How to Feed the Fetus

Vol. 78, Suppl. 1, 20–21

Guest Editor Ferdinand Haschke, Salzburg

Editorial Board Jatinder Bhatia, Augusta, GA Weili Lin, Chapel Hill, NC Carlos Lifschitz, Buenos Aires Andrew Prentice, Banjul/London Frank M. Ruemmele, Paris Hania Szajewska, Warsaw

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[email protected] Vol. 78, Suppl. 1, 20–21

Contents

11 Editorial Haschke, F. (Salzburg)

How to Feed the Fetus

1 3 Focus on: Gestational Diabetes Mellitus and Developmental Programming

14 Gestational Diabetes Mellitus and Developmental Programming Chu, A.H.Y. (Singapore); Godfrey, K.M. (Southampton)

15 Focus on: Nutrition Management of Gestational Diabetes Mellitus

16 Nutrition Management of Gestational Diabetes Mellitus Kapur, K. (Bangalore); Kapur, A. (Bagsvaerd); Hod, M. (Tel Aviv)

28 Focus on: Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth

29 Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth Best, K.P.; Gomersall, J.; Makrides, M. (Adelaide, SA)

37 Focus on: Maternal Undernutrition before and during Pregnancy and Offspring Health and Development

38 Maternal Undernutrition before and during Pregnancy and Offspring Health and Development Young, M.F.; Ramakrishnan, U. (Atlanta, GA)

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Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):1–2 DOI: 10.1159/000511240

How to Feed the Fetus

Ferdinand Haschke

Department of Pediatrics, PMU Salzburg, Salzburg , Austria

Many nutritional risks for maternal and child health begin GDM may also be associated with offspring negative health during the adolescent and young adult years prior to first outcomes, such as allergy, and neurocognitive conditions, pregnancy. Because they affect fetal development before the such as ADHD and autism. GDM as a maternal intrauterine initiation of antenatal care, the arguments for preventive ac- trigger could play a role in influencing offspring long-term tions in the field of nutrition during the adolescent and young outcomes through epigenetic modification of gene function adult years are compelling. Accelerating rates of female obe- [3] . Human studies indicate a causal relation between GDM sity have further complicated nutritional risks arising in fe- and the epigenetic regulation of the leptin gene, which could males between 15 and 25 years so that in many emerging explain offspring adiposity. Furthermore, GDM and altered societies, obesity coexists with food insecurity and undernu- methylation status has been reported of a gene associated trition. In 2017, the Nestlé Nutrition Institute provided an un- with autism spectrum disorder (OR2L13 promoter) and of the restricted educational grant to support a series of publications serotonin transporter gene (SLC6A4), which is involved in de- which summarize recent interventions and recommenda- pression, anxiety, and autism. A combined diet and exercise tions in the field of nutrition of young females before and dur- program before and during pregnancy can be useful in pre- ing pregnancy [1, 2] . The supplement “How to Feed the Fetus” venting GDM in high-risk women. In addition, there is some addresses short- and long-term consequences of nutrition evidence that probiotic and myo-inositol supplementation and health issues before and during pregnancy. can work [4] . Medical nutrition therapy provides the basis for One in 6 pregnancies worldwide is affected by the inabil- the management of GDM. The conventional approach of lim- ity of the mother’s metabolism to maintain normoglycemia. iting carbohydrates at the cost of increasing energy from fat Insulin resistance and insufficient insulin secretion result in source may not be the most optimal. Instead, allowing higher gestational diabetes mellitus (GDM). Because of the increas- levels of complex, low to medium glycemic index carbohy- ing number of pregnant women with higher body mass index drates and adequate fiber through higher consumption of (BMI), the prevalence is likely to increase. In addition to short- vegetables and fruits seems more beneficial. For medical nu- term consequences of non- or poorly treated GDM, such as trition therapy to work it is vital that dietary advice and nutri- fetal overgrowth, exposure of the fetus to hyperglycemia will tion counseling is provided by a dietician, is easy to under- predispose the offspring to noncommunicable diseases later stand and use, and includes healthy food options, cooking in life [3] : the effect of GDM on offspring overweight, obesity, methods, and practical guidance that empowers and moti- impaired glucose tolerance, and resulting cardio-metabolic vates to make changes towards a healthy eating pattern. disease may be in part triggered by maternal obesity. Maternal

[email protected] © 2021 Nestlé Nutrition Institute, Switzerland/ Prof. Ferdinand Haschke, MD S. Karger AG, Basel Department of Pediatrics, PMU Salzburg 48 Muellner Hauptstrasse AT–5020 Salzburg (Austria)

fhaschk @ gmail.com The literature on omega-3 LCPUFA fats supplementation enced by many conditions, including malaria, infection, he- before and during pregnancy in higher income countries is moglobinopathies, or other micronutrient deficiencies. Pre- also summarized in this issue [5] : the updated Cochrane re- conception anemia and maternal undernutrition are associ- view of marine oil supplementation includes 7 RCTs (19,927 ated with an increased risk of low-birth-weight and pregnant women) with LCPUFA fats in any form or dose dur- small-for-gestational-age births, while anemia in the first tri- ing the second half of pregnancy. Results show high-quality mester of pregnancy is associated with low birth weight, pre- evidence that supplementation with omega-3 LCPUFA during term birth, and neonatal mortality. Only a few trials report the

pregnancy reduces the risk of having a premature baby < 37 outcomes of preconception nutritional interventions with

weeks’ gestation by 11% and < 34 weeks’ gestation by 42% supplements containing multiple micronutrients with or with- compared with no omega-3 supplementation. Prenatal ome- out energy from lipids [6] : birth weight and length are higher ga-3 LCPUFA supplementation is safe because of no effect on and the risk of stunting in the offspring is 12–13% lower at 2 bleeding or postpartum hemorrhage, and it significantly re- years. There is strong evidence that during pregnancy multi- duces the incidence of low birth weight but increases the in- ple micronutrient supplements together with protein and en- cidence of pregnancies continuing beyond 42 weeks. The ergy reduce the risk of stillbirth by 40% and the risk of small- 2-day shift in mean gestation in the DOMInO trial (2,499 preg- for-gestational age by 21%, increase birth weight, and are nant women) increases the number of post-term pregnancies cost-effective. In addition, limited data from several develop- and, thus, the need for more obstetric interventions to initiate ing countries indicate better cognitive outcome in children

birth by approximately 4% [5] . Studies on omega-3 LCPUFA > 6 years after multiple micronutrient supplementation before supplementation during pregnancy and improved cognitive and during pregnancy and during the first 1,000 days of life. outcome in the offspring are still controversial. This supports In conclusion, metabolic imbalances during pregnancy, the need for further research to investigate the effects of pre- such as GDM, might result in epigenetic changes which affect natal omega-3 supplementation before adopting a universal the offspring and might predispose to noncommunicable dis- supplementation approach into routine antenatal care. eases later in life. Preventive measures for GDM must be initi- The WHO estimates that over 2 billion people are at risk for ated during pre-pregnancy and early pregnancy, in particular micronutrient deficiencies, mainly from developing countries in women with high BMI. In pregnant women who develop in Asia and Africa. Of public health concern are iron, vitamin GDM, medical nutrition therapy has to be provided by health- A, iodine, zinc, folate, and B vitamins deficiencies. Regional care professionals. Omega-3 LCPUFA supplementation dur- estimates of anemia and micronutrient deficiencies indicate a ing the second half of pregnancy is effective to prevent pre- high prevalence among women of reproductive age [6] . Ap- mature birth and low birth weight. In developing societies, proximately 50% of anemia among non-pregnant and preg- multiple micronutrient supplementation before and during nant women is amenable to iron supplementation. However, pregnancy can contribute to better growth and cognitive de- the regional role of iron deficiency in anemia has been shown velopment of the offspring.

to be extremely variable from < 1 to 75% and may be influ-

References

1 Salam RA, Hooda M, Das JK, Arshad A, Lassi ZS, Middleton P, et al. 4 Kapur K, Kapur A, Hod M. Nutrition management of gestational Interventions to improve adolescent nutrition: a systematic review diabetes mellitus. Ann Nutr Metab. doi: 10.1159/000509900.

and meta-analysis. J Adolesc Health . 2016 Oct; 59(4 Suppl):S29– 5 Best KP, Goersall J, Makrides M. Prenatal nutritional strategies to S39. reduce the risk of preterm birth. Ann Nutr Metab . doi: 2 Das JK, Salam RA, Thornburg KL, Prentice AM, Campisi S, Lassi ZS, 10.1159/000509901. et al. Nutrition in adolescents: physiology, metabolism, and nutri- 6 Young MF, Ramakrishnan U. Maternal undernutrition before and tional needs. Ann N Y Acad Sci. 2017 Apr; 1393(1): 21–33. during pregnancy and offspring health and development. Ann 3 Chu AHY, Godfrey KM. Gestational diabetes mellitus and develop- Nutr Metab. doi: 10.1159/000510595. mental programming. Ann Nutr Metab. doi: 10.1159/000509902.

2 Reprint with permission from: Haschke Ann Nutr Metab 2020;76(suppl 3):1–2 DOI: 10.1159/000511240 Focus

There is increasing epidemiological evidence linking early-life environmental exposures (i.e., maternal malnutrition/overnutrition, environmental chemicals, stress) with later-life health outcomese

Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):4–14 Gestational Diabetes Mellitus and Developmental Programming Anne H.Y. Chu and Keith M. Godfrey

Key insights Neurodevelopment Immune system Gestational diabetes mellitus (GDM) affects an estimated 14% of pregnancies worldwide. It is now clear that children born to mothers with GDM have an increased lifetime risk of metabolic diseases compared to unexposed children. Other Intra-uterine Cardiovascular environment long-term adverse consequences in the offspring include system Gut (GDM) microbiome cardiovascular abnormalities, dysregulation of glucose metabolism, increased risk of allergic/respiratory disease, and neurodevelopmental abnormalities. Together, these ﬁndings highlight the importance of the intra-uterine environment as Adiposity Metabolism a driver of epigenetic changes in the offspring.

Gestational diabetes mellitus (GDM) affects many organ systems in the offspring through the mechanism of epigenetics. Current knowledge

Several human studies have examined the association between in utero GDM exposure and DNA methylation in pla- low-up studies suggest that this treatment may not be suffi- centas, and offspring cord or infant blood. The findings have cient to reduce childhood obesity in the offspring. The current revealed several differentially methylated genes in the fetal evidence indicates that interventions delivered during preg- tissues of babies born to mothers with GDM: of interest are nancy may only partly alter fetal growth and development, those related to metabolic regulation, such as leptin, adipo- pointing towards the peri-conceptional period as an early nectin, and the SLC2A1/GLUT1 and SLC2A3/GLUT3 genes. modulator of health outcomes in the offspring. Further studies The effects of GDM, however, are not limited to offspring me- are needed to understand how we can leverage the peri-con- tabolism. Current research indicates that the epigenetic ad- ceptional period as a window of opportunity for optimizing the aptations triggered by maternal glycemia also affect other de- health of future generations. veloping organ systems in the infant, including neurodevelopment. Recommended reading

Practical implications Antoun E, Kitaba NT, Titcombe P, Dalrymple KV, Garratt ES, Barton SJ, et al. Maternal dysglycaemia, changes in the infant’s Infants born to mothers who receive GDM treatment (such as epigenome modified with a diet and physical activity interven- dietary advice, blood glucose monitoring, and insulin therapy) tion in pregnancy: Secondary analysis of a randomised con- have improved perinatal outcomes. However, long-term fol- trol trial. PLoS Med. 2020;17(11):e1003229.

Reprint with permission from: Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902

Gestational Diabetes Mellitus and Developmental Programming

a b Anne H.Y. Chu Keith M. Godfrey

a Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A* STAR), Singapore , Singapore ; b MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton , UK

Key Messages mother’s metabolism to maintain normoglycaemia, with the combination of insulin resistance and insufficient insulin se- • A mother’s glycaemic status and weight during before concep- cretion resulting in gestational diabetes mellitus (GDM). A tion and pregnancy influence the long-term health of the offspring. growing body of epidemiologic work demonstrates long- • The offspring’s future health can be programmed through the term implications for adverse offspring health resulting from role of epigenetic changes induced by a hyperglycaemic envi- exposure to GDM in utero. The effect of GDM on offspring ronment in utero. obesity and cardiometabolic health may be partly influenced • More longitudinal studies are warranted to investigate the cau- by maternal obesity; this suggests that improving glucose and sality and underlying mechanisms of GDM on offspring’s long- term health to provide a basis for developing effective interven- weight control during early pregnancy, or better still before tions during this critical period, with the aim of improving life- conception, has the potential to lessen the risk to the off- long health and wellbeing. spring. The consequences of GDM for microbiome modification in the offspring and the impact upon offspring immune dysregulation are actively developing research areas. Some studies have suggested that GDM impacts offspring neurode- Keywords velopmental and cognitive outcomes; confirmatory studies Developmental origins of health and disease · Epigenetics · will need to separate the effect of GDM exposure from the Gestational diabetes · Life course epidemiology · complex interplay of social and environmental factors. Ani- Non-communicable disease mal and human studies have demonstrated the role of epigenetic modifications in underpinning the predisposition to adverse health in offspring exposed to suboptimal hypergly- Abstract caemic in utero environment. To date, several epigenome- During normal pregnancy, increased insulin resistance acts as wide association studies in human have extended our knowl- an adaptation to enhance materno-foetal nutrient transfer edge on linking maternal diabetes-related DNA methylation and meet the nutritional needs of the developing foetus, par- marks with childhood adiposity-related outcomes. Identifi- ticularly in relation to glucose requirements. However, about cation of such epigenetic marks can help guide future re- 1 in 6 pregnancies worldwide is affected by the inability of the search to develop candidate diagnostic biomarkers and pre-

[email protected] © 2021 Nestlé Nutrition Institute, Switzerland/ Keith M. Godfrey S. Karger AG, Basel NIHR Southampton Biomedical Research Centre University of Southampton and University Hospital Southampton NHS Foundation Trust Mailpoint 95, Southampton SO16 6YD (UK)

kmg @ mrc.soton.ac.uk ventive or therapeutic strategies. Longer-term interventions consequences of early-life nutrition for later disease risk is and longitudinal studies will be needed to better understand widely termed “developmental programming” (Fig. 1 ). the causality, underlying mechanisms, or impact of GDM There is increasing epidemiological evidence linking the treatments to optimize the health of future generations. early-life environmental exposures (i.e., maternal malnutri- © 2021 Nestlé Nutrition Institute, Switzerland/ tion/overnutrition, environmental chemicals, and stress) with S. Karger AG, Basel later-life health outcomes – conceptualized as the “developmental origins of health and disease” (DOHaD). Compelling studies from animal models have provided strong evidence in Introduction support of the DOHaD concept. These have, for example, shown that in utero exposure to maternal diabetes and/or Gestational diabetes mellitus (GDM) is a glucose tolerance obesity disrupts the development and function of the hypo- disorder with onset during pregnancy [1] . GDM has been es- thalamus, predisposing offspring to obesity [6, 7] . Several de- timated to affect 14.4% of pregnancies globally, ranging from cades ago, Pedersen [8] proposed that foetal adipogenesis 7.5% in the Middle East and North Africa region to 27.0% in the can result from foetal hyperinsulinemia induced by maternal South-East Asia region [2] . Although dysglycaemia usually im- hyperglycaemia, with more recent evidence suggesting that proves after delivery, untreated GDM increases the risk of the mechanisms involved in lasting effects on obesity risk in- short-term complications including foetal overgrowth, shoul- clude epigenetic changes [9] . In this review, we highlight der dystocia, caesarean delivery, and hypertensive disorders some of the latest findings on the long-term health conse- [3] . In the long term, exposure to GDM will likely predispose quences in offspring born to mothers with GDM, specifically both the mother and her child to non-communicable dis- relating to body composition and cardiometabolic health, al- eases (NCDs) later in life. lergic diseases, immune dysregulation/infections, and neu- NCDs are often seen as diseases of adult lifestyle and are robehavioral outcomes and elaborate the epigenetic changes an important public health issue. Their aetiology is likely mul- as one of the major mechanisms linking GDM with long-term tifactorial, involving interactions between environmental and “programmed” adverse effects on the offspring. genetic factors and multiple risk pathways. Substantial evidence now suggests that NCDs partly originate through environmental exposures before and during pregnancy [4] , Offspring Body Composition and which have lasting effects on the developing foetus and serve Cardiometabolic Health as potential targets in reversing the epidemic of NCDs. It has become apparent that children born to mothers with GDM While GDM has been linked with a higher offspring body mass have an increased lifetime risk for metabolic diseases com- index (BMI), several studies have suggested that this associa- pared with unexposed children [5] . This concept of lasting tion is confounded by higher BMI in the mother. Table 1 summarizes selected studies that have examined the association

Insulin resistance + Genetic predisposition Maternal obesity impaired insulin secretion

Periconceptional Gestational diabetes influences

Early-life epigenetic mechanisms

DNA methylation, histone modifications + non-coding RNAs

Increased risk of metabolic diseases, allergy + neurodevelopmental Altered gene expressions deficits + physiological functions Fig. 1. Gestational diabetes mellitus and developmental programming.

GDM and Developmental Programming Reprint with permission from: 5 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 Table 1. Selected studies linking GDM with offspring body composition and cardiometabolic health

Study Design Cohort Sample size GDM criteria Offspring age, Major outcomes for GDM-exposed years offspring

Body composition Chen Cohort Medical Birth Registry of 33,157 International Association of Range: 1–6 GDM and large-for-gestational age not et al. [11], Xiamen, China; a Diabetes and Pregnancy associated with overweight (OR: 1.27, China population-based Study Groups (IADPSG) 95% CI: 0.96–1.68), adjusted for retrospective cohort maternal pre-pregnancy BMI

Kawasaki Meta- Included 2 cohort studies 5,941 Carpenter-Coustan, Range: 3–15.5 Not associated with BMI z-scores et al. [12], analysis adjusting for maternal BMI; questionnaire (pooled MD: −0.11, 95% CI: −0.33 to Japan UK, USA 0.12), adjusted for covariates including maternal pre-pregnancy BMI

Lowe Cohort Hyperglycaemia and 4,832 International Association of Mean (SD): Not associated with overweight/obesity et al. [10], Adverse Pregnancy Diabetes and Pregnancy 11.4 (1.2) (OR: 1.21, 95% CI: 1.00–1.46), adjusted USA Outcome (HAPO) study Study Groups (IADPSG) for maternal BMI at OGTT during pregnancy

Glucose metabolism Blotsky Matched A combination of health 36,590 mother- Two abnormal values on a From birth Associated with incident diabetes (HR: et al. [20], cohort administrative data with child pairs with 75-g OGTT or a 50-g to 22 1.77, 95% CI: 1.41–2.22), not adjusted Canada birth registry information GDM and glucose screen ≥10.3 for maternal BMI from Quebec, Canada matched 1:1 mmol/L with controls

Kawasaki Meta- Included 4 cohort studies 890 Self-report, questionnaire, Range: 7–20 Associated with 2-h plasma glucose et al. [12], analysis adjusting for maternal BMI; WHO criteria 1999, OGTT (pooled MD: 0.43 mmol/L, 95% CI: Japan Denmark, Hong Kong SAR, 0.18–0.69), adjusted for maternal USA pre-pregnancy BMI

Lowe Cohort HAPO Follow-up Study 4,160 International Association of Mean (SD): Associated with IGT (OR: 1.96, 1.41– et al. [21], (FUS) Diabetes and Pregnancy 11.4 (1.2) 2.73), insulin sensitivity (adjusted MD: USA Study Groups (IADPSG) Range: 10–14 −76.3, −130.3 to −22.4) and oral disposition index (adjusted MD: −0.12, −0.17 to −0.064), adjusted for family history of diabetes, maternal BMI, and child BMI z-score Not associated with IFG (OR: 1.09, 95% CI: 0.78–1.52)

Pathirana Meta- Included 11 cohort studies; 6,423 NDDG, self-reported/ Range: 7–27 Associated with fasting glucose et al. [19], analysis China, Denmark, Greece, confirmed with hospital (standardized MD: 0.43, 95% CI: 0.08– Australia USA records, Carpenter- 0.77), not adjusted for maternal BMI Coustan, WHO criteria 1999, IADPSG, based on GDM risk factors followed by OGTT

Cardiovascular outcomes Øyen Cohort Data linkage of Denmark’s 2,025,727 Medical record From birth GDM in third trimester associated with et al. [23], nationwide registers to 34 any type of congenital heart defects Denmark (adjusted relative risk: 1.36, 95% CI: 1.07–1.69) No association for GDM in second trimester

Yu Cohort Danish national health 26,272 Medical record From birth Associated with overall CVD (HR: 1.19, et al. [22], registries to 40 95% CI: 1.07–1.32), hypertensive Denmark disease (HR 1.77, 1.27–2.48), adjusted for sociodemographic status and maternal/paternal history of CVD

CI, confidence interval; CVD, cardiovascular disease; GDM, gestational diabetes mellitus; HR, hazard ratio; MD, mean difference; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NDDG, National Diabetes Data Group; OGTT, oral glucose tolerance test; OR, odds ratio; SD, standard deviation; WHO, World Health Organization.

