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Maia, S.B.;  Souza, A.S.R.;  Caminha, M.D.F.C.;  Silva, S.L.D.;  Cruz, R.D.S.B.L.C.;  Santos, C.C.D.;  Filho, M.B. Vitamin A and Pregnancy. Encyclopedia. Available online: https://encyclopedia.pub/entry/25962 (accessed on 10 May 2024).
Maia SB,  Souza ASR,  Caminha MDFC,  Silva SLD,  Cruz RDSBLC,  Santos CCD, et al. Vitamin A and Pregnancy. Encyclopedia. Available at: https://encyclopedia.pub/entry/25962. Accessed May 10, 2024.
Maia, Sabina Bastos, Alex Sandro Rolland Souza, Maria De Fátima Costa Caminha, Suzana Lins Da Silva, Rachel De Sá Barreto Luna Callou Cruz, Camila Carvalho Dos Santos, Malaquias Batista Filho. "Vitamin A and Pregnancy" Encyclopedia, https://encyclopedia.pub/entry/25962 (accessed May 10, 2024).
Maia, S.B.,  Souza, A.S.R.,  Caminha, M.D.F.C.,  Silva, S.L.D.,  Cruz, R.D.S.B.L.C.,  Santos, C.C.D., & Filho, M.B. (2022, August 08). Vitamin A and Pregnancy. In Encyclopedia. https://encyclopedia.pub/entry/25962
Maia, Sabina Bastos, et al. "Vitamin A and Pregnancy." Encyclopedia. Web. 08 August, 2022.
Vitamin A and Pregnancy
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This entry is adapted from the peer-reviewed paper 10.3390/nu11030681

Vitamin A is a crucial micronutrient for pregnant women and their fetuses. In addition to being essential for morphological and functional development and for ocular integrity, vitamin A exerts systemic effects on several fetal organs and on the fetal skeleton. 

Vitamin A vitamin A deficiency pregnancy

1. Introduction

Vitamin A was discovered 106 years ago [1] and has been recognized as a public health priority by the World Health Organization (WHO) for more than six decades [2]. Nevertheless, many aspects of vitamin A deficiency (VAD), such as its epidemiology, classification, and even its metabolism and pathophysiology, are still not fully understood. 
Vitamin A plays an important role in ocular function, as it is involved in cell differentiation, in the maintenance of eye integrity, and in the prevention of xerophthalmia. Its deficiency is the main cause of preventable blindness worldwide . Vitamin A is also associated with bone development, has a protective effect on the skin and mucosa, plays a vital role in the functional capacity of reproductive organs, participates in strengthening the immune system, is related to the development and maintenance of epithelial tissue, and contributes to the development of normal teeth and hair [3][4][5]. In addition to its important role in various body tissues [3], vitamin A is essential to the normal development of the embryo [6].
Pregnancy is a period of specific nutritional needs for maintaining the health of both the mother and the fetus. During this period, there is an increase in the demand for vitamin A, particularly in the third quarter because of the accelerated fetal development in this phase [7]. According to the WHO, VAD is still considered a public health issue at a population level, particularly in some developing countries, affecting approximately 19 million pregnant women .
In contrast, due to the possible teratogenic effects associated with high doses of vitamin A [8], excessive intake of this vitamin is a concern, principally in developed countries. The main adverse effects associated with excessive vitamin A intake, particularly at the beginning of the first quarter of pregnancy, are congenital malformations involving the central nervous and cardiovascular systems and spontaneous abortion [9][10].

