INTRODUCTION

Recent scientific research has shown pre-gestational and gestational parent diet, and environmental exposures as two potential contributors to preterm labor activation, preterm birth (PTB) and the related adverse short- and long-term outcomes. Although diet has been associated with PTB, data often remain inconsistent. This is, in part, because of differing methods of dietary analysis. Various dietary patterns, both empirically derived (e.g., exploratory factor analysis) and defined a priori (e.g., Western, Mediterranean, Prudent, Dietary Approach to Stop Hypertension [DASH] diets), have been investigated in relation to preterm birth both prior to conception and during pregnancy, showing increased or decreased risk association with this obstetric complication.^1,2,3

The pathophysiological basis by which diet patterns are able to affect outcomes (both positive and negative) is still not clearly known. Theories suggested include nutrient deficiencies, which interfere with the compensation mechanisms normally responsible for moderating physiological responses, potentially leading to systemic alterations, including inflammation and oxidative stress imbalance.^4,5,6

Table 1 shows the short- and long-term consequences derived from maternal micronutrient deficiency for both the fetus/newborn and the mother.

PRE-PREGNANCY BODY MASS INDEX AND GESTATIONAL WEIGHT GAIN

Maternal prepregnancy body mass index (BMI) and sufficient gestational weight gain are measures of maternal health and nutrition that are key to meeting the nutrient demands of pregnancy. These factors are also vital for healthy embryonic and fetal development, infant health, and even adulthood. Although sufficient dietary intake is critically important for fetal development, excessive maternal weight is associated with severe pregnancy complications and increases short- and long-term risks in newborns.

Studies have indicated a negative correlation between pregestational maternal BMI (both overweight/obese and underweight) and PTB, even if the risk is influenced by non-modifiable factors such as maternal age, race, and ethnicity.⁷

Maternal obesity is a global health problem, and the pre-pregnancy BMI of women of childbearing age has shown an increasing trend in recent years. In developed countries, nearly half of all women of childbearing age are either overweight or obese.⁸

High maternal prepregnancy BMI increases the risk of complications, including pre-eclampsia, gestational diabetes mellitus, cesarean delivery, preterm delivery, stillbirth, large-for-gestational-age or fetal macrosomia, postpartum infection or blood clots, and postpartum weight retention.

However, mothers with low prepregnancy BMI are more likely to have suboptimal fetal growth, leading to low birth weight (LBW), preterm delivery, intrauterine growth restriction (IUGR), smaller head circumference, and low ponderal index, all of which are associated with higher infant morbidity and mortality.^9,10,11

Preterm birth and inappropriate prepregnancy BMI probably operate through complex inflammatory pathways, leading to impaired fetoplacental dialog.¹²

Sufficient gestational weight gain (GWG) is the amount of weight a woman gains during pregnancy and is another key element that scientific studies indicate is significant in influencing the pregnancy length. Both low GWG, particularly among lean women,^13,14 and high GWG¹⁴ have been associated with preterm delivery.

DIET PATTERNS: MEDITERRANEAN VERSUS WESTERN DIET

There is growing evidence that maternal dietary patterns can affect the risk of pregnancy outcomes. For example, the risk may decrease with a high intake of vegetables, fruits, and whole grains or a low intake of fast food and added sugars.^15,16

This intake pattern is similar to a Mediterranean-style diet (MSD), which, despite lacking a uniform definition in terms of its specific food items, intake frequency, and amount, generally encourages a variety of food groups (Figure 1), including cereals, vegetables, fruits, legumes, beans, dairy, eggs and fish, depending on the cultural and socio-economic contexts of countries.^{17,18,19,20,21}

A recently published meta-analysis and systematic review reported the MSD is a global, well-known healthy dietary pattern.²² The MSD is rich in omega-3 poly unsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, and polyphenols, which could explain how it can mitigate adverse perinatal outcomes. One theory is that this diet’s anti-inflammatory and antioxidative properties play a crucial role. The MSD was linked to reduced inflammation markers (IL-6 and C-reactive protein) and endothelial dysfunction. This finding was further confirmed by a meta-analysis of 17 trials involving 2300 patients, which identified the MSD as the first dietary pattern associated with significant reductions in proinflammatory and cytokine levels in a clinical trial.^23,24

Moreover, significant advantages derived from the low-carbohydrate, low-glycemic index, high-fiber, and high-protein components are the promotion of satiety and a sense of fullness, aiding in weight control and obesity prevention.²⁵

These key components may also positively impact the gut microbiota-immune system.²⁶ Recent studies reported that maternal gut microbiome reflecting poor diet quality is associated with spontaneous preterm birth. During pregnancy, a healthy gut microbiota-immune system could reduce endotoxin levels and systemic inflammation, potentially lowering the risk of preterm labor.²⁷