6 Reprint with permission from: Chu/Godfrey Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 of GDM with offspring body composition and cardiometa- pre-pubertal to early adulthood (pooled mean difference: bolic health. In the Hyperglycaemia and Adverse Pregnancy 0.43 mmol/L, 95% CI: 0.18–0.69, 890 children) [12] . This find- Outcomes (HAPO) follow-up study of children aged 10–14 ing was independent of maternal pre-pregnancy BMI. Simi- years, no association was found between GDM and over- larly, GDM was associated with higher risk of impaired glu- weight/obesity defined by BMI after adjusting for maternal cose tolerance (based on 30-min, 1-h, and 2-h plasma glu- BMI during pregnancy [10] . Similarly, a recent population- cose) but not impaired fasting glucose in 4,160 children from based retrospective study of 33,157 children aged 1–6 years the HAPO follow-up study [21] . showed that the significant associations of GDM coupled with The observed discrepancies in the relation of GDM with large-for-gestational age on childhood overweight were no impaired glucose tolerance and impaired fasting glucose may longer apparent after adjusting for pre-pregnancy BMI [11] . result from distinct pathophysiology induced by in utero ex- These findings are consistent with those of a meta-analysis posure to GDM, in which skeletal muscle function (implicated [12] , suggesting that GDM was not associated with BMI z - in the insulin resistance of impaired glucose tolerance), not scores when accounting for maternal pre-pregnancy BMI, but the liver, may be more vulnerable to GDM. Also, the HAPO few studies have accounted for maternal treatment for GDM follow-up study found that GDM was associated with lower as a moderating influence [13] . Higher maternal BMI could be child insulin sensitivity (Matsuda index) and β-cell compensa- associated with higher childhood adiposity through genetic tion for insulin resistance (disposition index) [10] . These asso- transmission, shared postnatal lifestyle/environment, and in- ciations were independent of maternal BMI during pregnancy trauterine environment [14] . Alternatively, since BMI does not and child’s BMI z -score, reinforcing the hypothesis that intra- distinguish the contributions of fat and lean mass, using direct uterine exposure to hyperglycaemia plays a part in glucose measures of child adiposity (based on skinfold or simple im- intolerance among offspring. Foetal β-cell insulin dysfunc- aging measurements) could be feasible options in epidemio- tion, arising from intrauterine hyperglycaemia and manifest- logical studies [10, 15, 16] . Positive associations between GDM ing as a decline in β-cell compensation, is likely to contribute and skinfold thickness have been observed in children at birth to a progressively increasing metabolic load and an increased and later childhood (aged 5–10 years), with limited evidence risk of impaired glucose tolerance in children of mothers with in children aged 2–5 years [17] . GDM. This does not preclude the possibility that the above Evidence for an effect of GDM on offspring abnormal glu- associations could be partly due to some overlap in genetic cose tolerance is mixed as data from several meta-analyses susceptibility to GDM and type 2 diabetes, given that insulin have provided somewhat inconsistent findings. Positive as- resistance and/or insulin secretory defects are key players in sociations between GDM and the pathogenesis of these con- postnatal abnormal glucose ditions. metabolism (fasting plasma glu- The effect of GDM on To date there are relatively cose, post-prandial, and diabe- few studies on the association tes mellitus) in the offspring offspring obesity and between GDM and cardiovascu- were reported in a systematic cardiometabolic health may lar morbidity. Nonetheless, a re- review of prospective cohort cent 40-year follow-up study of studies [18] . In a meta-analysis be in part inﬂuenced by the Danish population-based including 11 studies, marginally maternal obesity cohort found an increased rate higher fasting plasma glucose of early-onset cardiovascular levels were found in offspring disease (HR: 1.19, 95% CI: 1.07– exposed to GDM compared with those who were not (stan- 1.32) and hypertensive disease (HR 1.77, 95% CI: 1.27–2.48) in dard mean difference: 0.43, 95% confidence interval [CI]: offspring of mothers with GDM [22] . These associations were 0.08–0.77, 6,423 children) [19] . Likewise, in a retrospective independent of sociodemographic status and maternal/pa- matched cohort study of Canadian mother-offspring pairs, ternal history of cardiovascular disease. A 34-year follow-up incident diabetes in offspring from birth to 22 years was high- of the Danish cohort with over 2 million births reported a er in those born to mothers with GDM (hazard ratio [HR]: 1.77, modest increase in risk of specific congenital heart defects in 95% CI: 1.41–2.22) [20] . However, the aforementioned stud- offspring born to mothers with GDM compared with mothers ies did not account for a potential confounding effect of ma- with pre-gestational diabetes [23] . Interestingly, a systematic ternal BMI. In contrast, an earlier meta-analysis showed no review suggested that the association between GDM and association of GDM with childhood diabetes or fasting plas- congenital heart defects was evident only in women who had ma glucose but a higher level of 2-h plasma glucose from both GDM and pre-pregnancy obesity [24] . The effect of GDM

GDM and Developmental Programming Reprint with permission from: 7 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 Table 2. Selected studies linking GDM with offspring allergy

Study Design Cohort Sample GDM criteria Offspring Major outcomes for GDM-exposed offspring size age, years

Kumar Cohort Boston birth cohort 680 Medical Mean (SD): In term births, GDM associated with atopic et al. [26], record 3.2 (2.3) dermatitis (OR: 7.2, 95% CI: 1.5–34.5), allergen USA sensitization (5.7, 1.2–28.0), food sensitization (8.3, 1.6–43.3)

Martinez Cohort Kaiser Permanente Southern California 97,554 Carpenter- Median age: GDM requiring antidiabetic medications associated et al. [25], hospitals (retrospective birth cohort) Coustan 7.6 with childhood asthma (HR: 1.12, 95% CI: 1.01–1.25), USA adjusted for maternal asthma

Zugna Meta- Eleven European birth cohorts 85,509 Exposure: From birth to Maternal diabetes (regardless of type) associated et al. [27], analysis participating in the CHICOS (developing maternal 1–2 with ever wheezing (pooled RR: 1.02, 95% CI: 0.98– Italy a child cohort research strategy for diabetes 1.06) and recurrent wheezing (1.24, 0.86–1.79) Europe) project

CI, confidence interval; GDM, gestational diabetes mellitus; HR, hazard ratio; SMD, standardized mean difference; RR, risk ratio.

on offspring obesity and cardiometabolic health may be in Although the immune system is a complex network af- part influenced by maternal obesity; this has led to the notion fected by various environmental and genetic factors, the po- that improving glycaemia and weight control during early tential role of the human microbiota in influencing the host gestation, or better still before conceiving, has the potential immune system has drawn considerable attention. It has been to lessen the risk. proposed that GDM triggers gut microbiota dysbiosis (i.e., altered gut microbial ecosystem) in both the mother and neonate [28] , which could lead to alteration of T-cell subpopula- Offspring Allergic Diseases tions, in turn implicated in maintaining immune tolerance. In- deed, mothers with GDM exhibited higher levels of Children born to mothers with GDM may be at risk of immune peripheral Th2, Th17, and regulatory T cells, with these re- dysregulation. Table 2 summarizes selected studies that have maining unchanged from the third trimester of pregnancy up examined the association of GDM and offspring allergy. A re- to 6 months post-partum [29] . Hence, it is plausible that al- cent US study of 97,554 children (median age: 7.6 years) re- tered levels of T cells in the mother have an epigenetic impact ported evidence that the rate of childhood asthma might be on the immunological function of the offspring. influenced by more severe GDM requiring medication use [25] . Compared with no diabetes during pregnancy, an increased risk of childhood asthma was reported only in GDM Offspring Neurocognitive Development and cases requiring antidiabetic medications (HR: 1.12, 95% CI: Behavioural Outcomes 1.01–1.25) but not in those without requiring medications. These findings were independent of maternal asthma. The While more is known about the association between maternal Boston Birth cohort found that GDM, independently of ma- diabetes (regardless of the type) and offspring neurodevelop- ternal pregnancy BMI and foetal growth, was associated with mental outcomes, evidence on the adverse effect of GDM is atopic dermatitis and allergen sensitization (driven primarily currently inconclusive. A systematic review reported that by food sensitization) in term births but not preterm, with while overall intellectual function may be within the normal speculation that term births had longer exposure to the hy- range in children born to mothers with GDM, they may have perglycaemic insult at a specific point of immunological de- an increased risk for problems related to fine and gross motor velopment [26] . A meta-analysis did not find an association of coordination, attention span, and activity level compared to maternal diabetes (defined as either chronic diabetes before children born to mothers without GDM [30] . A number of im- pregnancy or overt diabetes or glucose intolerance in preg- portant confounding factors, such as socioeconomic status, nancy) with ever and recurrent wheezing in early childhood parental educational level, and family upbringing, contribute from birth up to 1–2 years of age [27] . to children’s cognitive performance [31] . Table 3 summarizes selected cohort studies and meta-analyses that have exam-

8 Reprint with permission from: Chu/Godfrey Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 Table 3. Selected studies linking GDM with neurodevelopmental outcomes

Study Design Cohort Sample GDM criteria Offspring age, years Major outcomes for GDM-exposed size offspring

Kong Cohort Data linkage of Finland’s 649,043 Medical record From birth to 11 GDM + maternal obesity associated with et al. [36], nationwide registers autism spectrum disorders (HR: 1.56, Sweden 95% CI: 1.26–1.93) Non-significant increase in GDM + normal weight for autism, adjusted for maternal psychiatric disorder, maternal age at delivery, maternal smoking, and maternal systemic inflammatory disease

Nahum Cohort A university medical 231,271 Medical record Not specified (study population Associated with autistic spectrum Sacks centre which serves the included all patients who disorder (OR: 4.44; 95% CI: 1.55–12.69), et al. [38], entire population of the delivered between the years adjusted for maternal age, obesity, Israel southern region of 1991 through 2014 and their gestational week Israel offspring)

Robles Meta- Included 7 cohort 6,140 Exposure: maternal 1–2 years for mental and Maternal diabetes associated with mental et al. [32], analysis studies; USA, Israel diabetes (regardless psychomotor development; development (SMD: −0.41, 95% CI: −0.59 Spain of type) 3–12 years for IQ to −0.24), psychomotor development (−0.31, −0.55 to −0.07), and IQ (−0.78, −1.42 to −0.13)

Wan Meta- Included 16 case- Not Exposure: maternal Not specified Associated with autism spectrum et al. [35], analysis control/cohort studies; specified diabetes disorders (relative risk: 1.48; 95% CI: China USA, Canada, Sweden, 1.26–1.75), adjusted for obesity, maternal Israel, Australia, Egypt age, gestational age

Xiang Cohort Kaiser Permanente 29,534 Carpenter-Coustan Median age: 4.9 GDM requiring antidiabetic medications et al. [34], Southern California associated with ADHD (HR: 1.26, 95% CI: USA hospitals (retrospective 1.14–1.41) birth cohort) No association for GDM not requiring medications

Zhao Meta- Included 4 cohort 985,984 Medical record, Range: 4–19 Associated with ADHD (RR: 2.00, 95% CI: et al. [33], analysis studies; Denmark, self-report, ADA 1.42–2.81) China Greece, USA, China criteria

ADHD, attention deficit hyperactivity disorder; CI, confidence interval; GDM, gestational diabetes mellitus; IQ, intelligence quotient; HR, hazard ratio; OR, odds ratio; RR, risk ratio; SMD, standardized mean difference.

ined the association of GDM and offspring neurodevelop- that severe GDM requiring antidiabetic medications was as- mental outcomes. In a meta-analysis adjusting for parental sociated with increased ADHD risk (HR: 1.26, 95% CI: 1.14– educational attainment, a deleterious effect of maternal dia- 1.41) in children (median age: 4.9 years) compared to the non- betes (encompassing GDM and type 1 and type 2 diabetes) on exposed group [34] . Neither GDM requiring no medications lower IQ score was observed in children aged 3–12 years, but nor gestational age at GDM diagnosis was associated with the authors cautioned against drawing conclusions due to offspring ADHD risk. These associations were independent of significant heterogeneity in included studies [32] . It is plausible sociodemographic factors, smoking and alcohol use, mater- that women with pre-existing diabetes may have received nal history of ADHD, and maternal pre-pregnancy BMI. monitoring and counselling prior to pregnancy and therefore There are a number of observational epidemiologic studies have better controlled glucose levels. Offspring born to moth- published on offspring autism spectrum disorder outcome. A ers with GDM may have a higher exposure to a greater level meta-analysis detected a positive association between GDM of circulating glucose during the early stages of pregnancy and child autism spectrum disorders even after adjustment for than those with pre-existing diagnosed diabetes. important covariates such as obesity, maternal age, and ges- An increased risk for attention deficit hyperactivity disorder tational age [35] . However, a Finnish cohort of 649,043 births (ADHD) in children born to mothers with GDM (risk ratio: 2.00, followed up to 11 years reported no increased risk of child’s 95% CI: 1.42–2.81, 985,984 children) has been shown in a autism spectrum disorders in women with GDM and normal meta-analysis [33] . Notably, a large-sample US study suggests weight, after adjusting for important covariates including ma-

GDM and Developmental Programming Reprint with permission from: 9 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 ternal psychiatric disorder, maternal age at delivery, maternal to date mainly involved nutritional, toxin exposure, selective smoking, and maternal systemic inflammatory disease [36] . Of breeding, and direct genetic manipulations. note, more-pronounced risk effects for child autism spec- A study of streptozotocin-induced maternal diabetes in trum disorders were reported in obese mothers with GDM mice showed an inhibitory effect of intrauterine hyperglycae- and/or maternal pre-gestational diabetes [36, 37] . Joint ef- mia exposure on the development of brown adipose tissue fects of maternal obesity and pre-gestational diabetes were (BAT) in offspring, thereby impairing the glucose uptake func- also observed on conduct disorders with onset in childhood tion of BAT in adulthood [40] . The authors found a downreg- as well as mixed disorders of conduct and emotions, disorders ulation of BAT-associated genes, Ucp1 , Cox5b , and Elovl3 , of social functioning, and tic disorders with onset in childhood which is accompanied by disorganized ultra-structure of mi- and adolescence [36] . Possible explanations for the joint ef- tochondria in BAT, probably contributing to intracellular lipid fects between obesity and maternal pre-gestational diabetes accumulation and fat-induced insulin resistance [40] . Anoth- are the stronger neural impact of long-term exposure to con- er GDM mouse model showed altered DNA methylation pat- comitant contribution of lipotoxicity, inflammation, metabol- terns in pancreatic tissues, manifested as dyslipidaemia, im- ic stress, and hyperglycaemia. Limited data exist regarding paired glucose tolerance, and insulin resistance with advanc- other offspring neuropsychiatric disorders, with some showing age [41] . The authors rationalized that the pancreas has a ing either higher rates [38] or null associations [36] with eating direct role in regulating blood glucose levels and should disorders and positive associations of sleep disorders [36, 38] hence serve as an important target tissue to demonstrate the in children exposed to GDM. role of DNA methylation as opposed to the more widely studied samples such as the placenta, umbilical cord blood, or maternal peripheral blood. Developmental Programming by Epigenetic However, animal models using chemical approaches such Mechanisms as streptozotocin to induce permanent pancreatic damage with impaired insulin secreting function and irreversible dia- In the context of foetal programming, epigenetic processes betes may be of limited relevance to GDM, which is transient are thought to be an important mechanism underpinning in nature and usually returns to euglycaemia after childbirth. lasting effects on the offspring [9] . Epigenetic modifications A recent mice experiment studied the induction of transient are cell type and tissue specific, which involve changes in glucose tolerance in pregnant mice with an insulin receptor gene expression and genomic structure without altering the antagonist (S961 ), reporting that mice born from S961 -treated DNA sequence. Epigenetic processes include DNA methyla- dams showed no susceptibility to physical or reflexes devel- tion, histone post-translational modifications, and expression opment in the early neonatal period but had long-term met- of non-coding RNAs. GDM, as an example of maternal envi- abolic (glucose intolerance) and cognitive impairment conse- ronmental trigger, can play a role in influencing offspring out- quences in adulthood when administered a high-fat diet [42] . comes through epigenetic regulation of genes. DNA meth- The administration of high-fat diets in mice mimics typical ylation is the classic and most studied epigenetic measure, energy-rich diets in both developing and industrialized coun- primarily found in the CpG (cytosine followed by a guanine) tries, implicating epigenetic alterations as an important mech- sequence contexts. The identification of DNA methylation anism underpinning the induction of altered phenotypes in patterns related to adverse health-related outcomes in off- response to environmental cues. spring is a potentially useful tool to assess individuals at risk for health problems in early life exposed to GDM, representing an important window of opportunity for early interventions Human Studies during childhood. The mechanistic pathways underlying long-term morbidity in offspring exposed to GDM are incompletely understood so Animal Studies far, but a growing number of studies have supported involve- ment of epigenetic mechanisms in the association of GDM Evidence from non-human animal models suggests that in with offspring health. Most human studies on epigenetic me- utero GDM exposure leads, for example, to developmental diation examined the associations of in utero GDM exposure and functional alterations of the hypothalamus [6, 39] , height- and DNA methylation in placentas, offspring cord, or infant ening the risk of developing overweight/obesity in the off- blood, as summarized in a recent review [43] . Several differ- spring. Animal models of developmental programming have entially methylated genes in foetal tissues of babies born to