2. Vitamin A: Summary Review of Metabolism

The metabolism of vitamin A is complex and involves different forms, sources, and mechanisms such as carrier proteins, enzymes, storage, and physiological and pathological complications [3]. In humans, vitamin A has three active forms (retinal, retinol and retinoic acid) and a form of storage in the liver (retinyl ester) [11]. This liposoluble micronutrient is not synthesized by the body and must be obtained through the diet. It is available from two main sources: preformed vitamin A (retinol and retinyl ester) and provitamin A (caratenoids) [12][13][14]. Of the numerous naturally occurring carotenoids, beta-carotene, alpha carotene, and beta-cryptoxanthin are major provitamin A carotenoids present in foods [15].
Preformed vitamin A is found in foods of animal origin such as dairy products (e.g., milk, yoghurt, and cheese), liver, fish oils, and human milk. Provitamin A, from vegetable sources, is found in fruits, leaves, and tubers such as carrots, pumpkin, kale, spinach, sweet potato, papaya, mango, and red palm oil [11][14][16][17]. Brazilian buriti (Mauritia vinifera) and palm oil (Elaeis guineensis) represent the richest sources of provitamin A in Brazil [18]. The absorption of vitamin A from vegetable sources is considered poor, and foods of animal origin may be necessary to achieve adequate levels in the body [12][13].
The digestion and absorption of vitamin A are associated with the absorption of lipids. Therefore, critically low dietary fat content (less than 5–10 g/day) or conditions such as pancreatic and hepatic diseases and frequent gastroenteritis that interfere with the digestion or absorption of lipids, resulting in steatorrhea, can interfere with the absorption of vitamin A [11][19][20].
With regard to provitamin A, mammals use both carotenoid oxygenases, β-carotene-15,15′-oxygenase (BCO1), and β-carotene-9′,10′-oxygenase (BCO2) to synthesize retinoids from provitamin A carotenoids. Cleavage by BCO2 produces apocaretenoids, which are converted into retinoids by BCO1. Furthermore, β-cryptoxanthin plays an important role in vitamin A production by limiting competition between the metabolites of β-carotene based on the substrate specificity of BCO2 for carotenoids with 3-OH-α-ionone ring sites. This is also evident from the occurrence of β-cryptoxanthin accumulation in BCO2-deficient mice [21]. The retinol absorbed can be released directly into the extrahepatic tissues or captured by the liver, where it can be stored or released back into the bloodstream to meet the body’s requirement [22]. The liver reserve may be able to fulfill the required demands for a long period of time (up to months) [11].
In any tissue, including the liver, vitamin A is converted to retinoic acid, which is the active metabolite required for proper morphogenesis. Unlike retinol, retinoic acid is not a stable metabolite, being present in very low levels in serum [23]. High concentrations of certain metabolites of retinoic acid (trans-retinoic acid and 13-cis-retinoic acid) can influence gene activity during critical periods of organogenesis and embryogenesis, leading to teratogenicity [24][25].
Circulating vitamin A is transported in the plasma in a 1:1 complex with retinol-binding protein (RBP). The retina and other tissues dependent on vitamin A have specific binding sites for RBP and vitamin A. As RBP is the only carrier [26], conditions that reduce its levels such as proteinuria, kwashiorkor (protein malnutrition), and zinc deficiency may contribute to VAD. For example, pre-eclampsia, which evolves with proteinuria [27], may cause a decrease in serum retinol levels [28][29].
The transfer of vitamin A from mother to child occurs via the placenta during gestation and at birth and via the mammary gland during lactation (breastfeeding). During pregnancy, due to the decrease in serum retinol levels in pregnant women (particularly in the third quarter) and the selective placental barrier, the newborn hepatic reserves of vitamin A are low at birth to avoid possible teratogenic effects [30]. After birth, a major part of serum retinol is transported to the breast by RBP, reaching the breast milk [31]. From then on, the transport of vitamin A to breast milk in the first six months of life provides 60-fold more vitamin A when compared with the placental route during the entire pregnancy [32]. Furthermore, breast milk also transports active provitamin A carotenoids, which serve as additional nutrients for the infant. Despite the importance of carotenoids in promoting the health of breast-feeding mothers and their newborns, in recent studies conducted with rats in early life (during breast-feeding), excess vitamin A intake has been associated with obesity [33][34].

