diabetes, obesity, and postpartum weight retention. Additionally, complications and adverse effects such as fetal macrosomia, caesarean section, childhood obesity, and adult cardiometabolic disease are also associated with malnutrition (Snetselaar, Jesus, Desilva, & Stoody, 2021). Consequently, continuous nutritional status monitoring should be advocated for in public policy guidelines pertaining to pregnant individuals. This practice generates early warning signs that safeguard both the mother and the unborn child, who warrant comprehensive care from infancy onwards to guarantee nutritional security and enable them to exercise their entitlement to sufficient nourishment. As doing so directly protects the growth, development, and health of the expectant child, assessing a woman's nutritional status during her pregnancy should be one of the most important goals of health services (García et al., 2020). The financial and resource implications are a contributing factor in the unwillingness to give universal nutritional assessments. However, part of the reason for this is that there isn't enough solid proof of its efficacy, or there is uncertainty over whether pregnant women and their carers find the present nutritional evaluation methods to be acceptable. Apart from the well-established significance of adequate nutrition throughout pregnancy, pregnancy is seen as a suitable time to modify the lifestyle of the expectant mother as well as that of her family, leading to better consequences (Anderson et al., 2015). To give moms and their families the best care possible, it is crucial to evaluate the pregnant woman's nutritional state before or early in the pregnancy. Numerous methods are used to conduct nutritional assessments, such as anthropometric measures, food intake assessments, and blood biomarker tests. Every strategy has advantages and disadvantages, and each one offers particular information on certain facets of nutritional status. One can directly evaluate the sufficiency of maternal nutrients and minerals by examining biochemical indicators. While some biomarkers, like plasma hemoglobin levels, are often checked for signs of anaemia, not all nutrients and minerals are routinely tested for these purposes since they are not always practicable or cost-effective in most situations. Although there are differences in the suggested threshold for supplementing, ferritin can be used to test for iron deficiency. Additionally, most studies do not perform the analysis of dietary FA ingestion as indicated by mass spectrometry red blood cell (RBC) FA analyses, which reflect 24 FA species and polyunsaturated essential omega-6 and omega-3 FA intakes. However, the analysis can now be performed on a single blood spot, and the cost has come down to a reasonable amount. It is difficult to evaluate the mothers' food intake; practitioners need to invest a lot of extra time, resources, knowledge, and expertise (Marshall et al., 2022). 

However, the most crucial step in preventing diet-related malnutrition is promoting health in women who are pregnant, nursing, and raising infants under the age of two. For the first four to six months of life, human milk is specially designed to satisfy the nutritional demands of healthy babies born on time. It is also linked to a decreased risk of developing chronic illnesses later in life when consumed during infancy. The amount of food a mother consumes during breastfeeding and the amount of nutrients she retains in her adipose tissue both affect the content and production of milk and the nutrients in it. Evidence suggests that exclusive breastfeeding for a minimum of six months protects the mother against type 2 diabetes (T2DM) and lowers the risk of childhood obesity in her kids who have GDM (Marshall et al., 2022). This should be accomplished within the political, social, and cultural context of this community. This public policy measure ought to have been accorded greater prominence in the Sustainable Development Goals guidelines, as opposed to being submerged beneath a global objective that would have given it only a cursory mention alongside other initiatives targeting this demographic. To promote optimal nutrition for a significant proportion of the global populace, existing comprehensive pregnancy care programmes must give precedence to the instruction of expectant families regarding the adoption of culturally suitable healthy lifestyles and dietary practices. Such measures are crucial in averting malnutrition and non-communicable chronic diseases, particularly among pregnant women, breastfeeding mothers, and children below the age of two (Castillo-Matamoros & Poveda, 2021).

As an endeavour to treat the newborn with FGR (Fetal growth retardation) more effectively outside the uterus, current prenatal care for pregnancies with FGR entails fetal observation and delivery of the fetus upon the onset of abnormal physiologic signs. Although a precise dietary regimen for addressing FGR does not exist, it has been demonstrated that uteroplacental gene therapy employing vascular endothelial growth factors can safely accelerate fetal development and reduce the incidence of FGR in sheep (Carr et al., 2014). Furthermore, new research suggests that exercise and dietary assistance before pregnancy may be more effective than throughout pregnancy at promoting a healthy placentation and fetal growth (Potdar, A, & M, 2014).

Conclusion

The greatest threat to the health of humankind and the leading cause of compromised mother and child health is still malnutrition. While pregnancy is among the most physically, emotionally, economically, and nutritionally challenging and demanding phases in a woman’s life, it requires that all the needs are met for not only one but two individuals- the pregnant and the developing fetus. Otherwise, both are at the disposal of varying risks which might be temporary or permanent, as it not only retards growth, development, and healing but also weakens the body making it incapable of combating infections. In this paper, we have aimed at elucidating the various aspects of micro- and macro-nutrient deficit, by exploring their function in maintaining good health and adverse conditions experienced otherwise. Ensuring adequate intake of essential nutrients such as calcium, iron, folic acid, iodine, and vitamin D during pregnancy is critical. This is shown to have a direct impact on the gut, and the subsequent microbiome-brain axis. Strains of Bifidobacterium sp., Lactobacillus sp., and Proteobacterium sp., among others are more prevalent and are boosted in a fiber-rich diet. They also directly influence the hormonal balance in the body, in the absence of which, hormonal intervention is a resort. In most cases, dietary modifications are made and supplements for isolated nutrients, or prescribed rich sources are consumed. Gut microbiota is given so much importance because it also plays a huge role in fetal programming. The "Barker hypothesis, posits that the critical phase of fetal development influences lifelong metabolic and hormonal changes, with maternal factors such as starvation and malnutrition permanently altering organ systems. Malnutrition affects glucose metabolism, bone strength, and tissue formation, while birth weight and hormonal balance are compromised. Nausea is usually a common sighting in the first trimester; however, diet-influenced excessive vomiting is considered a medical condition. Hypertension and high blood sugar are also not worrisome unless above a certain threshold, which has been discussed in detail. Out of the 17 Sustainable Development Goals, the very first 3 goals, namely, no poverty, zero hunger, and good health and well-being, must all be met immediately, as 2.5 million mothers are victims of acute and severe malnutrition. For lactating mothers, a daily intake of 1000mg of calcium is essential for bone health and milk production. Inadequate calcium and vitamin D can lead to conditions like osteoporosis and osteomalacia. Postpartum is accompanied by emotional stress, extended bleeding, and fatigue, which are exacerbated by nutritional deficits. Adequate intake of calories, vitamins, fluids, and protein is essential for wound healing and recovery. This can be tackled by emotional support, exercise, and improved intake, particularly of vitamin B2 and n-3 fatty acids. The review emphasizes the importance of holistic preventative strategies by recognizing societal norms, information gaps, and poverty as major contributors to malnutrition. To improve mother and infant health outcomes, these policies must be global in scope while being locally tailored.

Conflicts of interest

Given his role as Associate Editor, Balamuralikrishnan Balasubramanian has not been involved and has no access to information regarding the peer review of this article. Full responsibility for the editorial process for this article was delegated to Editor-in-Chief Kannan RR Rengasamy. The authors declare that there are no conflicts of interest regarding the publication of this article.

Author contributions

Conceptualization, M.P., B.B.; Writing-original draft preparation, L.P., S.S.H., M.K.D; Selected bibliographic sources, A.C. and A.C; Writing-review & editing, L.P., S.S.H., M.K.D., B.B., M.P., A.C. M.P; and B.B. supervised the overall project, provided critical revisions, and contributed to the final editing of the manuscript All authors have read and agreed to the published version of the manuscript.