10 Reprint with permission from: Chu/Godfrey Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 mothers with GDM have been identified using a candidate 7 pregnancy cohorts) showed that GDM was associated with gene approach; these include loci related to the leptin (LEP), offspring cord blood hypomethylation of the OR2L13 pro- adiponectin (ADIPOQ) , mesoderm-specific transcript (Mest) , moter, a gene associated with autism spectrum disorder [49] . ATP-binding cassette transporter A1 (ABCA1 ), SLC2A1/GLUT1 , Notably, the study accounted for numerous potential con- and SLC2A3/GLUT3 genes. Epigenetic modifications at these founding influences, including cord blood cell heterogeneity, loci in response to impaired glucose homeostasis during which is one of the potential sources of variability in DNA pregnancy might lead to lifelong susceptibility to adiposity methylation. development in offspring. In a human placenta study [50] , maternal dysglycaemia in Two epigenome-wide association studies (EWAS) using Il- pregnancy was associated with altered DNA methylation of lumina 450k methylation arrays have reported associations of the serotonin transporter gene (SLC6A4 ), a principal regulator maternal diabetes‐related DNA methylation marks with child- of serotonin homeostasis. Serotonin, a neurotransmitter, is hood adiposity-related outcomes [44, 45] . One of these stud- involved in neurodevelopmental disorders (e.g., depression, ies included data from 2 prospective cohorts – the EPOCH anxiety, and autism). SLC6A4 methylation levels were nega- (Exploring Perinatal Outcomes in Children) and the Colorado tively associated with maternal glucose levels (both fasting Healthy Start – which identified 6 GDM exposure‐associated and 2-h plasma glucose) in the 24–28 weeks of gestation, DNA methylation marks that were linked to measures of child- after adjustment for maternal pre-pregnancy BMI and gesta- hood adiposity and fat distribution [44] . Peripheral/cord blood tional weight gain. Further, placental SLC6A4 methylation was samples of GDM-exposed and non-GDM-exposed offspring inversely associated with SLC6A4 mRNA levels, suggesting a ( n = 285, aged 10.5 years) were profiled, revealing that DNA functional role of the CpG sites in regulating SLC6A4 gene methylation of the SH3PXD2A gene was associated with BMI, expression and that epigenetic changes predominate over waist circumference, skinfold thicknesses, subcutaneous adi- genetic mechanism in the human placenta. A separate study pose tissue, and leptin levels, after adjustment for cell propor- has shown differential SLC6A4 methylation as a predictive tions [44] . In the second study of 388 Pima Indian children of epigenetic marker of adiposity from birth to adulthood [51] . Arizona (aged 13.0 years) [45] , the observed DNA methylation Such studies provide valuable information on epigenetic marks altered by intrauterine exposure to maternal diabetes marks that can guide future research in developing potential and linked to offspring BMI and insulin secretory were differ- diagnostic biomarkers and predictive/treatment strategies for ent from those detected by the EPOCH study. The discrepan- adverse health events. cies in DNA methylation hits could be due to the different population studied, covariates adjusted for, and outcomes of interest. Transgenerational Epigenetic Inheritance A causal relation between maternal hyperglycaemia and epigenetic regulation of the leptin gene (with biological rel- Increasing research on animal models, mainly in mice and evance to long-term programming of offspring excessive ad- rats, suggests that developmental programming is a transgen- iposity) in offspring cord blood has been reported based on a erational phenomenon. The programmed phenotype is 2-step epigenetic Mendelian randomized approach [46] . The passed on through several possible mechanisms including epigenetic adaptations triggered by maternal glycaemia re- persistence of the adverse environmental exposures in sub- sulted in an association between lower DNA methylation lev- sequent generations, altered maternal phenotype, and inher- els at the CpG site cg12083122 (in the leptin gene of the off- itance of epigenetic modifications via alteration of the epi- spring) and higher cord blood leptin levels [46] . Using media- genome (germline and/or somatic line). Whilst most literature tion analysis, higher DNA methylation levels of the key genes on transgenerational transmission of traits have focused on responsible for glycaemic/lipid metabolism (PPARGC1 α ) were the maternal contributions to offspring, impacts of paternal found to be correlated with higher cord blood leptin levels in contributions have also been observed [4] . offspring exposed to maternal hyperglycaemia [47] . DNA A GDM mice model of intrauterine hyperglycaemia in- methylation (increased methylation of PYGO1 and CLN8 ) has duced by streptozotocin showed a pattern of dysregulation at also been reported to mediate effects of in utero GDM expo- key methylation sites in the placenta (reflected by downregu- sure on adverse offspring cardiometabolic traits (increased lation and upregulation of Dlk1 and Gtl2 genes, respectively) VCAM-1 levels) [48] . of the F1 and F2 generations [52] . A reduction in placental For neurodevelopmental outcome, a recent meta-analysis weight was found to be transmitted paternally to the F2 off- of EWAS data published by the Pregnancy and Childhood Epi- spring, but not maternally, which was believed to be linked to genetics Consortium (with 3,677 mother-neonate pairs from

GDM and Developmental Programming Reprint with permission from: 11 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 the susceptibility of the sperm under a suboptimal intrauterine and metabolic measures in children (aged 7–9 years) whose environment. mothers had been randomized to metformin and insulin GDM While the transgenerational transmission of traits has been treatment [59] . However, metformin-exposed children at 9 reported through to the F2 offspring, evidence on the trans- years of age were larger than the insulin-exposed group [59] . mission through to F3 and subsequent generations remains In line with this, a meta-analysis including 3 follow-up studies unclear [53] . Studying F3 and succeeding generations is im- of RCTs reported that children prenatally exposed to metfor- portant to eliminate the possible confounding effects by the min treatment for GDM were heavier than those whose moth- initial adverse maternal insults on the embryo. ers received insulin treatment [60] . Larger studies with longer Although there is substantial evidence on the transgenera- follow-up will be needed to better understand the health im- tional inheritance of epigenetic modifications in mice and pact of GDM treatments on offspring to optimize the health rats, the application of this concept in humans has been chal- of future generations. lenged by others [54] , mainly due to a complex sum of many There is also evidence for the periconceptional period as confounding factors including ecological and cultural inheri- an early window for which poor environmental exposures can tance [55] . Well-controlled experiments in mammalian animal induce adverse health effects in offspring [4] . Interventions models and large-scale cohorts/well-characterized epidemi- delivered during pregnancy may only partly alter foetal growth ological studies are required in the future. and development, and therefore studies examining interventions that begin before conception are warranted. A large multi-centre RCT is underway to investigate the effectiveness Do GDM Treatment Interventions Improve of a nutritional (containing myoinositol, probiotics, and addi- Long-Term Offspring Health? tional micronutrients) intervention commencing before conception and continuing during pregnancy to maintain good Infants born to mothers receiving treatment of GDM in the maternal glycaemic control, with the aim of improving off- form of dietary advice, blood glucose monitoring, and insu- spring health outcomes [61] . lin therapy have improved perinatal outcomes compared with those born to women receiving routine care [56] . How- ever, evidence from a Cochrane review of long-term fol- Conclusion low-up studies of GDM treatment interventions suggests that treatment may not reduce Overall, there is increasing evi- childhood obesity [13] . In 2 fol- dence for an impact of in utero low-up studies of children Female offspring of mothers GDM exposure on lifetime whose mothers participated in health in the offspring. However, pregnancy trials for the treat- treated for mild GDM had whether maternal GDM contrib- ment of mild GDM, there was lower fasting glucose levels, utes directly to childhood adi- no difference in child’s BMI posity remains to be elucidated, (aged 4–10 years) by treatment suggesting a beneﬁcial effect given that maternal BMI and and control groups [57, 58] . A of treatment of mild GDM in gestational weight gain are also possible reason for the null linked with childhood adiposity. finding is that more-pro- relation to reducing the risk of Other observed long-term off- nounced GDM might be neces- offspring insulin resistance in spring adverse consequences sary to program long-term include cardiovascular abnor- treatment effects on the devel- females malities, glucose/insulin dys- opment of offspring obesity. function, allergic/respiratory Nonetheless, female offspring health, and neurodevelopmen- of mothers treated for mild GDM had lower fasting glucose tal outcomes. Most evidence is based on observational pro- levels, suggesting a beneficial effect of treatment of mild spective cohorts, and further studies are required to advance GDM in relation to reducing the risk of offspring insulin re- our knowledge of the effect of GDM and its treatment on de- sistance in females [57] . velopment, function, and health in the offspring. Taken to- Compared with insulin treatment, findings from the Met- gether, the adverse health impacts of in utero GDM exposure formin in Gestational diabetes: The Offspring Follow-Up (MiG on offspring may rely upon epigenetic changes in selected TOFU) cohort reported no differences in the body fat percent genes. Notably, many of these epigenetic modifications may

12 Reprint with permission from: Chu/Godfrey Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 not be reversible and may persist throughout the offspring’s Conflict of Interest Statement life course. More studies in both animal and human models are needed to replicate the epigenetic findings, with careful K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an consideration of the selection of cell or tissue types for epi- academic consortium that has received research funding from Abbott genetic analysis because epigenetic mechanisms are gener- Nutrition, Nestec, BenevolentAI Bio Ltd., and Danone. K.M.G. is sup- ally tissue specific. There is also a need for larger studies with ported by the UK Medical Research Council (MC_UU_12011/4), the long-term follow-up to understand the health impact of GDM National Institute for Health Research (NIHR Senior Investigator [NF- treatments in preventing adverse programming of health out- SI-0515-10042] and NIHR Southampton Biomedical Research Centre [IS-BRC-1215-20004]), the European Union (Erasmus + Project Im- comes in offspring. pENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP), the British Heart Foundation (RG/15/17/3174), and the US National Institute On Aging of the National Institutes of Health (Award No. U24AG047867). The writing of this article was supported by Nestlé Nutrition Institute and the authors declare no other conflicts of interest.

References

1 American Diabetes Association. 2. Classification and diagnosis of 12 Kawasaki M, Arata N, Miyazaki C, Mori R, Kikuchi T, Ogawa Y, et al.

diabetes. Diabetes Care. 2016 Dec; 40(Suppl 1): S11–24. Obesity and abnormal glucose tolerance in offspring of diabetic

mothers: a systematic review and meta-analysis. PLoS One. 2018; 2 International Diabetes Federation. IDF diabetes atlas. 9th ed. Brus- 13(1): e0190676.

sels, Belgium: International Diabetes Federation; 2019. 13 Brown J, Alwan NA, West J, Brown S, Mckinlay CJ, Farrar D, et al. 3 Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey Lifestyle interventions for the treatment of women with gesta- B, et al. A multicenter, randomized trial of treatment for mild ges- tional diabetes. Cochrane Database Syst Rev. 2017; 5(5): CD011970.

tational diabetes. N Engl J Med . 2009; 361(14): 1339–48. 14 Godfrey KM, Reynolds RM, Prescott SL, Nyirenda M, Jaddoe VW, 4 Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, Prentice AM, Eriksson JG, et al. Influence of maternal obesity on the long-term Stephenson J, et al. Origins of lifetime health around the time of health of offspring. Lancet Diabetes Endocrinol. 2017; 5(1): 53–64.

conception: causes and consequences. Lancet . 2018; 391(10132): 1842–52. 15 Boeke CE, Oken E, Kleinman KP, Rifas-Shiman SL, Taveras EM, Gillman MW. Correlations among adiposity measures in school- 5 Burlina S, Dalfrà MG, Lapolla A. Short- and long-term conse- aged children. BMC Pediatr. 2013; 13: 99.

quences for offspring exposed to maternal diabetes: a review. J

Matern Fetal Neonatal Med. 2019; 32(4): 687–94. 16 Mooney A, Kelsey L, Fellingham GW, George JD, Hager RL, Myrer JW, et al. Assessing body composition of children and adolescents 6 Steculorum SM, Bouret SG. Maternal diabetes compromises the using dual-energy X-ray absorptiometry, skinfolds, and electrical organization of hypothalamic feeding circuits and impairs leptin impedance. Meas Phys Educ Exercise Sci. 2011; 15(1): 2–17.

sensitivity in offspring. Endocrinology . 2011; 152(11): 4171–9. 17 Shafaeizadeh S, Harvey L, Abrahamse-Berkeveld M, Muhardi L, van 7 Morris MJ, Chen H. Established maternal obesity in the rat repro- der Beek EM. Gestational diabetes mellitus is associated with age- grams hypothalamic appetite regulators and leptin signaling at specific alterations in markers of adiposity in offspring: a narrative

birth. Int J Obes. 2009; 33(1): 115–22. review. Int J Environ Res Public Health. 2020; 17(9): 3187. 8 Pedersen J. Glucose content of the amniotic fluid in diabetic preg- 18 Nattero-Chávez L, Luque-Ramírez M, Escobar-Morreale HF. Sys-

nancies; correlations with the maternal blood sugar. Acta Endo- temic endocrinopathies (thyroid conditions and diabetes): impact

crinol . 1954; 15(4): 342–54. on postnatal life of the offspring. Fertil Steril. 2019; 111(6): 1076–91. 9 Godfrey KM, Costello PM, Lillycrop KA. The developmental envi- 19 Pathirana MM, Lassi ZS, Roberts CT, Andraweera PH. Cardiovas- ronment, epigenetic biomarkers and long-term health. J Dev Orig cular risk factors in offspring exposed to gestational diabetes mel-

Health Dis. 2015; 6(5): 399–406. litus in utero: systematic review and meta-analysis. J Dev Orig

10 Lowe WL, Scholtens DM, Lowe LP, Kuang A, Nodzenski M, Talbot Health Dis. 2020; 6: 1–18. O, et al. Association of gestational diabetes with maternal disor- 20 Blotsky AL, Rahme E, Dahhou M, Nakhla M, Dasgupta K. Gesta-

ders of glucose metabolism and childhood adiposity. JAMA . 2018; tional diabetes associated with incident diabetes in childhood and

320(10): 1005–16. youth: a retrospective cohort study. CMAJ . 2019; 191(15): E410–7. 11 Chen YL, Han LL, Shi XL, Su WJ, Liu W, Wang LY, et al. Adverse 21 Lowe WL Jr, Scholtens DM, Kuang A, Linder B, Lawrence JM,

pregnancy outcomes on the risk of overweight offspring: a pop- Lebenthal Y, et al. Hyperglycemia and Adverse Pregnancy Out- ulation-based retrospective study in Xiamen, China. Sci Rep . come Follow-Up Study (HAPO FUS): maternal gestational diabe-

2020; 10(1): 1549. tes mellitus and childhood glucose metabolism. Diabetes Care.

2019; 42(3): 372–80.

GDM and Developmental Programming Reprint with permission from: 13 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 22 Yu Y, Arah OA, Liew Z, Cnattingius S, Olsen J, Sørensen HT, et al. 37 Li M, Fallin MD, Riley A, Landa R, Walker SO, Silverstein M, et al. The Maternal diabetes during pregnancy and early onset of cardiovas- association of maternal obesity and diabetes with autism and oth-

cular disease in offspring: population based cohort study with 40 er developmental disabilities. Pediatrics . 2016; 137(2): e20152206.

years of follow-up. BMJ . 2019; 367: l6398. 38 Nahum Sacks K, Friger M, Shoham-Vardi I, Abokaf H, Spiegel E, Ser- 23 Øyen N, Diaz LJ, Leirgul E, Boyd HA, Priest J, Mathiesen ER, et al. gienko R, et al. Prenatal exposure to gestational diabetes mellitus as Prepregnancy diabetes and offspring risk of congenital heart dis- an independent risk factor for long-term neuropsychiatric morbid-

ease: a nationwide cohort study. Circulation . 2016; 133(23): 2243– ity of the offspring. Am J Obstet Gynecol. 2016; 215(3): 380–7. 53. 39 Franke K, Harder T, Aerts L, Melchior K, Fahrenkrog S, Rodekamp 24 Parnell AS, Correa A, Reece EA. Pre-pregnancy obesity as a mod- E, et al. “Programming” of orexigenic and anorexigenic hypotha-

ifier of gestational diabetes and birth defects associations: a sys- lamic neurons in offspring of treated and untreated diabetic

tematic review. Matern Child Health J. 2017; 21(5): 1105–20. mother rats. Brain Res. 2005; 1031(2): 276–83. 25 Martinez MP, Lin J, Chow T, Chung J, Wang X, Xiang AH. Maternal 40 Yu DQ, Lv PP, Yan YS, Xu GX, Sadhukhan A, Dong S, et al. Intra- gestational diabetes and type 2 diabetes during pregnancy and risk uterine exposure to hyperglycemia retards the development of

of childhood asthma in offspring. J Pediatr . 2020; 219: 173–79.e1. brown adipose tissue. FASEB J . 2019; 33(4): 5425–39. 26 Kumar R, Ouyang F, Story RE, Pongracic JA, Hong X, Wang G, et 41 Zhu Z, Chen X, Xiao Y, Wen J, Chen J, Wang K, et al. Gestational al. Gestational diabetes, atopic dermatitis, and allergen sensitiza- diabetes mellitus alters DNA methylation profiles in pancreas of

tion in early childhood. J Allergy Clin Immunol. 2009; 124(5): the offspring mice. J Diabetes Complications. 2019; 33(1): 15–22. 1031–4. 42 de Sousa RAL, de Lima EV, da Silva TP, de Souza RV, Figueiredo 27 Zugna D, Galassi C, Annesi-Maesano I, Baïz N, Barros H, Baster- CP, Passos GF, et al. Late cognitive consequences of gestational rechea M, et al. Maternal complications in pregnancy and wheez- diabetes to the offspring, in a new mouse model. Mol Neurobiol.

ing in early childhood: a pooled analysis of 14 birth cohorts. Int J 2019; 56(11): 7754–64.