3. Vitamin A Deficiency during Pregnancy: Epidemiological Aspects

Despite extensive understanding of the pathophysiology of VAD, with its signs and symptoms being well recognized by health professionals and a proportion of the general population, VAD remains among the major collective health priorities in the world today, together with iron-deficiency anemia and iodine deficiency [35]. Regardless of national and international agreements involving policy makers, program managers in health and education, and multisector programs of action (e.g., agricultural policies, food supply and enrichment of industrialized foods with specific nutrients, and selective distribution of basic food baskets), epidemiological control of VAD remains a challenge in Brazil and in several other developing countries .
Regrettably, basic data for the development, implementation, and evaluation and monitoring of policies and programs (public or private) are therefore unavailable at the consistency required to resolve the problem at the population level. For example, and principally as an object of study, the important issue of VAD in pregnant women is without doubt the most obscure link in the chain of epidemiological events related to this specific nutritional deficiency at the national and international level.
Conceptually, the entire population may be exposed to the problem at any stage of the biological cycle, from embryonic/fetal life until old age. Nevertheless, it is in the short period of pregnancy/lactation that the risk of this deficiency increases . This process is fundamentally triggered by biological factors: during pregnancy, there is a considerable increase in nutritional vitamin A requirements due to the double demand from the mother and her child; during lactation, exclusively breastfeeding should be the autonomous and complete source of fluids, energy, and nutrients for the infant [11]. Nevertheless, not only should the physiological nutritional demands of children in the first months and years of life be taken into consideration, but also the impact of these demands on the health/illness process that may continue into adult life, including preventing and delaying the onset of chronic noncommunicable diseases [36].
Pregnancy represents a nutritionally crucial period, either because of previous deficiencies being reduced or aggravated by the gestational process, or because excesses and inadequacies of nutrients in the diet may produce specific nutritional disorders [37]. Thus, nutrients including vitamin A can interfere with the occurrence or worsening of previous or coexisting diseases during pregnancy, childbirth, and in the postpartum.
VAD is more frequent in the last quarter of pregnancy because of the physiological increase in maternal blood volume and accelerated fetal development in the final phase of pregnancy [38][39]. Pregnant women may be more prone to developing VAD during periods in which there is a shortage of foods rich in vitamin A or in the presence of infections, diabetes mellitus, or gestational diabetes [40][41][42].
The WHO defines VAD in pregnancy as serum retinol levels of <0.70 µmol/L, with the condition being considered a serious public health issue when the prevalence occurs in 20% or more of pregnant women; moderate when affecting between 10% and 20%; and mild when between 2% and 10% [43][44] (Table 1). It is noteworthy that serum retinol levels should ideally be analyzed using high performance liquid chromatography (HPLC) [45].
Table 1. Prevalence ranges of vitamin A deficiency (VAD) in the population and their level of public health significance.

VAD as a Public Health Issue

Public Health Significance (Degree of Severity)

Serum or Plasma Retinol <0.70 μmol/L in Preschool-Aged Children or Pregnant Women a

Mild

≥2% to <10%

Moderate

≥10% to <20%

Severe

≥20%

a Source: Reference 46; Children 6–71 months of age. As there is no World Health Organization (WHO) recommended cut-off for serum retinol in pregnant women, the cut-off level for children was used (<0.70 μmol/L). The distribution of prevalence cut-offs for pregnant women is provisional.