MICRONUTRIENTS

Deficiencies in micronutrients such as folic acid, iron, zinc, and vitamins are common in pregnant women. Low iron consumption, for example, has been associated with anemia, while low folate intake has been associated with neural tube defects or preterm birth.^28,29 Moreover, since vitamins (such as vitamin D and vitamin B12) and some minerals are important components of the immune system, deficiencies in these micronutrients can lead to harmful infections. A recent meta-analysis showed that copper (Cu) concentration was strongly correlated with infection status, suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB.³⁰

Studies associated maternal hypovitaminosis D during pregnancy with an increased risk of prematurity. However, the evidence of this association remains inconclusive, and the literature lacks consensus. The exact mechanism by which low vitamin D levels may increase the risk of preterm birth is not yet fully understood. Nevertheless, it is known that vitamin D may play a role in maintaining a healthy pregnancy by regulating inflammation and immunomodulation by acting on the maternal and fetal immune systems.³¹

Similarly, vitamin B12 deficiency in pregnancy has been associated with both lower birth weight and preterm birth. Nevertheless, the literature evidence is contradictory.³² Other vitamins (vitamin B6 and vitamin E) were associated with higher preterm delivery rates.

A growing body of evidence indicates that elevated long-chain omega-3 PUFAs (LC omega-3 PUFA) intake is associated with reduced risk PTB.

LCPUFAs are typically found in fish and fish oils, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA and EPA are precursors for anti-inflammatory products that are formed by the activity of cyclooxygenases (COXs), lipoxygenases (LOXs) and cytochrome P450 (CYP) (these are the same enzymes that produce inflammatory products from the omega 6 fatty acid, arachidonic acid. Lipid biomarkers formed by LOXs and CYP pathways have been found to predict spontaneous PTB.³³

A recent practice guideline on supplying omega-3 DHA and EPA in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations.³⁴ Women of childbearing age should obtain a supply of at least 250 mg/day of DHA + EPA from diet or supplements and in pregnancy, an additional intake of ≥100–200 mg/day of DHA.³⁴ Pregnant women with a low DHA intake and low DHA blood levels, who are thus at higher risk for PTB, should receive a supply of approximately 600–1000 mg/day of DHA + EPA, or DHA alone. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation.³⁴ An increased consumption of foods rich in omega-3 PUFA or supplements is associated with an 11% and 42% risk reduction of early and late preterm births, respectively.³⁵

Several recent small clinical trials of myo-inositol supplementation in pregnancy, which were primarily aimed at preventing gestational diabetes, have suggested an effect on reducing the incidence of PTB as a secondary outcome, highlighting the potential role of myo-inositol as a preventive agent through modulation of the uteroplacental environment and inhibition preterm labor onset.³⁶

Low maternal selenium status has been associated with poor pregnancy outcomes, including preterm birth, but there is limited evidence on the effects of selenium supplementation during pregnancy.³⁷ Other relationships between maternal micronutrients, such as zinc, and manganese levels and preterm labor have been investigated, and lower serum levels resulted in mothers with preterm delivery, showing a probable biological role in the pathogenesis of preterm delivery, but further research is still needed.^38,39

PREDICTION AND PREVENTION

Identification of women with inadequate micronutrient intake could be difficult due to a wide heterogeneity in geographic, epidemiological, and socio-cultural features. This information may be achievable starting with early investigation of the nutritional status of women using a set of standardized questions on intake (for example, diet history questionnaires).

Adolescents and women of childbearing age, as well as women in pre-conceptional periods, should be carefully analyzed regarding their diet pattern and lifestyle to identify nutritional deficiencies and provide information on how to achieve appropriate nutritional intake and recognize the need for supplements.

Micronutrients measurement in blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cut-off values is needed, and cost-effectiveness considerations must be considered. Nowadays, for some micronutrients, blood measurement is mainly available and used, for example, for iron status (serum ferritin and hemoglobin levels) and vitamin D status assessment. However, for others, it is not still available for use in daily practice. Figure 2 shows some easy and practical key interventions in women of childbearing age that may help to achieve an adequate peri-conceptional nutritional status to reduce obstetric risks, including PTB.

CONCLUSIONS

Preterm birth is well associated with an unbalanced maternal nutritional status, and probably able to trigger complex biological mechanisms underlined this condition (pro-inflammatory cascade activation, oxidative stress response, immunomodulation, infections).

Targeted pre-pregnancy intervention studies and programs that include counseling on the optimization of preconception health and lifestyle modification for improvement of subsequent pregnancy outcomes are crucial and a global priority.

The Mediterranean-style diet is considered a balanced, nutrient-rich diet due to the low consumption of meat products and fatty foods and the high consumption of vegetables, cheese, olive oil, fish, shellfish, and little meat. It could be a healthy diet model to refer to worldwide.

The investigation of women’s nutritional status is achievable; diet advice and supplements are available, thus promoting a decrease in obstetrics and postnatal short- and long-term complications.

Thus, further research and shared global recommendations are needed.

PRACTICE RECOMMENDATIONS