Epidemiol. 2015; 44(1): 199–208. 43 Elliott HR, Sharp GC, Relton CL, Lawlor DA. Epigenetics and ges-

28 Wang J, Zheng J, Shi W, Du N, Xu X, Zhang Y, et al. Dysbiosis of tational diabetes: a review of epigenetic epidemiology studies and maternal and neonatal microbiota associated with gestational di- their use to explore epigenetic mediation and improve prediction.

abetes mellitus. Gut . 2018; 67(9): 1614–25. Diabetologia. 2019; 62(12): 2171–8. 29 Sifnaios E, Mastorakos G, Psarra K, Panagopoulos ND, Panoulis K, 44 Yang IV, Zhang W, Davidson EJ, Fingerlin TE, Kechris K, Dabelea Vitoratos N, et al. Gestational diabetes and T-cell (Th1/Th2/Th17/ D. Epigenetic marks of in utero exposure to gestational diabetes

Treg) immune profile. In Vivo . 2019 Jan–Feb; 33(1): 31–40. and childhood adiposity outcomes: the EPOCH study. Diabet

Med. 2018; 35(5): 612–20. 30 Ornoy A, Reece EA, Pavlinkova G, Kappen C, Miller RK. Effect of

maternal diabetes on the embryo, fetus, and children: congenital 45 Chen P, Piaggi P, Traurig M, Bogardus C, Knowler WC, Baier LJ, et anomalies, genetic and epigenetic changes and developmental al. Differential methylation of genes in individuals exposed to ma-

outcomes. Birth Defects Res C Embryo Today. 2015; 105(1): 53–72. ternal diabetes in utero. Diabetologia . 2017; 60(4): 645–55. 31 Kelstrup L, Bytoft B, Hjort L, Houshmand-Oeregaard A, Mathiesen 46 Allard C, Desgagné V, Patenaude J, Lacroix M, Guillemette L, Bat-

ER, Damm P, et al. Diabetes in pregnancy: long-term complica- tista MC, et al. Mendelian randomization supports causality be-

tions of offsprings. Front Diabetes. 2019; 28: 201–22. tween maternal hyperglycemia and epigenetic regulation of leptin

gene in newborns. Epigenetics . 2015; 10(4): 342–51. 32 Robles MC, Campoy C, Fernandez LG, Lopez-Pedrosa JM, Rueda R, Martin MJ. Maternal diabetes and cognitive performance in the 47 Côté S, Gagné-Ouellet V, Guay SP, Allard C, Houde AA, Perron P,

offspring: a systematic review and meta-analysis. PLoS One. 2015; et al. PPARGC1α gene DNA methylation variations in human pla-

10(11): e0142583. centa mediate the link between maternal hyperglycemia and

leptin levels in newborns. Clin Epigenetics. 2016; 8: 72–8. 33 Zhao L, Li X, Liu G, Han B, Wang J, Jiang X. The association of maternal diabetes with attention deficit and hyperactivity disorder in 48 West NA, Kechris K, Dabelea D. Exposure to maternal diabetes in

offspring: a meta-analysis. Neuropsychiatr Dis Treat. 2019; 15: utero and DNA methylation patterns in the offspring. Immunome-

675–84. tabolism. 2013; 1: 1–9. 34 Xiang AH, Wang X, Martinez MP, Getahun D, Page KA, Buchanan 49 Howe CG, Cox B, Fore R, Jungius J, Kvist T, Lent S, et al. Maternal

TA, et al. Maternal gestational diabetes mellitus, type 1 diabetes, gestational diabetes mellitus and newborn DNA methylation: find- and type 2 diabetes during pregnancy and risk of ADHD in off- ings from the pregnancy and childhood epigenetics consortium.

spring. Diabetes Care. 2018; 41(12): 2502–8. Diabetes Care. 2020; 43(1): 98–105. 35 Wan H, Zhang C, Li H, Luan S, Liu C. Association of maternal dia- 50 Blazevic S, Horvaticek M, Kesic M, Zill P, Hranilovic D, Ivanisevic M,

betes with autism spectrum disorders in offspring: a systemic re- et al. Epigenetic adaptation of the placental serotonin transporter

view and meta-analysis. Medicine . 2018; 97(2): e9438. gene (SLC6A4) to gestational diabetes mellitus. PLoS One . 2017;

12(6): e0179934. 36 Kong L, Norstedt G, Schalling M, Gissler M, Lavebratt C. The risk of offspring psychiatric disorders in the setting of maternal obesity 51 Lillycrop KA, Garratt ES, Garratt ES, Titcombe P, Melton PE, Murray

and diabetes. Pediatrics . 2018 Sep; 142(3): e20180776. RJS, et al. Differential SLC6A4 methylation: a predictive epigenetic

marker of adiposity from birth to adulthood. Int J Obes . 2019;

43(5): 974–88.

14 Reprint with permission from: Chu/Godfrey Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 52 Jiang Y, Yu YC, Ding GL, Gao Q, Chen F, Luo Q. Intrauterine hy- 58 Gillman MW, Oakey H, Baghurst PA, Volkmer RE, Robinson JS, perglycemia induces intergenerational Dlk1-Gtl2 methylation Crowther CA. Effect of treatment of gestational diabetes mellitus

changes in mouse placenta. Oncotarget . 2018; 9(32): 22398–405. on obesity in the next generation. Diabetes Care. 2010; 33(5): 964– 8. 53 Aiken CE, Ozanne SE. Transgenerational developmental program-

ming. Hum Reprod Update. 2014; 20(1): 63–75. 59 Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al.

Metformin in gestational diabetes: the offspring follow-up (MiG 54 Heard E, Martienssen RA. Transgenerational epigenetic inheri- TOFU): body composition and metabolic outcomes at 7–9 years

tance: myths and mechanisms. Cell . 2014; 157(1): 95–109. of age. BMJ Open Diabetes Res Care. 2018; 6(1): e000456. 55 Horsthemke B. A critical view on transgenerational epigenetic in- 60 van Weelden W, Wekker V, de Wit L, Limpens J, Ijäs H, van Was-

heritance in humans. Nat Commun. 2018; 9(1): 2973. senaer-Leemhuis AG, et al. Long-term effects of oral antidiabetic

56 Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robin- drugs during pregnancy on offspring: a systematic review and me-

son JS. Effect of treatment of gestational diabetes mellitus on ta-analysis of follow-up studies of RCTs. Diabetes Ther. 2018; 9(5): 1811–29. pregnancy outcomes. N Engl J Med. 2005; 352(24): 2477–86.

57 Landon MB, Rice MM, Varner MW, Casey BM, Reddy UM, Wapner 61 Godfrey KM, Cutfield W, Chan SY, Baker PN, Chong YS; NiPPeR RJ, et al. Mild gestational diabetes mellitus and long-term child Study Group. Nutritional intervention preconception and during pregnancy to maintain healthy glucose metabolism and offspring health. Diabetes Care. 2015; 38(3): 445–52.

health (“NiPPeR”): study protocol for a randomised controlled tri-

al. Trials . 2017; 18(1): 131.

GDM and Developmental Programming Reprint with permission from: 15 Ann Nutr Metab 2020;76(suppl 3):4–15 DOI: 10.1159/000509902 Focus Pregnancy provides an eminent window of opportunity for changing behaviour towards healthy eating and lifestyle

Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):16–27 Nutrition Management of Gestational Diabetes Mellitus Kavita Kapur et al.

Key Insight

Gestational diabetes mellitus (GDM) is one of the most common metabolic disturbances that occurs during pregnancy. A successful approach for addressing GDM is the Signal system Portion size Food exchange Food journal tables use of medical nutrition therapy. The goal of medical nutrition Color-coding Use of shaped Enables the user Facilitates therapy is to meet maternal and fetal nutritional needs while to categorize plates provide to substitute user maintaining optimal glycemic control. This strategy is based different foods a visual cue of foods, providing compliance portion sizes flexibility yet and helps on providing individualized advice alongside practical tools maintaining monitor the and training to optimize nutrition self-management and tractability dietary plan healthy eating. Rather than focusing on dietary restriction, it is important to shift the emphasis towards the consumption Nutrition counseling may be used alongside some easily implemented of quality foods, such as fruits, vegetables, and complex tools to promote nutritional self-awareness and enhance compliance. carbohydrates high in ﬁber.

Practical implications

Besides conventional carbohydrate restriction, studies dem- Current knowledge onstrate that the type and quality of carbohydrate is an important consideration. In general, diets with a low to moderate The combination of high pre-pregnancy body mass index glycemic index have been shown to have a positive effect on (BMI) and excessive weight gain during pregnancy increases maternal outcomes with no adverse effects on the newborn. the risk of complications including GDM, pre-eclampsia, and Intake of fiber (particularly soluble fiber) is beneficial for lower- babies born large for gestational age. In spite of the well-es- ing serum lipids and reducing glycemic fluctuations. In addi- tablished risks for mothers and babies, there is a lack of clear tion, limiting total and saturated fats, while ensuring adequate guidance on the best way to address GDM. The most widely levels of protein, are important for maintaining optimal fetal used guideline for gestational weight gain is from the Institute growth. There is evidence that regimens such as the Mediter- of Medicine (IOM); however, the IOM does not provide spe- ranean and DASH diets may be beneficial within this context. cific recommendations for women with GDM. The conven- For women at risk of developing GDM, nutritional strategies, tional strategy for addressing GDM is based on a rigid limita- such as probiotics and myo-inositol, might help reduce the tion of all types of carbohydrates. Although this may help to risk of GDM when associated with a healthy lifestyle. control glucose levels, this approach fosters maternal anxiety and is an important barrier to adherence. Considering the impact of GDM on future health of the mother and the offspring, preventive strategies could have several benefits.Practical im- Recommended reading plications Reader DM. Medical nutrition therapy and lifestyle interventions. Diabetes Care. 2007;30(Suppl 2):S188–93.

Reprint with permission from: Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900

Nutrition Management of Gestational Diabetes Mellitus

a b c Kavita Kapur Anil Kapur Moshe Hod

a Consultant Dietician, Bangalore , India ; b World Diabetes Foundation, FIGO Pregnancy and NCD Committee, Bagsvaerd , Denmark ; c Clalit Health Services and Mor Women’s Health Center, FIGO Pregnancy and NCD Committee, Tel Aviv, Israel

Key Messages as to what constitutes an ideal approach. The conventional approach of limiting carbohydrates at the cost of increasing • Medical nutrition therapy is the bedrock for managing GDM. energy from the fat source may not be most optimal. Instead, • Many different approaches to nutrition therapy work and are allowing higher levels of complex, low-to-medium glycae- equally effective. More than restriction, it is important to focus on quality of carbohydrates and encourage mic index carbohydrates and adequate fibre through higher consumption of vegetables, fruits, complex carbohydrates, consumption of vegetables and fruits seems more beneficial. and high-fibre foods. No particular diet or dietary protocol is superior to another as • Monitoring gestational weight gain, self-monitoring of blood shown in several comparative studies. However, in each of glucose and foetal growth is important to modify nutrition these studies, one thing was common – the intervention arm advice to achieve optimal outcome for the mother and the newborn. included more intensive diet counselling and more frequent • Key to success is to provide individualized advice supported visits to the dieticians. For MNT to work, it is imperative that by practical tools and training for nutrition self-management diet advice and nutrition counselling is provided by a dietician, and healthy eating and regular follow-up with a dietician or which is easy to understand and use and includes healthy other health care professional trained to provide nutrition food options, cooking methods, and practical guidance that counselling. empower and motivate to make changes towards a healthy eating pattern. Various simple tools to achieve these objec- Keywords tives are available, and in the absence of qualified dieticians, Gestational diabetes · Management · Nutrition they can be used to train other health care professionals to provide nutrition counselling to women with GDM. Given the impact of GDM on the future health of the mother and off- Abstract spring, dietary and lifestyle behaviour changes during preg- Medical nutrition therapy (MNT) is the bedrock for the man- nancy in women with GDM are not only relevant for immedi- agement of gestational diabetes mellitus (GDM). Several dif- ate pregnancy outcomes, but continued adherence is also ferent types of dietary approaches are used globally, and important for future health. there is no consensus among the various professional groups © 2021 Nestlé Nutrition Institute, Switzerland/ S. Karger AG, Basel

hodroyal @ inter.net.il Introduction irrespective of pre-pregnancy BMI, is a significant risk factor for higher fat mass deposit during pregnancy and higher post- The rising prevalence of gestational diabetes mellitus (GDM) partum fat retention [7] which adds to the already high risk of globally and the recognition that medical nutrition therapy future type 2 diabetes and cardiovascular disease in these (MNT) is the bedrock for its management have led to the women. Overweight and obesity among women with GDM search for a pragmatic, feasible, and widely adaptable ap- complicate dietary management. proach to nutrition therapy to help control maternal glycaemia effectively while also promoting normal foetal growth. The conventional focus so far has been to rigidly limit all types Excessive GWG, irrespective of carbohydrates; though it may help control glucose, it also fosters maternal anxiety and is an important barrier to adher- of pre-pregnancy BMI, is a ence [1] . Carbohydrates in the form of rice, wheat, pulses, po- significant risk factor for tato, sugar, etc., account for a substantial portion of traditional diets across the world, and limiting their consumption higher fat mass deposit is challenging. In general, nutrition requirements of women with GDM are during pregnancy and higher similar to non-GDM pregnancies but require a special focus post-partum fat retention on dietary modification to ensure healthy and mindful eating to achieve and maintain maternal euglycaemia, prevent wide glycaemic excursions, and ensure appropriate gestational weight gain (GWG) and foetal growth. MNT and lifestyle Globally, the most widely used guideline for GWG is the changes are the key elements in the management of GDM. To Institute of Medicine (IOM) guideline [8] which recommends ensure success of the MNT programme, besides making ap- appropriate amount of weight gain per trimester depending propriate adjustments in diet and lifestyle, women with GDM on the pre-pregnancy BMI. The IOM guideline does not pro- also need to learn about self-monitoring of blood glucose vide any specific recommendation for women with GDM. The (SMBG) and require education, counselling, emotional sup- FIGO guideline [9] states that for normal-weight and under- port, and regular follow-up [2] . weight women, the IOM guidelines apply. Also, usual amount Despite several recent studies, the ideal diet (energy con- of weight gain and no restriction in calories are recommend- tent, carbohydrate restriction, and quality and quantity of ed to ensure normal infant birth weight. For overweight and macronutrients) for women with GDM remains unclear [3, 4] . obese women, there is no consensus regarding calorie intake While Evert et al. [5] suggest individualizing dietary advice as and weight gain during GDM pregnancy [9] . There is some per the American Diabetes Association guidelines applicable evidence to support no weight gain or weight loss in obese to all persons with diabetes (not restricted to pregnancy) women with GDM [10] . would suffice, the Academy of Nutrition and Dietetics latest Surprisingly, there are very few country-specific guidelines clinical guideline states that one type of nutrition plan would on GWG and most follow the IOM guidelines [11] . Health Can- not be appropriate for all women with GDM [6] , and various ada [12] in their pre-natal guidelines for health professionals national and sub-national strategies based on local culture has developed a GWG graph using the IOM guidelines to and eating habits may be needed. monitor and motivate women to stay within the optimal weight gain range. There is limited research on caloric requirements and op- GWG and Energy Intake timum weight gain for women with GDM, and a systemic review of the guidelines from various professional organizations The combination of high pre-pregnancy body mass index shows varied recommendations. Some recommend between (BMI) and excessive weight gain during pregnancy increases 1,500 and 2,000 kcal/day and others a 30% calorie restriction the risk of GDM, pre-eclampsia, large for gestational age ba- for overweight or obese GDM women, while yet another rec- bies, and complications for both the mother and the newborn ommends reducing calorie intake by 300 kcal/day [11] . Even at delivery. Overweight or obese pregnant women are also though the recommendations of various organizations vary, more likely to exceed weight gain recommendations. Fur- there is an emerging consensus supporting calorie restriction thermore, post-partum weight retention is influenced by the for overweight and obese women with GDM to avoid exces- amount of weight gained during pregnancy. Excessive GWG, sive GWG [13] . When possible, sequential foetal growth mea-

18 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 surements can provide a more useful benchmark to deter- diet (40% carbohydrate/45% fat/15% protein; n = 6) or a high- mine permissible energy intake (EI) in overweight and obese er complex carbohydrate/lower fat (CHOICE) (60% carbohy- women with GDM than GWG. drate/25% fat/15% protein; n = 6) diet. After 7 weeks on the According to a WHO report [14] , high-risk women who fol- diet, fasting glucose (p = 0.03) and FFAs (p = 0.06) decreased low lifestyle change interventions (both diet and exercise) re- in those on the CHOICE diet, whereas fasting glucose induce the risk of excessive GWG, thereby reducing risk of peri- creased in those on the low-carbohydrate diet (p = 0.03). The natal complications. In a study by Vestgaard et al. [15] , there CHOICE diet with higher complex carbohydrates may im- was relatively lower mean birth weight in newborns of GDM prove maternal IR and lower infant adiposity [23] . Higher in- mothers on extended-duration MNT as compared to non- take of nutrient-dense complex carbohydrates may result in GDM women or GDM women who had no MNT. Birth weight improved metabolic outcomes and reduce excess infant adi- above 4 kg was seen in 18% of MNT-treated GDM women posity [24] . versus 27 and 24% (p = 0.012) in non-diabetic and no MNT In low-carbohydrate diets, the source of fat and protein GDM women, respectively. Early diagnosis of GDM and ear- makes a difference. A pre-pregnancy low-carbohydrate diet lier MNT intervention seem beneficial. A Cochrane report with high protein and fat from animal food sources is posi- states that a combined diet and exercise programme can be tively associated with GDM risk, whereas a pre-pregnancy useful in preventing GDM in high-risk women [16] . low-carbohydrate dietary pattern with high protein and fat from vegetable food sources is not associated with the risk. Women of reproductive age who follow a low-carbohydrate Carbohydrate Restriction dietary pattern may consider consuming vegetables rather than animal sources of protein and fat to minimize their risk Carbohydrate restriction remains the most common ap- of GDM [25] . proach for MNT in GDM. The focus on carbohydrate restriction seems to vary in recommendations from different organizations. The American College of Obstetricians and Gynae- cologists (ACOG) [17] and the Endocrine Society [18] A pre-pregnancy low- recommend restricting carbohydrates in all GDM women on carbohydrate diet with high the MNT programme, while the FIGO advises monitoring the carbohydrate intake and the quality of carbohydrates con- protein and fat from animal sumed and distributing them throughout the day to attain and food sources is positively maintain euglycaemia [9] . On the amount of permissible carbohydrates, the guidance varies from 35 to 40% of total calo- associated with GDM risk ries in the lower carbohydrate range to 50–60% in the moderate carbohydrate range. However, there seems consensus on not limiting carbohydrate intake to <175 g/day (Table 1 ). According to Romon et al. [19] , carbohydrate restriction to Low-Glycaemic Index Diets <39% may result in higher birth weight. A lower carbohydrate and higher fat and protein intake may increase the risk of GDM The type and quality of carbohydrate is an important consid- in at-risk women [20] . While restricting carbohydrates helps eration in nutrition advice for people with diabetes, as not all control hyperglycaemia, substituting fat for carbohydrate, es- carbohydrates have the same glycaemic response [26] . The pecially in obese women with pre-pregnancy insulin resis- glycaemic index (GI) of foods is an important factor, as foods tance (IR), could increase lipolysis and circulating free fatty with a low GI reduce post-meal glycaemic excursions and acids (FFA) available for transplacental transfer leading to ex- flatten the glucose curve. People with diabetes on high-GI cess foetal fat accumulation, as well as worsening maternal IR diets (>70) exhibit higher post-prandial values, and in non- [1, 21] which in turn may worsen hyperglycaemia in the moth- pregnant patients with diabetes, low-GI diets lead to an ad- er [22] . ditional 0.4% reduction in haemoglobin A1C [27] . To understand the effect of low carbohydrate on maternal Besides the conventional advice of restricting carbohy- IR, adipose tissue lipolysis, and infant adiposity, a randomized drates, studies demonstrate an important role for low-GI diets pilot study was undertaken by Hernandez et al. [23] . At 31 in GDM [13] . In fact, in GDM, diets higher in unrefined/com- weeks, 12 diet-controlled overweight/obese women with plex carbohydrates have been shown to effectively blunt GDM were randomized to an isocaloric low-carbohydrate post-prandial glycaemia [28, 29] , reduce the need for insulin