4. Vitamin A and Pregnancy: Importance and Effects of Deficiency and Excess

The more common scenario involving VAD occurs when there is an acutely reduced dietary intake of vitamin A, or when there is a prolonged period of dietary scarcity, or a simultaneous combination of these two conditions, i.e., both prolonged and severe, with the possible mediation of an underlying disease [46]. VAD can lead to subclinical disorders such as impaired iron mobilization, altered cellular differentiation, and decreased immune response, or clinical disorders such as increased infectious morbidity, growth retardation, anemia, and xerophthalmia [47].
The term xerophthalmia is used to designate the ocular manifestations of VAD. These ocular manifestations also include night blindness caused by corneal ulceration and keratomalacia [47]. Night blindness is one of the first manifestations of this specific micronutrient deficiency, although not a pathognomonic signal as it can also occur in retinitis pigmentosa [48][49].
Vitamin A is important for the pregnant woman and for the fetus, being essential for the maintenance of maternal night vision and fetal ocular health besides the development of other organs and the fetal skeleton and maintenance of the fetal immune system [14][50][51][52]. Maternal and infant concentrations of vitamin A compounds have been associated with neonatal outcome [53]. In this section, the effects of maternal vitamin A levels during pregnancy on fetal and perinatal health are discussed, with a focus on studies published in the last decade together with the classical references on the theme.
There is strong evidence from animal studies that VAD is associated with adverse effects on offspring during the embryonic and post-natal period [1][54][55][56]. From the moment of the formation of the primitive heart and circulatory system and specification of the rhombencephalon, there is already a need for vitamin A. During this critical time, VAD results in severe abnormalities, including early embryonic death. The need for vitamin A in more advanced stages of development is also evident in experimental rodent models. The main target tissues of VAD include the heart, the central nervous system and its derived structures, the circulatory, urogenital and respiratory systems, and the skull, skeleton, and limbs [55]. Recently, a study in rats showed that dietary vitamin A deficiency two weeks before and during pregnancy can result in anorectal malformations and that the development of the enteric nervous system may be affected by the pathological changes involved in these malformations [57].

5. Vitamin A Supplementation during Pregnancy: Recent Evidence and Current Recommendations

5.1. Recent Evidence

The three strategies for the prevention and control of VAD according to the WHO are as follows: (1) supplementation with massive doses as an emergency measure in the short term; (2) fortification of foods (redistribution of nutrients) in the medium term; and (3) dietary diversification as a definitive solution in the long term [43].
Programs for the distribution of massive doses usually attain good results; however, over time, they become ineffective because they depend on the active participation of the community and political interest. Dietary diversification, as an ideal solution, is difficult and slow since it involves changing habits and the consumption of specific foods. Accordingly, the strategy that remains is the fortification of foods, which consists of increasing the nutrient content in certain foods, involving several essential elements such as a food vector, nutrient aggregation in a manner that ensures its stability until reaching the consumer, the integrity of the organoleptic characteristics of the vector, and a simple and low-cost fortification technology [43].
During pregnancy, the most recent evidence is related to vitamin A supplementation. When this strategic alternative was applied to women before, during, and after pregnancy in a population with chronic VAD, children’s pulmonary function improved in a large cohort of 9 to 13-year-old children in rural Nepal whose mothers had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation [58]. The benefit of maternal supplementation with vitamin A was limited to children whose mothers received preformed vitamin A and was not seen in those whose mothers received beta-carotene, possibly because beta-carotene is a less efficient source of vitamin A than the preformed ester [58].
A cohort study of rural Bangladeshi children from two previous trials showed that vitamin A supplementation in women during prenatal and postnatal periods is associated with an improvement in school performance and aspects of executive function in children assessed at 8 years of age, while general intelligence, memory, and motor functions are not affected by prenatal or postnatal supplementation with vitamin A [59].
In relation to food fortification, a recent study in Denmark suggested an association between fetal exposure to an increase of 25% in the amount of vitamin A in margarine ingested by the mother during pregnancy and a reduced risk (OR = 0.88) of type 2 diabetes in the offspring during adulthood [60].
Some studies suggest a reduction in the risk of infections after vitamin A supplementation as a consequence of its important function in the immune system, improving host defenses [61][62]. Secretory IgA contributes to intestinal barrier function, with evidence suggesting that these antibodies are involved in immunological homeostasis. Its production depends on IgA antibody-secreting plasma cells and their immediate precursors (plasmablasts), which accumulate in the mucosa [63][64]. All-trans retinoic acid is a metabolite of vitamin A that plays an important role in the immune responses of the intestinal mucosa and it also acts in the feedback loop for the production of enzymes involved in its own synthesis, increasing mucosal IgA responses and enhancing the effectiveness of oral vaccines [63]. However, clinical trials that evaluated vitamin A supplementation in pregnant women showed no reduction in the risk of placental malaria and adverse events during pregnancy [65]. Similarly, another clinical trial that assessed the incidence of malaria among HIV-infected Tanzanian women concluded that vitamin A supplementation did not alter the incidence of malaria during the study [66].
Observational studies conducted in sub-Saharan Africa have suggested that low levels of vitamin A in pregnant women infected with HIV are associated with a significantly increased rate of vertical transmission [67][68] and infant mortality [68][69]. However, a systematic review concluded that vitamin A supplementation during the prenatal or postnatal period probably has little or no effect on the transmission of HIV from mother to child [70].
A recent study reported that vitamin A supplementation during pregnancy increased hemoglobin concentrations and reduced the occurrence of anemia [71]. The improvement of serum retinol levels and the reduction of anemia define an important relationship, as anemia is the most common deficiency of pregnancy [72][73][74]. VAD is, therefore, one of the main causes of anemia; however, the pathogenesis of this relationship remains to be clarified. Vitamin A is known to exert an effect on hematopoiesis, to increase immunity to diseases (thus preventing anemia from infection), and to play a role in the modulation of iron metabolism [75].
Regarding the diversification of diet as a means of preventing and controlling VAD, a cohort study conducted in Rio de Janeiro to assess the impact of nutritional prenatal care found that the ingestion of a medium-sized piece of ox liver (110 g) per week by pregnant women resulted in a significant reduction in the prevalence of night blindness during follow-up [76].
According to a systematic review conducted in 2015, vitamin A supplementation during prenatal care failed to reduce maternal or perinatal mortality. However, most of the studies analyzed during the review included different populations in relation to the basal level of vitamin A, with no information concerning vitamin deficiency. In addition, there were difficulties in the follow-up of these women. The review suggests that supplementation in HIV-positive pregnant women and those living in vitamin A-deficient areas may reduce nocturnal blindness and anemia, but it is unrelated to the reduction in vertical HIV transmission. A reduction in maternal infection rate has also been suggested; however, it is important to bear in mind that these data are not of good quality [61].