GDM and Nutrition Management Reprint with permission from: 19 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 >71 g/d >71 g/d (or 1.1 g/ kg) OB patients must prefer low-fat protein intake: 60–80 g/d First trimester: 0.8 g/kg/d Second, third trimester: 1.1 g/kg/d or þ25 g/d Multifoetal gestation: þ50 g/d from 20 wk until delivery CHO consideration PRO Complex CHO, LGI, high fibre, CHO distributed over 3 meals and 2–3 snacks Fibre: 28 g/d 175 g/d, fibre 28 LGI <55 or MGI 55–69, breakfast GI <55 (15–60 g), CHO distributed in 3 meals and 2 snacks Refrain from fast absorb CHO with HGI. Fibre: 30 g/d (e.g., grains, fruit, and vegetables) CHO allocation: 3 medium meals and 2–3 snacks. Breakfast CHO 15–30 g Distributed in 3 small-to- medium-sized meals and 2–4 snacks, with 1 evening snack distributed in 3 meals and ≥2 snacks (1 at bedtime) CHO >175 g/d, moderate CHO restriction, provision of consistent CHO amounts, LGI, low- breakfast CHO (fibre [<50 g/d]) (soluble fibre oats, beans, psyllium, barley, etc.) Macronutrient distribution EI PRO: 20% EI Fat: 40% EI CHO: 36.7– 60% EI (LGI/ MGI) CHO: >65% in the DASH diet CHO: 40–50% EI PRO: 20–25% EI Fat: 30–35% EI CHO: >40% EI CHO: 35–45% EI CHO: 45–60% EI PRO: 15–20% EI Fat: 20–35% EI SFA: <7% EI 3 meals and 2–4 snacks/d restriction recommendation No evidence CHO: >175 g/d Inconclusive For obese reduce by 30% of EER Inconclusive CHO: >175 g/d, LGI OB: 30–33% of EER EI: 1,600–1,800 kcal/d OW/OB EI: 1,600–1,800 kcal/d underweight/ normal weight no restriction In OW/OB <300 kcal/d MNT intervention Energy assessment and dietary reference intakes prescription and nutrition counselling pregnancy basal metabolic rate, body weight, SES, and religious status to achieve goal BG, GWG, and foetal growth without ketosis/ hyperglycaemia portion control, and good cooking practices, taking into account personal and cultural eating preferences, pre- gravid BMI, desired body weight, physical activity, and BG levels micro nutrient adequacy. Based on diet history, GWG, 24-h recall, food records, pre-natal nutrition assessment, SMBG and ketones, sensitive to culture, lifestyle, SES, willingness, and ability to change Nutrition assessment mentioned Nutrition education mentioned Yes Cover eating habits, [11] Dietician involve- ment mentioned Yes YesYes Yes Based on maternal BMI Yes Based on nutrition CHO: 33–40% Yes YesYes Yes Yes Individual nutrition Healthy diet for Yes Healthy food choices, Yes Yes Yes Ensure macro and MNT goals and recommendations Achieve euglycaemia, prevent ketosis, adequate GWG and foetal growth Adequate calorie intake for foetal/neonatal/maternal health, euglycaemia, and GWG Achieve and maintain euglycaemia, promote adequate GWG and foetal growth Promote adequate intake without ketosis, achieve GWG, glycaemic goals, and foetal growth CHO-controlled meal plan promoting adequate nutrition, appropriate GWG, euglycaemia, and no ketones Promote optimum nutrition for maternal/ foetal health, provide adequate GWG, maintain normal BG and ketone absence Achieve therapy objectives: pregnancy- specific BG target levels without ketosis/ hyperglycaemia, GWG, and foetal growth Analysis of GDM guidelines adapted from Table 1. Organization and region, year American College of Obstetricians and Gynaecologists, USA, 2018 American Diabetes Association, USA, 2018 Academy of Nutrition and Dietetics, USA, 2018 Diabetes Canada, Canada, 2018 Endocrine Society, international, 2013 Diabetes Care Programme of Nova Scotia, Canada, 2014 Deutsche Diabetes Gessellschaft/ Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, Germany, 2014

20 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Diabetic nephropathy: low PRO to 0.6–0.8 g/kg ideal body weight +23 g/d above non-pregnant RDA in 3 servings/d Breakfast: 1 serving of protein-rich foods Reduce fat milk >175 g CHO/d, LGI, CHO distributed in 3 small-to- medium-sized meals and 2–4 snacks. Evening snack needed to prevent overnight ketosis. Fibre: <28 g/d CHO >40% EI Spread CHO foods over 3 small meals and 2–3 snacks/d. Prefer complex CHO. Aim for 2–3 CHO servings/meal and 1–2 CHO servings/snack Breakfast: 1–2 CHO servings CHO >175 g/d, LGI, exchanges distributed according to SMBG, lifestyle, and medications. Sucrose intake counted in total CHO. High fibre CHO consideration PRO Modest CHO restriction in OW/OB. Monitor CHO intake. Prefer fruit, vegetables, whole grains, legumes CHO: 35–45% EI CHO: 50% EI PRO: 20% EI Fat: 30% EI Fibre: 28 g/d Night snack: 25 g CHO, 10 PRO PRO: 10–20% Fat: 20–30% EI SFA <10% EI In OB: low-fat diet CHO: 45–60% PRO: 15–20% Fat: 25–35% EI Macronutrient distribution OW: <30% EER LGI EI: 2,050 kcal/d irrespective of body weight EI: >1,500 kcal/d Underweight: 40 kcal/kg/d Normal weight: 30 kcal/kg/d OW: 24 kcal/ kg/d OW/OB: might be needed OB: 30% EER CHO: 50–60% OB: 30–33% EER (25 kcal/ kg/d) Normal weight: 35 kcal/kg/d restriction recommendation culturally sensitive cultural eating habits, physical activity, BG levels, and gestation’s physiological effects diet habits and pre- gravid BMI based on glycaemic control and gestational age CHO-controlled meal plan for appropriate GWG 350 kcal/d above RDA during second and third trimesters MNT intervention Energy Nutrition assessment mentioned Yes Individualized and Nutrition education mentioned Yes Healthy diet Low GI Yes Yes Based on personal and Yes Yes Personalized, based on Yes Culturally appropriate, Yes YesYes Yes Healthy, balanced Healthy diet Dietician involve- ment mentioned Appropriate maternal and foetal nutrition (calorie, vitamin, and mineral intake), euglycaemia, and lack of ketonuria Food choices for maternal/foetal health, appropriate GWG, normoglycaemia, and absence of ketones Nutrition diagnosis and therapy with dietary intervention and counselling CHO-controlled meal plan promoting adequate nutrition and GWG normoglycaemia, and absence of ketosis MNT goals and recommendations (continued)

Hong Kong College of Obstetrics and Gynaecology (HKCOG), Hong Kong, 2016 Italian Association of Diabetes/Diabetes Italia/Italian Society for Diabetes, Italy, 2007 International Diabetes Federation, international, 2009 Irish Health Service Executive, Ireland, 2010 Malaysian Health Technology Assessment Section, Malaysia, 2017 National Institute for Clinical Excellence (NICE), UK, 2015 Organization and region, year International Federation of Gynaecology and Obstetrics, international, 2015 Indian Ministry of Health and Family Welfare, India, 2014 Table 1 Table

GDM and Nutrition Management Reprint with permission from: 21 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Lean protein CHO consideration PRO evenly throughout the day, between meals/ snacks Low GI erweight; SFA, saturated fatty acids. Macronutrient distribution stimated energy requirement; RDA, recommended daily allowance; restriction recommendation MNT intervention Energy Nutrition assessment mentioned Nutrition education mentioned Yes Dietician involve- ment mentioned Yes Yes YesYes Yes >1,800 kcal/dYes Low SFA 175 g/d, CHO distributed MNT goals and recommendations CHO-controlled meal plan with specific dietary recommendations determined and regularly modified by individual assessment (continued)

MNT, medical nutrition therapy; GWG, gestational weight gain; SMBG, self-monitoring of blood glucose; EI, energy intake; EER, e Table 1 Table Organization and region, year New Zealand Ministry of Health, New Zealand, 2014 Polish Diabetes and Pregnancy Study Group, Poland, 2017 CHO, carbohydrate; PRO, protein; LGI, low glycaemic index; MGI, medium OB, obese; BMI, body mass OW, ov Royal Australian College of General Practitioners (RACGP), Australia, 2016 Royal College of Obstetrics and Gynaecology (RCOG), UK, 2011 Scottish Intercollegiate Guideline Network (SIGN), Scotland, 2017

22 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 therapy [30] , lower fasting LDL cholesterol levels [28, 31] and intake per day is recommended for women. Fibre also helps

FFAs [28] , and improve insulin sensitivity [32] , HbA1 C [31] , and reduce constipation, a common problem in pregnancy. Apart systolic blood pressure [31] . from the use of low-GI and high-fibre diets, another com- The role of low-GI diets in GDM has been extensively stud- monly used method to reduce high post-prandial levels and ied. A meta-analysis of 5 randomized clinical trials with 302 wide post-meal glucose excursions and high fasting glucose, participants studied the effect of low GI versus control diets recommended by most guidelines, is distributing the total dai- and found that low-GI diets reduced the risk of macrosomia ly allocated carbohydrate portions into 3 small meals and 2–3 in women with GDM and low-GI diets with added dietary fibre snacks per day [11] . reduced usage of insulin [33] . The key effect of low-GI diet was reduction in 2-h post-prandial glucose, fasting plasma glucose, and lipid profile in women with GDM and a substan- Fat tial decrease in insulin requirement [34] . Another meta-analysis of 11 trials involving 1,985 women MNT in GDM has primarily focussed on control of maternal evaluated both maternal and newborn outcomes. Low-GI glycaemia; however, data suggest that maternal lipids, espe- diet was shown to have a positive effect on maternal out- cially triglycerides, may be stronger drivers of foetal growth comes even for those at risk of hyperglycaemia without ad- than glucose [39, 40] . verse outcomes on newborns [35] . Three recent meta-analysis and systematic reviews studied various diets and pregnancy outcomes. Viana et al. [36] and Wei et al. [33] concluded that low-GI diets were associ- Maternal lipids, especially ated with a decreased risk of infant macrosomia, whereas a triglycerides, may be Cochrane review, including 19 trials randomizing 1,398 women, found no clear difference in large for gestational age or stronger drivers of foetal other primary neonatal outcomes with the low-GI diet [37] . It is nonetheless important to note that more than 9 guidelines growth than glucose on nutrition recommendation for GDM from professional organizations recommend a low-to-moderate GI diet [11] . Increased consumption of total and saturated fat could worsen IR (Barbour LA, 2007) and increase foetal nutrient ex- Dietary Fibre posure, promoting overgrowth patterns. In a randomized study of women with GDM, CHO restriction (40% of total cal- Fibre intake, particularly soluble fibre, is beneficial in lowering ories, compared to 60% complex CHO) was accompanied by serum lipid levels and reducing glycaemic excursions. Low-GI 20% higher post-prandial FFAs [41] . foods often have higher fibre content, but that is not always It is therefore important that the fat content total and sat- the case. High-fibre foods in a mixed meal can serve the same urated fat of diets of women with GDM need to be moder- purpose as low-GI diets. ated. Most GDM guidelines of various professional organiza- To understand the difference between low-GI diets and tions (Table 1 ) do not specify the amount of recommended high-fibre diets, 139 women at high risk of GDM (mean [SD] fat intake; amongst those who do, there is a wide variation in age: 34.7 [0.4] years and pre-pregnancy BMI: 25.2 [0.5] kg/m2 ) recommendations. Most fall in the range of 20–35% of daily were randomly assigned to either a low-GI diet (GI target ∼ 50) EI with the ACOG guideline being the outlier recommending or a high-fibre, moderate-GI diet (target GI ∼ 60) during 14– up to 40% of daily EI. 20 weeks of gestation. The average daily amount of fibre intake in each diet group was not stated. Similar pregnancy outcomes (glycosylated haemoglobin, fructosamine or lipids at Protein 36 weeks, or differences in birth weight, Ponderal index birth weight centile, % fat mass, or incidence of GDM) were seen in Adequate protein intake during pregnancy is essential to both groups [38] . prevent depletion of maternal stores and prevent muscle No good quality studies on the benefits of fibre-rich diets breakdown to supply for the foetal needs. Most nutrition in women with GDM are available; it is however recommend- guidelines recommend a protein intake between 10 and ed that foods rich in fibre should be preferred. Up to 28-g fibre 20% of daily EI and between 60 and 80 g of protein intake

GDM and Nutrition Management Reprint with permission from: 23 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 daily. The Indian guidelines recommend a minimum addi- nal and neonatal outcomes [43] . Mediterranean diet interven- tional 23 g of protein intake daily during pregnancy over and tion advised early in the pregnancy or to pre-pregnant wom- above the normal recommended daily allowance for adult en has been shown to reduce GDM incidence and maternal- women. Protein intake restrictions may be required in pres- foetal adverse outcomes [44, 45] . ence of renal failure. Several specialized dietary protocols have also been tested in women with GDM. Some of these studies are briefly de- Non-Nutritive Sweeteners scribed below. Several non-nutritive sweeteners have become available and are widely used by women, but their use during pregnancy has DASH Diet not been well studied, and there is still no clear understanding on their use in pregnancy, with only a couple of international A randomized controlled trial was conducted to study the ef- guidelines approving the use of some of them during preg- fects of the DASH (Dietary Approaches to Stop Hypertension) nancy. Aspartame, saccharin, acesulfame, and sucralose are diet on pregnancy outcomes in women with GDM. Fifty-two recommended by a few guidelines in moderate amounts. Be- participants were randomly assigned to either the control diet sides the above, the Academy of Nutrition and Dietetics also or DASH diet for 4 weeks. The control diet contained 45–55% accepts usage of advantame, neotame, luo han guo extracts, carbohydrates, 15–20% protein, and 25–30% total fat while and steviol glycosides as per the FDA ADI limits. Cyclamates the DASH diet was rich in fruits, vegetables, whole grains, and are not approved [11] . low-fat dairy products and contained lower amounts of saturated fats, cholesterol, and refined grains with a total of 2,400 mg/day sodium. Participants on the DASH diet had better Interventions to Prevent GDM – Probiotics and metabolic outcomes than those in the control group. Also, Myoinositol infants born to mothers on the DASH diet had significantly lower weight, head circumference, and Ponderal index com- Preventing GDM could have several benefits such as reduc- pared with those born to mothers on the control diet. Only tion in the immediate adverse outcomes during pregnancy, a 46.2% of women in the DASH diet group needed caesarean reduced risk of long-term sequelae, and a decrease in the section as compared to 80.8% (p < 0.01) in the control group. economic burden to health care systems. Current available Similarly, only 23% participants on the DASH diet needed in- evidence about the prevention of GDM showed that the ma- sulin therapy as compared to 73% for the control group (p < jority of the interventions done during pregnancy have non- 0.0001) [42] . significant effect in preventing GDM [46, 47] . Dietary intervention can reduce the risk of developing GDM and the proportion of infants born with macrosomia among pregnant Mediterranean Diet women with obesity; physical activity interventions have not had the same effect. However, conclusive evidence is not yet The Mediterranean diet was studied as part of the St Carlos available to guide practice [48, 49] . Supplement interventions GDM Prevention Study – a prospective randomized study with probiotics and myoinositol during pregnancy showed a wherein both the intervention group and control group were decrease in the rates of GDM compared with a placebo [47, given the same basic Mediterranean diet (MedDiet) recom- 50] . Intervention showed that probiotics (Lactobacillus rham- mendations of 2 servings/day of vegetables, 3 servings/day of nosus and Bifidobacterium lactis Bb12) reduced the incidence fruit (avoiding juices), 3 servings/day of skimmed dairy prod- of GDM, from 36 to 13%; probiotic consumption may protect ucts and wholegrain cereals, 2–3 servings of legumes/week, against GDM because these microorganisms can modify in- moderate to high consumption of fish, and a low consump- testinal microbiota, altering the fermentation of dietary poly- tion of red and processed meat and avoidance of refined saccharides and improving intestinal barrier function [50] . grains, processed baked goods, pre-sliced bread, soft drinks Moreover, myoinositol supplements (4 g) were found to re- and fresh juices, fast foods, and precooked meals. All GDM duce 50–60% of the incidence of GDM in high-risk pregnant participants were advised Mediterranean diets plus a recom- women (overweight, obese, or first-degree relative of type 2 mended daily extra virgin olive oil intake ≥40 mL and a daily diabetes mellitus) [47, 51] . Myoinositol, an isomer of inositol, handful of nuts. Results showed that the intervention group is one of the intracellular mediators of the insulin signal and had reduced incidence of GDM and improved several mater- correlated with insulin sensitivity in type 2 diabetes. The po-

24 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Table 2. Signal system [56]

Principles Green Yellow Red

Refined cereals and sugars Low Moderate to high High

Saturated fat Low Low High

Total fat Low Moderate High

Glycaemic index Low Moderate to high High

Fibre High Low Negligible

Cooking method Steaming, boiling, roasting, Pan fried, sautéed, moderate Deep fried, rich in fat and sugar, grilling, less fat in cooking amount of fat in cooking rich sauce/cream dressing Processing Rich in fibre, parboiled Low fibre, refined, milled Low fibre, ready to eat, highly processed How much to eat Eat as permitted Moderate Restrict

tential beneficial effect on improving insulin sensitivity sug- associated with adverse neonatal outcomes in women with gests that myoinositol may be useful for women in preventing GDM [53] . GDM. In conclusion, in women at high risk of developing Hrolfsdottir et al. [54] recommend a simple dietary screen- GDM, the current evidence has showed that dietary advice, ing questionnaire given early in the first trimester to help iden- probiotics, and myoinositol supplementation might reduce tify women with high-risk eating habits associated with GDM the incidence of GDM. and providing individualized dietary feedback and advice. This could help improve eating habits and better manage the pregnancy. Interventions to Enhance Healthy Eating and Pregnancy provides an eminent window of opportunity for Meal Planning changing behaviour towards healthy eating and lifestyle and is considered a wonderful teachable moment for women and Systematic reviews studying 19 trials and comparing the ef- their families. Change preparedness is high, as emotion is in- fects of 10 different types of dietary advice for women with creased because of perceived risk but with the possibility of GDM found no conclusive evidence to show superiority of improved outcome with change. There is also greater motiva- one approach or diet programme over others [37] . These in- tion, sense of self-efficacy, and willingness to acquire new cluded studies comparing a low-to-moderate GI diet versus skills. This is particularly relevant for GDM pregnancy where a moderate high-GI diet; an energy-restricted diet versus no nutrition and lifestyle change provides the bedrock for man- energy restriction; a DASH diet versus a control diet; a low- aging the condition. Given the impact of GDM on the future carbohydrate diet versus a high-carbohydrate diet; a high- health of the mother and offspring, these changes are not unsaturated fat diet versus a low-unsaturated fat diet; a low- only relevant for the immediate pregnancy outcomes, but GI diet versus a high-fibre moderate-GI diet; diet recommen- continued adherence is also important for future health. De- dations and diet-related behavioural advice versus diet spite this, adherence to nutrition advice is often less than sat- recommendations only; a soy protein-enriched diet versus no isfactory. An important barrier for non-adherence is the dif- soy protein; a high-fibre diet versus a standard-fibre diet; and ficult to understand, impractical, and prescriptive advice that an ethnic-specific diet versus a standard healthy diet. is often given, rather than advice that is practical, contextual, However, other meta-analyses show that the low-GI diet, and empowers women to make healthy choices. Most of the characterized by intake of high-quality, complex carbohy- modifiable barriers to improving adherence to diet are related drates, demonstrated lower insulin use and reduced risk of to nutrition self-management training and counselling skills macrosomia. Recent evidence suggests the Mediterranean of care providers [55] . diet is safe in pregnancy [52] . In developing countries, a one- No particular diet or dietary protocol is superior to anoth- on-one simple dietary advice for higher consumption of er as mentioned earlier. However, in each of the studies eval- whole grain, dairy products, and dietary fibre was inversely uating different dietary protocols, one thing was common –

GDM and Nutrition Management Reprint with permission from: 25 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Feedback Enabling Using feedback to train and Impart skills on how to choose impart knowledge healthy portion size Meal and time Food Color coding Portion 8.00 a.m. White bread 2 nos. Understanding portion sizes Breakfast Low fat cheese 1 slice Boiled egg 1 nos. Jam 2 tsp Carbohydrate/ Coffee with low fat milk 1 cup starch 10.00 a.m. Mid Apple morning snack 1 medium Vegetables Rice boiled – 80 g Rice boiled – 160 g 12.00 Lunch Fish stew 1 serving Carbohydrates – 20 g Carbohydrates – 40 g White rice 2 servings Salad (lettuce, tomato, onion) 1 serving Protein Soft drink 1 glass 16.00 Tea Coffee with low fat milk 1 cup Cookies 2 nos. 25 g carb 13 g carb 20.00 Dinner White pasta 1 serving Beef steak 1 serving T-shaped plate model French fries 1 serving 22.00 Post meal Empanada de pino 1

Fig. 1. Tools to support sustained behaviour change.

the intervention arm included more intensive diet counselling used as an educational tool which can be easily adapted to and more frequent visits to the dieticians. Advice given by a different regional and local foods across the world [56] . The qualified dietician, more frequent visits to a dietician, advice basic principle of the signal system is shown in Table 2 . that includes elements to promote overall health not merely control of blood sugar, nutrition counselling that is easy to Portion Size understand and use and includes healthy food options, cook- The T-shaped plate model especially for the main meals is ef- ing methods, and practical guidance to deal with lifestyle is- fective as a basic teaching tool to control portion size and plan sues are the most important facilitators to improve nutrition meals more effectively (Fig. 1 ). The healthy plate models are advice adherence [55] . simple and accessible and help enhance the consumption of Several easy-to-implement tools are available to make nu- fruits and vegetables [58] . Visuals of portion sizes and use of trition counselling more effective. Some of these are dis- household containers (cups and glass) as measures of food cussed below. quantity are practical and easy teaching tools to help improve adherence to quantity of food consumed. Signal System The signal system is an easy-to-use educational tool which Food Exchange Tables highlights the basic principle of healthy food and healthy Food exchange tables is a great tool to enhance individualiza- cooking methods to help patients make informed choices. It tion of dietary advice as it empowers patients to add variety to follows a simple traffic light concept of red for “stop,” yellow the prescribed meal plan while at the same time ensuring a for “go slow,” and green for “go” and helps people make in- balanced intake of all necessary nutrients. A retrospective co- formed choices on which foods are healthy and which are hort study showed reduced adverse events in the group re- not. The signal system focuses not only on the number of ceiving MNT using the food exchange tables as compared to calories and fat in the food, glycaemic load, and fibre content the group not receiving MNT [59] . of food but also on the cooking and processing method [56] . It is similar to the traffic light diet promoted in Australia [57] Food Journal for healthy eating. Maintaining a food journal and SMBG records and analyzing Mapping foods according to red, yellow, and green colour them together help to understand the effect of different foods codes helps in educating people on healthy and not so healthy on glucose levels, to adjust the diet to change portion size of foods and how processing and different cooking methods carbohydrates in different meals, and to improve glycaemic impact foods making healthy foods unhealthy. It has been control.

26 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Individualizing Diet Advice age appropriate intake of vegetables and fruits, whole grain A simple two-step process to individualize dietary advice is as cereal, and starch, while discouraging excess intake of fat follows: and Na+ -rich foods. • Step 1: Identifying both the good eating habits and not so This combined with the signal system, plate model, food good eating habits in the current eating pattern of the pa- journal, and food exchange tables helps empower patients to tient by colour coding the diet history using the signal sys- understand and adapt healthy eating behaviour. Almost all tem/traffic light concept (see Fig. 1 ). Understanding the guidelines recommend health education sessions and using portion sizes for each food consumed. Using the colour- the services of a dietician to give MNT [11] . Availability of coded diet history to discuss and emphasize the good eat- trained dieticians maybe a concern in many developing and ing habits as well as identify unhealthy patterns. Are the low-resource countries, but this shortfall can be overcome by portion sizes appropriate? What are the sources for starch training other health care workers to give focussed guidance and their quantity (bread, rice, pulses, potato, sweetened on healthy eating using some of the principles and tools de- beverages, juice, and sugar)? Are source and amount of fat scribed above. and salt intake in the diet at large? Are there sufficient vegetables and fruit in the diet? The information gathered is used to first praise and motivate the patient on positive Conflict of Interest Statement aspects while highlighting the need to change unhealthy The writing of this article was supported by Nestlé Nutrition Institute, eating habits. and the authors declare no other conflicts of interest. • Step 2: Using shared decision-making skills, negotiating goals, and keeping the patient’s target in mind to encour-

References

1 Hernandez TL. Carbohydrate content in the GDM diet: two views: 10 Artal R, Catanzaro RB, Gavard JA, Mostello DJ, Friganza JC. A life-

view 1: nutrition therapy in gestational diabetes: the case for com- style intervention of weight-gain restriction: diet and exercise in

plex carbohydrates. Diabetes Spectr. 2016; 29(2): 82–8. obese women with gestational diabetes mellitus. Appl Physiol

Nutr Metab. 2007; 32(3): 596–601. 2 Reader DM. Medical nutrition therapy and lifestyle interventions.

Diabetes Care. 2007; 30(Suppl 2): S188–93. 11 Tsirou E, Grammatikopoulou MG, Theodoridis X, Gkiouras K, Pet- alidou A, Taousani E, et al. Guidelines for medical nutrition thera-

3 Kim C. Gestational diabetes: risks, management, and treatment py in gestational diabetes mellitus: systematic review and critical

options. Int J Womens Health. 2010; 2(2): 339–51. appraisal. J Acad Nutr Diet. 2019; 119(8): 1320–39. 4 Han S, Middleton P, Shepherd E, Van Ryswyk E, Crowther CA. Dif- 12 Prenatal Nutrition Guidelines for Health Professionals. Gestation- ferent types of dietary advice for women with gestational diabetes al weight gain. Health Canada. 2010.

mellitus. Cochrane Database Syst Rev. 2017; 2: CD009275. 13 Moreno-Castilla C, Mauricio D, Hernandez M. Role of medical nu- 5 Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer- trition therapy in the management of gestational diabetes mellitus. Davis EJ, et al. Nutrition therapy recommendations for the man- Curr Diab Rep. 2016; 16(4): 22.

agement of adults with diabetes. Diabetes Care. 2013; 36(11): 3821–42. 14 Muktabhant B, Lawrie TA, Lumbiganon P, Laopaiboon M. Diet or exercise, or both, for preventing excessive weight gain in preg- 6 Duarte-Gardea MO, Gonzales-Pacheco DM, Reader DM, Thomas nancy. Cochrane Database Syst Rev. 2015; (6): CD007145. AM, Wang SR, Gregory RP, et al. Academy of nutrition and dietetics gestational diabetes evidence-based nutrition practice guide- 15 Vestgaard M, Christensen AS, Viggers L, Lauszus FF. Birth weight

line. J Acad Nutr Diet. 2018; 118(9): 1719–42. and its relation with medical nutrition therapy in gestational dia-

betes. Arch Gynecol Obstet. 2017 Jul; 296(1): 35–41.

7 Subhan FB, Shulman L, Yuan Y, McCargar LJ, Kong L, Bell RC; APrON Study Team and ENRICH. Association of pre-pregnancy 16 Shepherd E, Gomersall JC, Tieu J, Han S, Crowther CA, Middleton BMI and gestational weight gain with fat mass distribution and ac- P. Combined diet and exercise interventions for preventing ges-

cretion during pregnancy and early postpartum: a prospective tational diabetes mellitus. Cochrane Database Syst Rev. 2017; 11:

study of Albertan women. BMJ Open. 2019; 9(7): e026908. CD010443.

8 Institute of Medicine. Implementing guidelines on weight gain and 17 ACOG Practice Bulletin No. 180. Practice bulletin No. 180 summary:

pregnancy. Bethesda, MD: Institute of Medicine and National Re- gestational diabetes mellitus. Obstet Gynecol. 2017; 130(1): 244–6.

search Council; 2013. 18 Blumer I, Hadar E, Hadden DR, Jovanovič L, Mestman JH, Murad

9 Hod M, Kapur A, Sacks DA, Hadar E, Agarwal M, Carlo Di, et al. The MH, et al. Diabetes and pregnancy: an Endocrine Society clinical

International Federation of Gynecology and Obstetrics (FIGO) initia- practice guideline. J Clin Endocrinol Metab. 2013; 98(11): 4227–49.

tive on gestational diabetes mellitus: a pragmatic guide for diagno-

sis, management, and care. Int J Gynaecol Obstet. 2015; 131: S3.

GDM and Nutrition Management Reprint with permission from: 27 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 19 Romon M, Nuttens MC, Vambergue A, Vérier-Mine O, Biausque S, 33 Wei J, Heng W, Gao J. Effects of low glycemic index diets on ges-

Lemaire C, et al. Higher carbohydrate intake is associated with tational diabetes mellitus: a meta-analysis of randomized con-

decreased incidence of newborn macrosomia in women with trolled clinical trials. Medicine . 2016; 95(22): e3792.

gestational diabetes. J Am Diet Assoc. 2001; 101(8): 897–902. 34 Filardi T, Panimolle F, Crescioli C, Lenzi A, Morano S. Gestational

20 Looman M, Schoenaker DAJM, Soedamah-Muthu SS, Geelen A, diabetes mellitus: the impact of carbohydrate quality in diet. Nu-

Feskens EJM, Mishra GD. Pre-pregnancy dietary carbohydrate trients. 2019; 11(7): 1549.

quantity and quality, and risk of developing gestational diabetes: 35 Zhang R, Han S, Chen GC, Li ZN, Silva-Zolezzi I, Parés GV, et al. the Australian longitudinal study on women’s health. Br J Nutr. Effects of low-glycemic-index diets in pregnancy on maternal and 2018; 120(4): 435–44.

newborn outcomes in pregnant women: a meta-analysis of ran-

21 Barbour LA, Hernandez TL. Maternal lipids and fetal overgrowth: domized controlled trials. Eur J Nutr. 2018; 57(1): 167–77.

making fat from fat. Clin Ther . 2018; 40(10): 1638–47. 36 Viana LV, Gross JL, Azevedo MJ. Dietary intervention in patients

22 Olmos PR, Rigotti A, Busso D, Berkowitz L, Santos JL, Borzone GR, with gestational diabetes mellitus: a systematic review and meta-

et al. Maternal hypertriglyceridemia: a link between maternal analysis of randomized clinical trials on maternal and new born

overweight-obesity and macrosomia in gestational diabetes. outcomes. Diabetes Care. 2014; 37: 3345–55.

Obesity. 2014; 22(10): 2156–63. 37 Han S, Middleton P, Shepherd E, Van Ryswyk E, Crowther CA. Dif- 23 Hernandez TL, Van Pelt RE, Anderson MA, Reece MS, Reynolds RM, ferent types of dietary advice for women with gestational diabetes

de la Houssaye BA, et al. Women with gestational diabetes mellitus mellitus. Cochrane Database Syst Rev. 2017; 2(2): CD009275. randomized to a higher-complex carbohydrate/low-fat diet man- 38 Markovic TP, Muirhead R, Overs S, Ross GP, Louie JC, Kizirian N, ifest lower adipose tissue insulin resistance, inflammation, glu- et al. Randomized controlled trial investigating the effects of a cose, and free fatty acids: a pilot study. Diabetes Care. 2016; 39(1): low-glycemic index diet on pregnancy outcomes in women at 39–42.

high risk of gestational diabetes mellitus: the GI baby 3 study. Di-

24 Hernandez TL, Mande A, Barbour LA. Nutrition therapy within and abetes Care. 2016; 39(1): 31–8.

beyond gestational diabetes. Diabetes Res Clin Pract. 2018; 145: 39 Schaefer-Graf UM, Graf K, Kulbacka I, Kjos SL, Dudenhausen J, 39–50. Vetter K, et al. Maternal lipids as strong determinants of fetal en- 25 Bao W, Bowers K, Tobias DK, Olsen SF, Chavarro J, Vaag A, et al. vironment and growth in pregnancies with gestational diabetes

Prepregnancy low-carbohydrate dietary pattern and risk of ges- mellitus. Diabetes Care. 2008; 31(9): 1858–63.

tational diabetes mellitus: a prospective cohort study. Am J Clin 40 Eslamian L, Akbari S, Marsoosi V, Jamal A. Effect of different ma- Nutr . 2014; 99(6): 1378–84. ternal metabolic characteristics on fetal growth in women with

26 Augustin LS, Kendall CW, Jenkins DJ, Willett WC, Astrup A, Barclay gestational diabetes mellitus. Iran J Reprod Med . 2013; 11(4): 325–

AW, et al. Glycemic index, glycemic load and glycemic response: 34. an international scientific consensus summit from the Interna- 41 Hernandez TL, van Pelt RE, Anderson MA, Daniels LJ, West NA, tional Carbohydrate Quality Consortium (ICQC). Nutr Metab Car- Donahoo WT, et al. A higher-complex carbohydrate diet in gesta- diovasc Dis. 2015; 25(9): 795–815. tional diabetes mellitus achieves glucose targets and lowers post-

27 Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic in- prandial lipids: a randomized crossover study. Diabetes Care.

dex diets in the management of diabetes: a meta-analysis of ran- 2014; 37(5): 1254–62.

domized controlled trials. Diabetes Care. 2003; 26(8): 2261–7.

42 Asemi Z, Samimi M, Tabassi Z, Esmaillzadeh A. The effect of DASH

28 Nolan CJ. Improved glucose tolerance in gestational diabetic diet on pregnancy outcomes in gestational diabetes: a random-

women on a low fat, high unrefined carbohydrate diet. Aust N Z J ized controlled clinical trial. Eur J Clin Nutr. 2014; 68(4): 490–5.

Obstet Gynaecol. 1984; 24(3): 174–7. 43 Assaf-Balut C, García de la Torre N, Durán A, Fuentes M, Bordiú E, 29 Cypryk K, Kamińska P, Kosiński M, Pertyńska-Marczewska M, del Valle L, et al. A Mediterranean diet with additional extra virgin Lewiński A. A comparison of the effectiveness, tolerability and olive oil and pistachios reduces the incidence of gestational dia-

safety of high and low carbohydrate diets in women with gesta- betes mellitus (GDM): a randomized controlled trial: the St. Carlos

tional diabetes. Endokrynol Pol . 2007; 58(4): 314–9. GDM prevention study. PLoS One . 2017; 12(10): e0185873. 30 Moses RG, Barker M, Winter M, Petocz P, Brand-Miller JC. Can a 44 Olmedo-Requena R, Gómez-Fernández J, Amezcua-Prieto C, low-glycemic index diet reduce the need for insulin in gestation- Mozas-Moreno J, Khan KS, Jiménez-Moleón JJ. Pre-pregnancy

al diabetes mellitus? A randomized trial. Diabetes Care. 2009; adherence to the Mediterranean diet and gestational diabetes

32(6): 996–1000. mellitus: a case-control study. Nutrients . 2019; 11(5): 1003. 31 Asemi Z, Tabassi Z, Samimi M, Fahiminejad T, Esmaillzadeh A. Fa- 45 de la Torre NG, Assaf-Balut C, Jiménez Varas I. Effectiveness of vourable effects of the dietary approaches to stop hypertension following Mediterranean diet recommendations in the real world

diet on glucose tolerance and lipid profiles in gestational diabetes: in the incidence of gestational diabetes mellitus (GDM) and ad-

a randomised clinical trial. Br J Nutr. 2013; 109(11): 2024–30. verse maternal-foetal outcomes: a prospective, universal, inter- ventional study with a single group. The St Carlos study. Nutrients . 32 Lauszus FF, Rasmussen OW, Henriksen JE, Klebe JG, Jensen L, 2019; 11(6): 1210. Lauszus KS, et al. Effect of a high monounsaturated fatty acid diet on blood pressure and glucose metabolism in women with ges- 46 Committee on Practice Bulletins – Obstetrics. ACOG practice

tational diabetes mellitus. Eur J Clin Nutr. 2001; 55(6): 436–43. bulletin no. 190: gestational diabetes mellitus. Obstet Gynecol.

2018; 131: e49–64.

28 Reprint with permission from: Kapur/Kapur/Hod Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 47 Agha-Jaffar R, Oliver N, Johnston D, Robinson S. Gestational dia- 53 Anjana RM, Vijayalakshmi P, Bhavadharini B, Gayathri R, Laksh-

betes mellitus: does an effective prevention strategy exist? Nat Rev mipriya N, Uthra S. Association of whole grains, dairy and dietary

Endocrinol. 2016; 12(9): 533–46. fibre with neonatal outcomes in women with gestational diabetes

mellitus: the WINGS project (WINGS-12). J Diabetol. 2019; 10: 48 Tieu J, Shepherd E, Middleton P, Crowther CA. Dietary advice in- 127–33. terventions in pregnancy for preventing gestational diabetes mel-

litus. Cochrane Database Syst Rev. 2017; 1: CD006674. 54 Hrolfsdottir L, Gunnarsdottir I, Birgisdottir BE, Hreidarsdottir IT, Smarason AK, Hardardottir H, et al. Can a simple dietary screening 49 Donazar-Ezcurra M, López-Del Burgo C, Bes-Rastrollo M. Prima- in early pregnancy identify dietary habits associated with gesta- ry prevention of gestational diabetes mellitus through nutritional tional diabetes? Nutrients . 2019; 11(8): 1868.

factors: a systematic review. BMC Pregnancy Childbirth. 2017;

17(1): 30. 55 Kapur K, Kapur A, Ramachandran S, Mohan V, Aravind SR, Badgan- di M, et al. Barriers to changing dietary behavior. J Assoc Physi- 50 Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal pro- cians India. 2008; 56: 27–32. biotic-supplemented dietary counselling on pregnancy outcome

and prenatal and postnatal growth: a double-blind, placebo-con- 56 Kapur K, Kapur A. The signal system: an empowering tool for

trolled study. Br J Nutr. 2010; 103(12): 1792–9. healthy food choices. IDF Diabetes Voice. 2005; 50(2). 51 Zhang H, Lv Y, Li Z, Sun L, Guo W. The efficacy of myo-inositol 57 Booth K, Youde S, Bennett T; Sydney Diabetes, Northern Sydney

supplementation to prevent gestational diabetes onset: a meta- Central Coast Health (NSW). The traffic light guide to food: type 2

analysis of randomized controlled trials. J Matern Fetal Neonatal diabetes and gestational diabetes. 7th ed. St. Leonards, NSW: Dia-

Med . 2018: 1–7. betes Education Centre, RNSH; 2010. 52 Mahajan A, Donovan LE, Vallee R, Yamamoto JM. Evidenced- 58 Raidl M, Spain K, Lanting R, Lockard M, Johnson S, Spencer M, et

based nutrition for gestational diabetes mellitus. Curr Diab Rep . al. The healthy diabetes plate. Prev Chronic Dis. 2007; 4(1): A12

2019; 19(10): 94. 59 Shi M, Liu ZL, Steinmann P, Chen J, Chen C, Ma XT, et al. Medical nutrition therapy for pregnant women with gestational diabetes

mellitus: a retrospective cohort study. Taiwan J Obstet Gynecol

2016; 55(5): 666–71.