5.2. Current Recommendations

According to the 2013 WHO guideline [7], routine supplementation of vitamin A in the prenatal period to prevent maternal or perinatal morbidity and mortality is not recommended. However, in places where VAD is a public health issue, vitamin A supplementation in pregnant women is recommended to prevent night blindness [7].
During pregnancy, there is an increase of approximately 10% to 20% [30] in the need for vitamin A, with the recommended dose being 800 µg/day. It may be difficult to obtain this dose through diet alone, particularly in populations affected by VAD [11].
For prenatal care, vitamin A is available in several formulations. When administered alone, the most commonly used components are retinyl palmitate and retinyl acetate in the form of pills or oil-based solutions. There are other alternatives such as oil, fish liver oil, beta-carotene, and a combination of beta-carotene and vitamin A. The schemes suggested for vitamin A supplementation in pregnant women for the prevention of night blindness in areas with a severe public health problem related to vitamin A are detailed in Table 2 [7]. Food diversification and fortification is also recommended along with supplementation to improve the intake of vitamin A [7].
Table 2. Suggested vitamin A supplementation scheme in pregnant women for the prevention of night blindness.

Target Group

Pregnant Women

Dose

Up to 10,000 IU vitamin A (daily dose) OR

Up to 25,000 IU vitamin A (weekly dose)

Frequency

Daily or weekly

Route of administration

Oral liquid, oil-based preparation of retinyl palmitate or retinyl acetate

Duration

A minimum of 12 weeks during pregnancy until delivery

Settings

Populations where the prevalence of night blindness is 5% or higher in pregnant women or 5% or higher in children aged 24–59 months

IU: international units. Source: Reference [7].

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Sabina Bastos Maia
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Alex Sandro Rolland Souza
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Maria de Fátima Costa Caminha
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Suzana Lins da Silva
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Rachel de Sá Barreto Luna Callou Cruz
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Camila Carvalho dos Santos
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Malaquias Batista Filho
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