GDM and Nutrition Management Reprint with permission from: 29 Ann Nutr Metab 2020;76(suppl 3):17–29 DOI: 10.1159/000509900 Focus Nutrients contribute to a variety of mechanisms that are potentially important to preterm delivery, such as infection, inﬂammation, oxidative stress, and muscle contractility

Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):29–36 Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth Karen Patricia Best et al.

Key insights /RZ£VWDWXV£- ULVN£RI£HDUO\£SUHWHUP£ELUWK£LV£LQFUHDVHG£ '+$£RU£DOJDO£RLO£VXSSOHPHQWVWR££ZHHNV£PD\£UHGXFH Preterm birth (PTB) is one of the most challenging problems LOW WKH£ULVN£RI£HDUO\£SUHWHUP£ELUWK in obstetric and neonatal care. Because of its complex etiology, the causes of PTB are unclear and there are currently 0RGHUDWH£RPHJD-£VWDWXV£QR£DFWLRQ£UHTXLUHG no reliable strategies for prevention or treatment. Maternal nutrition before and during pregnancy plays a critical role in providing the necessary nutrients for fetal growth and may be +LJK£VWDWXV£- DGGLWLRQDO£RPHJD-£VXSSOHPHQWDWLRQ£PD\ an important modiﬁable risk factor for the prevention of PTB. HIGH LQFUHDVH£WKH£ULVN£RI£HDUO\£SUHWHUP£ELUWK Current evidence indicates that the use of omega-3 polyunsaturated fatty acids (PUFA) may be a promising approach for PTB prevention. Different nutritional solutions have the potential for preventing preterm birth, but the strongest evidence supports the use of omega-3 Current knowledge polyunsaturated fatty acids (PUFA).

A normal human pregnancy lasts around 40 weeks, with most babies delivered at 37–42 weeks’ gestation. The World Health nance of normal gestational length, cervical ripening, and the Organization (WHO) defines PTB as all births occurring before 37 initiation of labor. The standard Western diet is generally low weeks’ gestation. Worldwide, PTB is the second leading cause of in omega-3 but high in omega-6 fatty acids. Based on the death in children under 5 years of age. An estimated 15 million available evidence, omega-3 supplementation during preg- babies are born preterm each year; among these, 20% are born nancy to prevent EPTB should be targeted towards women before 34 weeks (referred to as early preterm birth [EPTB]). Infants with low omega-3 status in early pregnancy. Women with re- born early preterm may require extended periods in hospital in- plete omega-3 levels in early pregnancy should continue their tensive care and some exhibit developmental problems that can current dietary practices to maintain their status. Correcting last a lifetime, including problems with their lungs, gut, immune low maternal omega-3 levels through supplementation (such system, vision, and hearing. Furthermore, developmental difficul- as the use of low-dose fish oil supplements) may reduce the ties may emerge in early childhood, with later societal and eco- risk of EPTB. nomic impacts caused by low educational achievement, high un- employment, and deficits in social and emotional well-being. Recommended reading

Practical implications Samuel TM, Sakwinska O, Makinen K, Burdge GC, Godfrey KM, Silva-Zolezzi I. Preterm birth: a narrative review of the current The homeostatic balance between the metabolites of ome- evidence on nutritional and bioactive solutions for risk reduc- ga-3 and omega-6 fatty acids play a vital role in the mainte- tion. Nutrients. 2019;11(8):1811.

Reprint with permission from: Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901

Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth

a, b a, c a, b Karen Patricia Best Judith Gomersall Maria Makrides

a Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide , SA , Australia; b School of Medicine, University of Adelaide, Adelaide , SA , Australia ; c School of Public Health, University of Adelaide, Adelaide , SA , Australia

Key Messages tially important to preterm delivery, such as infection, inflammation, oxidative stress, and muscle contractility. Several ob- • Cost-effective primary prevention strategies to reduce preterm birth (PTB) are required to reduce the ∼ 15 million preterm ba- servational studies have explored the association between bies born every year worldwide. Nutritional interventions may dietary nutrients and/or dietary patterns and PTB, often with offer a promising solution. contrasting results. Randomized trial evidence on the effects • The strongest evidence to date for a nutritional solution to re- of supplementation with zinc, multiple micronutrients (iron duce PTB exists for omega-3 long-chain polyunsaturated fatty and folic acid), and vitamin D is promising; however, results acids and suggests that women with low levels of omega-3 in early pregnancy may benefit from supplementation. are inconsistent, and many studies are not adequately pow- • Recent findings suggest that determining an individual wom- ered for outcomes of PTB. Large-scale clinical trials with PTB an’s polyunsaturated fatty acid status in early pregnancy may as the primary outcome are needed before any firm conclu- be a precise way to inform recommendations to reduce her risk sions can be drawn for these nutrients. The strongest evi- of PTB. dence to date for a nutritional solution exists for omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), key nutrients in fish. In 2018, a Cochrane Review (including 70 studies) Keywords showed that prenatal supplementation with omega-3 LCPU- Preterm birth · Nutrition · Pregnancy · Omega-3 · FAs reduced the risk of PTB and early PTB (EPTB) compared Prevention · Supplementation · Prematurity with no omega-3 supplementation. However, the largest trial of omega-3 supplementation in pregnancy, the Omega-3 to Reduce the Incidence of Prematurity (ORIP) trial (n = Abstract 5,544), showed no reduction in EPTB and a reduction in PTB Worldwide, around 15 million preterm babies are born annu- only in a prespecified analysis of singleton pregnancies. Ex- ally, and despite intensive research, the specific mechanisms ploratory analyses from the ORIP trial found that women with triggering preterm birth (PTB) remain unclear. Cost-effective low baseline total omega-3 status were at higher risk of EPTB, primary prevention strategies to reduce PTB are required, and and that this risk was substantially reduced with omega-3 nutritional interventions offer a promising alternative. Nutri- supplementation. In contrast, women with replete or high ents contribute to a variety of mechanisms that are poten- baseline total omega-3 status were already at low risk of EPTB

[email protected] © 2021 Nestlé Nutrition Institute, Switzerland/ Karen Patricia Best S. Karger AG, Basel Women and Kids, South Australian Health and Medical Research Institute 72 King William Road North Adelaide, ADL 5006 (Australia)

karen.best @ sahmri.com and additional omega-3 supplementation increased the risk Preventing PTB, a Challenging Issue of EPTB compared to control. These findings suggest that determining an individual woman’s PUFA status may be the PTB is one of the most challenging issues in obstetric and most precise way to inform recommendations to reduce her neonatal care and is caused by multiple etiologies [7] . About risk of PTB. © 2021 Nestlé Nutrition Institute, Switzerland/ half of the time, the causes of PTB are unclear, and there are S. Karger AG, Basel no current satisfactory prevention strategies or treatments. Several Cochrane systematic reviews have been conducted

on the effects of interventions designed to prevent PTB with Preterm Birth treatments ranging from bed rest and smoking cessation to therapeutic drugs such as betamimetics, magnesium sulfate, A human pregnancy usually lasts around 40 weeks, with most and calcium channel blockers. While there has been some babies delivered at term (between 37 and 42 weeks of gesta- success in reducing the risk of PTB in high-risk women with tion; Fig. 1 ). Preterm birth (PTB) is defined by the World Health tocolytic agents [8, 9] , these are not suitable as prophylactic Organization (WHO) as all births before 37 completed weeks strategies because the risks associated with these interven- of gestation or fewer than 259 days since the first day of a tions are not acceptable to the general population. One phar- woman’s last menstrual period [1] . PTB is the second leading macological intervention, which has been shown to be some- cause of death globally for children under 5 years of age [1] . It what effective is progesterone, however, only in singleton is estimated that ∼ 15 million babies each year worldwide are pregnancies with a history of PTB [10] . In the absence of pre- born preterm with 20% occurring before 34 weeks gestation, dictive tests that are sensitive, specific, and feasible to imple- referred to as early PTB (EPTB). EPTB is the major cause of ment, more general cost-effective primary prevention strate- perinatal mortality, serious neonatal morbidity, and moder- gies for PTB are required [7] . Nutritional interventions are ate-to-severe childhood disability in developed countries [2– promising alternatives. 4] . These infants often require extended periods in hospital intensive care and may have developmental problems that can last a lifetime, including problems with their lungs, gut, Maternal Nutrition and immune system function, in addition to problems with their vision and hearing. In early childhood, developmental Maternal nutrition before and during pregnancy plays an im- difficulties may emerge, with later societal and economic important role in providing the necessary nutrients for fetal pacts due to low educational achievement, high unemploy- growth [11] and may be a key factor in the risk of PTB [12] . ment, and deficits in social and emotional well-being [5] . Several observational studies have explored the association These outcomes have enormous economic and public health between dietary nutrients and PTB and present contrasting impact [6] , and addressing PTB is an urgent priority. results. A cohort study in 60,000 women with singleton preg-

Pregnancy

Post Second trimester Third trimester term

Completed weeks of 16 20 24 28 32 36 40 gestation

Preterm birth Term Post (<37 weeks) (37–42 term weeks) 42 Early preterm birth weeks (<34 weeks)

Fig. 1. Gestation at birth definitions.

32 Reprint with permission from: Best/Gomersall/Makrides Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 Table 1. Summary of Cochrane reviews assessing RCT evidence on effects of nutrients during pregnancy on PTB and EPTB

Nutrients and outcome assessed Effects Quality of the evidence (grade)

Magnesium versus no magnesium and PTB [22] 7 trials, 5,981 women RR 0.89 (95% CI 0.69–1.14) Not applicablea Calcium versus placebo/no treatment and EPTB [23] 4 trials, 5,669 women RR 1.04 (95% CI 0.8–1.36) Moderate Calcium versus placebo/no treatment and PTB [23] 13 trials; 16,139 women RR 0.86 (95% CI 0.7–1.05) Moderate Iron alone versus placebo/no treatment and PTB [24] 6 trials, 1,713 women RR 0.82 (95% CI 0.58–1.14) Not applicablea Folic acid alone versus placebo/no treatment and PTB [25] 3 trials, 2,959 women RR 1.01 (95% CI 0.73–1.38) Not applicablea Iron and folic acid versus placebo/no treatment and PTB [24] 3 trials, 1,479 women RR 1.55 (95% CI 0–4.6) Not applicablea Supplements containing iron and folic acid versus same supplements without iron 3 trials, 1,497 women RR 1.55 (95% CI 0.40–6.00) Low nor folic acid or placebo and PTB [24] MMN (with iron and folic acid) versus iron with or without folic acid and PTB [26] 8 trials, 91,425 women RR 0.95 (95% CI 0.90–1.01) Moderate Zinc alone or in combination with other micronutrients versus placebo and PTB [29] 16 trials, 7,637 women RR 0. 86 (95% CI 0.76–0.97) Moderate Vitamin D alone versus placebo/no treatment and PTB [27] 7 trials, 1,640 women RR 0.66 (95% CI 0.34–1.30) Low certainty Vitamin D and calcium versus placebo/no treatment and PTB [27] 5 trials, 942 women RR 1.52 (95% CI 1.01–2.28) Low certainty Omega-3 LCPUFA compared with no omega-3 and PTB [28] 26 trials, 10,304 women RR 0.89 (95% CI 0.81–0.97) High Omega-3 LCPUFA compared with no omega-3 and EPTB [28] 9 trials, 5,204 women RR 0.58 (95% CI 0.44–0.77) High

EPTB, early preterm birth (<34 weeks); LCPUFA, long-chain polyunsaturated fatty acid; PTB, preterm birth (<37 weeks); RCT, randomized controlled trial; MD, mean difference; MMN, multiple micronutrients; RR, relative risk. a Quality of evidence not assessed in the review.

nancies in Norway observed an association between higher assess the association between adherence to a “healthy di- intake of artificially sweetened and sugar-sweetened bever- etary pattern” defined as high intake of vegetables, fruits, ages and increased risk of PTB [13] . Another study based on whole grain foods, poultry and fish, and PTB. Reduced odds the same pregnancy cohort assessed the risk of PTB for 3 di- of PTB were observed (OR 0.75, 95% CI 0.57–0.93), although etary patterns: “prudent” (vegetables, fruits, oils, water as bev- there was significant heterogeneity between studies (I 2 = erage, whole grain cereals, and fiber-rich bread), “Western” 89.6%). Analysis based on 4 of the studies presented in this (salty and sweet snacks, white bread, desserts, and processed review showed a “Western” diet, comprising mostly refined meat products), and “traditional” (potatoes and fish), reporting grains, processed meats or snacks, high-sugar and high-fat that high scores on the “prudent” dietary pattern were associ- dairy products, eggs, and white potatoes had no effect on the ated with significantly reduced risk of PTB (hazard ratio for the odds of PTB (OR 1.11, 95% CI 0.87–1.34), though again sub- highest vs. the lowest third: 0.88, 95% CI 0.80–0.97). The “tra- stantial heterogeneity was seen (I 2 = 77.8%) [17] . Raghavan and ditional” diet was associated with reduced risk of PTB for the colleagues [18] performed a narrative review of the evidence highest versus the lowest third (hazard ratio 0.91, 0.83–0.99), for associations between dietary patterns during pregnancy and no independent association with PTB was found for the and PTB. They concluded that although the evidence is lim- “Western” diet [14] . Another cohort study, in Denmark (Danish ited, there is some evidence (mostly studies involving Cauca- National Birth Cohort), showed consumption of a Mediterra- sian women) to support protective associations with PTB. nean diet in mid-pregnancy (including fish at least bi-weekly, These protective dietary patterns are higher in vegetables; using olive or grape seed oil, >5 portions of fruit and vegeta- fruits; whole grains; nuts; legumes and seeds; and seafood, bles/day, meat no more than twice a week, and at most 2 cups and lower in red and processed meats and fried foods [18] . of coffee/day) was associated with a 72% lower risk of EPTB Fish is a rich source of essential nutrients for fetal develop- [15] . ment which has been linked to a reduction in PTB since the The epidemiological evidence on dietary patterns and PTB 1980s when it was noticed that women who ate a lot of fish has been summarized in 3 recent systematic reviews [16–18] . in the Faroe Islands (in Scandinavia) had longer pregnancies The review by Chia and colleagues [16] , a meta-analysis in- than their Danish neighbors [19] . A systematic review by Lev- cluding 6 studies, showed adherence to a “healthy” diet com- entakou et al. [20] assessed the evidence for associations be- prising high intakes of vegetables, fruits, whole grains, low-fat tween fish intake and PTB, adjusting for a wide range of po- dairy, and lean protein foods lowered the risk of PTB (odds tentially important confounding variables in all meta-analy- ratio [OR] for the top compared to bottom tertile [0.79, 95% ses. A total of 19 population-based European birth cohort CI 0.68–0.91]). Kibret et al. [17] pooled data from 9 studies to studies and 151,880 mother-child pairs were included in this

Nutritional Strategies to Reduce Risk of Reprint with permission from: 33 Prematurity Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 Omega-3 Omega-6 polyunsaturated fatty acids polyunsaturated fatty acids

Alpha-linolenic acid (ALA) Linoleic acid (LA) 18:3n-3 18:2n-6

Omega-3 and omega-6 compete for the same desaturation and elongation enzymes

Eicosapentaenoic acid (EPA) Arachidonic acid (AA) 20:5n-3 20:4n-6

Decosahexaenoic acid (DHA) 22:6n-3 Fig. 2. Synthesis of polyunsaturated fatty acids.

review. Findings were consistent across cohorts; the adjusted and folic acid compared with the same supplements without RR of fish intake >1 but <3 times/week compared to ≤1 time/ iron nor folic acid or placebo [24] . More recently, a Cochrane week was 0.87 (95% CI 0.82–0.92) and of fish intake ≥3 times/ review evaluating benefits of MMNs supplementation with week compared to ≤1 time/week was 0.89 (95% CI 0.84– iron and folic acid during pregnancy found moderate quality 0.96). This large international study indicates that moderate evidence for a small effect of MMNs (with iron and folic acid) fish intake during pregnancy is associated with lower risk of compared to iron with or without folic acid on the risk of PTB PTB [20] . Although some conclusions regarding dietary pat- [26] . terns and fish intake can be drawn from these reviews, inter- There is some limited evidence for administration of zinc pretation is difficult due to the methodological limitations of supplements (5–44 mg/day) as well as vitamin D supplemen- epidemiological studies and the risk of bias from residual con- tation as potentially effective interventions to prevent PTB [7] . founding [21] . A Cochrane review demonstrated moderate quality evidence Randomized controlled trials (RCTs) are the most reliable of a small but significant 14% reduction in PTB with antenatal type of research to inform questions about cause and effect. supplementation of zinc alone or in combination with other A substantial body of RCT evidence on the effects of supple- micronutrients compared to placebo [29] . However, most of mentation with individual nutrients, including magnesium, the RCTs assessing zinc have been conducted in low-income calcium, iron, folic acid, zinc, vitamin D, omega-3, or multiple countries among women with poor nutritional status, likely to micronutrients (MMNs), on PTB has accumulated. Samuel et have had low zinc concentrations. The reduction in PTB ob- al. [7] have provided a systematic overview of the evidence on served in these studies has not been accompanied by a reduc- nutritional solutions for PTB risk reduction, and various Co- tion in LBW or a difference in gestational age at birth, suggest- chrane reviews [22–28] assess the RCT evidence on the ef- ing that it is too early to be certain about the beneficial effects fects of these nutrients on PTB (Table 1 ). A review of magne- of zinc [7] . Vitamin D deficiency in women of reproductive age sium supplementation during pregnancy showed no differ- is widespread, and low maternal vitamin D status during preg- ence in risk of PTB between women who received magnesium nancy is a risk factor for several adverse birth outcomes in- versus no magnesium [22] . Another review found moderate cluding PTB [30] . A recent review by De-Regil et al. [27] found quality evidence indicating no reduction in PTB or EPTB risk low-quality evidence showing no difference in PTB between between women who received calcium during pregnancy women who received vitamin D alone compared to placebo compared to placebo or no treatment [23] . Two early Co- or no treatment, or between women who received vitamin D chrane reviews found no differences in PTB between women and calcium versus placebo or no treatment during pregnan- who received iron alone compared with no treatment/pla- cy. The only high-quality evidence to date for a nutritional cebo [24] ; folic acid alone compared with no treatment or solution to prevent PTB (in singleton pregnancies) exists for placebo [25] ; daily iron and folic acid supplements versus no omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). treatment/placebo [24] ; or any supplements containing iron

34 Reprint with permission from: Best/Gomersall/Makrides Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 Table 2. Summary of 2018 Cochrane review of marine oil supplementation in pregnancy outcomes [35]

Variable Effect of omega-3 LCPUFA treatment relative to control Quality of the evidence (grade)

Birth <34 weeks 11 trials, 5,409 women RR 0.58 (95% CI 0.44–0.77) High Birth <37 weeks 25 trials, 10,256 women RR 0.89 (95% CI 0.81–0.97) High Birth >42 weeks 6 trials with 5,141 women RR 1.61 (95% CI 1.11–2.33) Moderate Gestational length 41 trials with 12,517 women MD 1.67 days (0.95–2.39) Moderate Preeclampsiaa 20 trials with 8,306 women RR 0.84 (0.69–1.01) Low Perinatal death 10 trials with 7,416 women RR 0.75 (0.54–1.03) Moderate Birth weight, g 42 trials with 11,584 women MD 76 g higher (38 to 113 higher) Not applicableb Low birth weight <2,500 g 15 trials with 8,449 women RR 0.90 (0.82–0.99) High SGA 8 trials with 6,907 women RR 1.01 (0.90–1.13) Moderate LGA RR 1.15 (0.97–1.36) Moderate

LGA, large for gestational age; LCPUFA, long-chain polyunsaturated fatty acid; MD, mean difference; RR, relative risk; SGA, small for gestational age. a Defined as hypertension with proteinuria. b Quality of evidence for this outcome not assessed in the review.

Omega-3 and PTB women; however, the median intake among Australian and American women of childbearing age is less than one-third Omega-3 is an essential fatty acid which must be obtained of this, compared with 1,000 mg/day in many women from from the diet and is a key nutrient in fish. First observed in the nations with high fish consumption, such as Japan, Korea, 1980s and recently supported in the large Leventakou review, and Norway [35] . Several epidemiological studies and RCTs long-chain omega-3 fatty acids from marine sources such as have investigated the effect of increased maternal omega-3 fish and algae are thought to be responsible for longer preg- intake and PTB. Middleton et al. [28] recently updated the nancies (and fewer preterm babies) [19, 20] . There are plau- Cochrane Review of Marine Oil Supplementation in Pregnan- sible biological mechanisms to indicate that dietary insuffi- cy, which was first published in 2006 [36] . This updated re- ciency of omega-3 LCPUFA may play a role in the pathophys- view includes all trials of LCPUFAs in any form or dose during iology of preterm delivery, and this presents a potential target pregnancy (including as supplements, food, or dietary ad- for intervention. Prostaglandins and other oxylipins derived vice). The latest search of the literature was conducted in from omega-6 and omega-3 fatty acids play essential roles in August 2018. The review included 70 RCTs, involving 19,927 normal and pathologic initiation of labor [31, 32] . The feto- women. Most of the trials were conducted in high-income placental unit is supplied with LCPUFAs from the maternal countries (e.g., USA, England, The Netherlands, Australia, and circulation, which is influenced by maternal LCPUFA intake Denmark), and most included women were carrying single- and endogenous synthesis (Fig. 2 ). The prostaglandins and ton pregnancies. The intervention dose ranged between 200 oxylipins derived from omega-6 arachidonic acid within the and 2,700 mg omega-3 LCPUFA as docosahexaenoic acid utero-placental unit in normal pregnancy are countered by (DHA) or eicosapentaenoic acid (EPA) and was administered local production of prostaglandins and oxylipins derived from mainly throughout the second half of pregnancy. Results omega-3 LCPUFA within the same tissues. The balance be- show high-quality evidence that supplementation with ome- tween the metabolites of omega-3 and omega-6 fatty acids ga-3 LCPUFA during pregnancy reduced the risk of having a plays a vital role in the maintenance of normal gestational premature baby <37 weeks’ gestation by 11% and <34 weeks’ length and is a critical element in cervical ripening and the gestation by 42% compared with no omega-3 supplementa- initiation of labor [33, 34] . If local production of omega-6-de- tion. Additional outcomes for the systematic reviewed rived prostaglandins within the feto-placental unit is too high, showed that prenatal omega-3 LCPUFA supplementation or local accumulation of omega-3 LCPUFA is too low, the was safe (in terms of no effect on bleeding or postpartum cervix may prematurely ripen and uterine contractions in- hemorrhage) and significantly reduced the incidence of low crease, which may in turn lead to PTB. birth weight and increased the incidence of pregnancies Current Western diets are low in omega-3 LCPUFAs and continuing beyond 42 weeks, although there was no differ- high in omega-6 fatty acids. The WHO recommends an in- ence identified in induction of labor for post-term pregnan- take of 300 mg of omega-3 LCPUFAs per day in pregnant cies ( Table 2).

Nutritional Strategies to Reduce Risk of Reprint with permission from: 35 Prematurity Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 Table 3. Summary of the ORIP trial outcomes [39]

Variable Omega-3 group Control group Adjusted RR (n = 2,734), n (%) (n = 2,752), n (%) (95% CI)a

Birth <34 weeks 61 (2.2) 55 (2.0) 1.13 (0.79–1.63) Birth <37 weeks 211 (7.7) 246 (8.9) 0.86 (0.72–1.03) Prolonged gestation 12 (0.4) 12 (0.4) N/A Gestational length, daysb 273.2±15.2 273.2±14.9 0.02 (−0.78 to 0.82) Preeclampsia 96 (3.5) 91 (3.3) 1.07 (0.80–1.43) Perinatal death 32 (1.1) 25 (0.9) 1.28 (0.76–2.17) Birth weight, gb 3,351±628 3,340±591 10.56 (−23.87 to 44.99) Low birth weight <2,500 g 204/2,787 (7.3) 173/2,800 (6.2) 1.18 (0.95–1.47) SGA 206/2,787 (7.4) 196/2,800 (7.0) 1.06 (0.87–1.28) LGA 392/2,787 (14.1) 355/2,800 (12.7) 1.11 (0.97–1.27)

g, grams; LGA, large for gestational age; LCPUFA, long-chain polyunsaturated fatty acid; MD, mean difference; RR, relative risk; SGA, small for gestational age; ORIP, Omega-3 to Reduce the Incidence of Prematurity. a The effect sizes are relative risks (omega-3 group vs. control group) unless otherwise indicated. The adjusted values were adjusted for randomization strata: recruitment hospital and consumption of dietary supplements containing n-3 LCPUFA in the previous 3 months (yes or no). Except in the case of the primary outcome, the 95% CI were not adjusted for multiplicity and therefore should not be used to infer treatment effects. b The effect size is the difference in means (omega-3 group minus control group).

It is important to note that this latest Cochrane review in- ton and multiple pregnancies, inclusive of women regard- cludes studies mainly from high-income countries with low- less of prematurity risk, and inclusive of many women al- risk, normal-risk, and high-risk women, and almost all women ready taking low-dose omega-3 supplements. This con- had singleton pregnancies. Reporting biases may underesti- trasts with most other studies that included only singleton mate or overestimate omega-3 effects on prematurity and pregnancies and/or focused on women with low intakes. other adverse birth outcomes and further work is needed to This heterogeneity may, in part, explain why the results of address concerns that supplementation in late pregnancy the ORIP trial are discordant with those of the systematic may prolong gestation beyond term. For example, the 2-day review. The ORIP trial found that supplementation of preg- shift in mean gestation in our DOMInO trial (the largest trial nant women with 900 mg per day of omega-3 LCPUFA (800 included in the systematic review with 2,499 women) in- mg DHA/100 mg EPA) did not reduce the overall risk of EPTB creased the number of post-term pregnancies and thus the or PTB, even though omega-3 PUFA concentrations in the need for more obstetric interventions to initiate birth (17.6 vs. intervention group at 34 weeks’ gestation were elevated rel- 13.7%; RR 1.28, 95% CI 1.06–1.54) [37] . This highlighted the ative to the control group (Table 3 ). need for further research to investigate the effects of prenatal Prespecified secondary analyses of only singleton preg- omega-3 supplementation in a broad representation of wom- nancies in the ORIP trial suggested a reduction in the risk of en before adopting a universal supplementation approach PTB with omega-3 supplementation in singleton but not mul- into routine antenatal care. tiple pregnancies (RR 0.81, 95% CI 0.67, 0.99) [39] . The ORIP The Omega-3 to Reduce the Incidence of Prematurity trial also comprised the valuable inclusion of blood samples (ORIP) RCT of 5,544 pregnancies was published in 2019 [38] . to determine maternal baseline omega-3 status prior to com- It is the largest trial to assess whether omega-3 LCPUFA mencing supplementation (trial entry <20 weeks’ gestation), a supplementation, mainly as DHA, reduced the risk of EPTB design feature most of the prior trials lack. Exploratory analy- (<34 weeks’ gestation) [39] . This trial was designed with the ses in women with a singleton pregnancy (n = 5,070) found unique feature of ceasing the intervention at 34 weeks’ ges- that women with low baseline total omega-3 blood PUFA sta- tation (when the risk of EPTB has passed) to avoid prolonga- tus (<4.1%, n = 885) were at higher risk of EPTB and that this tion of pregnancy requiring post-term obstetric interven- risk was substantially reduced by 77% with omega-3 supple- tion. The ORIP trial was specifically designed to assess a mentation (relative risk = 0.23, 95% CI 0.07–0.79) [40] . In con- broad-based supplementation strategy inclusive of single- trast, women with higher or replete total omega-3 status at

36 Reprint with permission from: Best/Gomersall/Makrides Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 baseline (>4.9%, n = 2,277) were at lower risk of EPTB, and Summary supplementing these women with omega-3 increased the risk of EPTB compared to control (relative risk = 2.27, 95% CI 1.13– Despite intensive research, the mechanisms triggering the 4.58) [40] . ∼ 15 million PTBs occurring worldwide every year remain un- This observation that EPTB is altered by baseline omega-3 clear. Nutritional interventions are promising primary preven- status is consistent with epidemiological data showing that tion strategies, yet to date, many broad-based interventions low fish intake [20] or low omega-3 status [41] is associated with the potential to reduce the risk of PTB are effective only with an increased risk of EPTB in singleton pregnancies. In a in specific groups of women, most likely due to the hetero- case-control study nested within the Danish National Birth geneity of the population and the etiopathogenesis of PTB. At Cohort, 376 EPTB cases were identified. When comparing present, omega-3 PUFA seems to be the nutrient holding the concentrations of EPA plus DHA, women in the lowest quintile most promise for the prevention of EPTB. Based on the avail- of the distribution had a 10 times (95% CI 6.8–16, p < 0.0001) able evidence, omega-3 supplementation during pregnancy increased risk of EPTB, and women in the second lowest quin- to prevent EPTB should be targeted to women with low ome- tile had a 2.9 times (95% CI 1.8–4.6, p < 0.0001) increased risk ga-3 status in early pregnancy. Clinicians should discuss the of EPTB, when compared to women in the 3 aggregated high- importance of a good diet with pregnant women and in the est quintiles [41] . A moderate fish intake during pregnancy absence of measured maternal omega-3 PUFA levels, advise (1–2 fish meals per week) would generally be associated with dietary source essential fatty acids be regularly consumed a total omega-3 status of >4.1% of total omega-3 fatty acids during pregnancy, and low-dose fish oil supplements may be in whole blood, the conservative cutoff reported in the ORIP explored to provide the necessary omega-3 required for op- exploratory analysis showing a protective association with timal maternal and fetal outcomes. Advancement of this field EPTB [40] . requires the development and implementation of a targeted The unexpected findings from the ORIP exploratory analy- approach and evidence-based precision nutrition in antenatal sis suggesting an increased risk of EPTB in women with re- care [7] . plete omega-3 status have been proposed previously. Kle- banoff et al. [42] conducted a secondary analysis of a prenatal omega-3 supplementation RCT and report that for women at Statement of Ethics risk of recurrent PTB, the probability of PTB was highest at low No approval was required for this review. and high intakes, and lowest with moderate fish consumption. Similar patterns have been seen for several micronutrients and higher risks of adverse health outcomes for both low and high Conflict of Interest Statement nutrient intakes – a U-shaped relationship [43] . Determining a woman’s omega-3 status in early pregnancy and likelihood The writing of this article was supported by Nestlé Nutrition Institute. of benefiting from omega-3 supplementation to reduce her Professor Makrides serves at the Board of Directors for Trajan Nutri- risk of EPTB would be the most precise way to inform supple- tion. Dr. Best and Dr. Gomersall have nothing to disclose. mentation practices. We would recommend that women with replete omega-3 status in early pregnancy should continue their current dietary practices to maintain their status. How- Funding Sources ever, correcting low maternal omega-3 status through sup- Dr. Best is supported by a MS McLeod Post-Doctoral Fellowship. Pro- plementation may reduce her risk of EPTB. fessor Makrides is supported by a National Health and Medical Re- search Fellowship. References

1 March of dimes, the partnership for maternal, newborn and child 4 Pretorius C, Jagatt A, Lamont RF. The relationship between peri-

health, save the children, WHO. Born too soon: the global action odontal disease, bacterial vaginosis, and preterm birth. J Perinat

report on preterm birth. Geneva, Switzerland: World Health Or- Med. 2007; 35(2): 93–9.

ganisation; 2012. 5 Westrupp E, Lucas N, Mensah F, Gold L, Wake M, Nicholson JM.

2 Lumley J. Defining the problem: the epidemiology of preterm Community-based healthcare costs for children born low birth-

birth. BJOG . 2003; 110(Suppl 20): 3–7. weight, preterm and/or small for gestational age: data from the Longitudinal Study of Australian Children. Child Care Health Dev. 3 Martin JAOM. Describing the increase in preterm births in the 2014; 40(2): 259–66.

United States, 2014–2016. In: NCHS, editor. Data Brief, no 312 ed.

Hyattsville, MD: National Center for Health Statistics; 2018.

Nutritional Strategies to Reduce Risk of Reprint with permission from: 37 Prematurity Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 6 Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Nar- 20 Leventakou V, Roumeliotaki T, Martinez D, Barros H, Brantsaeter wal R, et al. National, regional, and worldwide estimates of pre- AL, Casas M, et al. Fish intake during pregnancy, fetal growth, and term birth rates in the year 2010 with time trends since 1990 for gestational length in 19 European birth cohort studies. Am J Clin

selected countries: a systematic analysis and implications. Lancet . Nutr. 2014; 99(3): 506–16.

2012; 379(9832): 2162–72. 21 Khoury J, Henriksen T, Christophersen B, Tonstad S. Effect of a 7 Samuel TM, Sakwinska O, Makinen K, Burdge GC, Godfrey KM, cholesterol-lowering diet on maternal, cord, and neonatal lipids,

Silva-Zolezzi I. Preterm birth: a narrative review of the current ev- and pregnancy outcome: a randomized clinical trial. Am J Obstet

idence on nutritional and bioactive solutions for risk reduction. Gynecol. 2005; 193(4): 1292–301.

Nutrients. 2019; 11(8): 1811. 22 Makrides M, Crosby DD, Bain E, Crowther CA. Magnesium supple- 8 Dodd JM, Flenady VJ, Cincotta R, Crowther CA. Progesterone for mentation in pregnancy. Cochrane Database Syst Rev. 2014 Apr

the prevention of preterm birth: a systematic review. Obstet Gy- 3; 2014(4): CD000937.

necol . 2008; 112(1): 127–34. 23 Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C, Lao- 9 King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium paiboon M, Medley N. Calcium supplementation (other than for

channel blockers for inhibiting preterm labour; a systematic re- preventing or treating hypertension) for improving pregnancy and

view of the evidence and a protocol for administration of nifedip- infant outcomes. Cochrane Database Syst Rev. 2015 Feb;25(2):

ine. Aust N Z J Obstet Gynaecol. 2003; 43(3): 192. CD007079. 10 Romero R, Nicolaides KH, Conde-Agudelo A, O’Brien JM, Cetin- 24 Pena-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Dai- goz E, Da Fonseca E, et al. Vaginal progesterone decreases pre- ly oral iron supplementation during pregnancy. Cochrane Data-

term birth < /= 34 weeks of gestation in women with a singleton base Syst Rev. 2015 Jul 22;(7): CD004736.

pregnancy and a short cervix: an updated meta-analysis including 25 Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementa- data from the OPPTIMUM study. Ultrasound Obstet Gynecol. tion during pregnancy for maternal health and pregnancy out- 2016; 48(3): 308–17.

comes. Cochrane Database Syst Rev. 2013;(3): CD006896. 11 Nnam NM. Improving maternal nutrition for better pregnancy 26 Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for outcomes. Proc Nutr Soc. 2015; 74(4): 454–9.

women during pregnancy. Cochrane Database Syst Rev. 2017;

12 Fuchs F, Senat MV. Multiple gestations and preterm birth. Semin 4(4): CD004905.

Fetal Neonatal Med. 2016; 21(2): 113–20. 27 De-Regil LM, Palacios C, Kostiuk LK, Peña-Rosas JP. Vitamin D 13 Englund-Ögge L, Brantsæter AL, Haugen M, Sengpiel V, Khatibi A, supplementation for women during pregnancy. Cochrane Data-

Myhre R, et al. Association between intake of artificially sweetened base Syst Rev. 2016 Jan 14;(1): CD008873.

and sugar-sweetened beverages and preterm delivery: a large 28 Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, prospective cohort study. Am J Clin Nutr. 2012; 96(3): 552–9. Makrides M. Omega-3 fatty acid addition during pregnancy. Co-

14 Englund-Ögge L, Brantsæter AL, Sengpiel V, Haugen M, Birgisdot- chrane Database Syst Rev. 2018; 11(11): CD003402. tir BE, Myhre R, et al. Maternal dietary patterns and preterm deliv- 29 Ota E, Mori R, Middleton P, Tobe-Gai R, Mahomed K, Miyazaki C, ery: results from large prospective cohort study. BMJ . 2014; 348: et al. Zinc supplementation for improving pregnancy and infant g1446.

outcome. Cochrane Database Syst Rev . 2015 Feb 2; 2015(2): 15 Mikkelsen TB, Osterdal ML, Knudsen VK, Haugen M, Meltzer HM, CD000230. Bakketeig L, et al. Association between a Mediterranean-type diet 30 Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, and risk of preterm birth among Danish women: a prospective Eisman JA, et al. Global vitamin D status and determinants of hy- cohort study. Acta Obstet Gynecol Scand. 2008; 87(3): 325–30.

povitaminosis D. Osteoporos Int . 2009; 20(11): 1807–20. 16 Chia A-R, Chen L-W, Lai JS, Wong CH, Neelakantan N, van Dam

31 Gravett MG. Causes of preterm delivery. Semin Perinatol. 1984; RM, et al. Maternal dietary patterns and birth outcomes. a system-

8(4): 246–57. atic review and meta-analysis. Adv Nutr . 2019 Jul 1; 10(4): 685–95. 32 Karim SM. The role of prostaglandins in human parturition. Proc R 17 Kibret KT, Chojenta C, Gresham E, Tegegne TK, Loxton DJP. Ma-

Soc Med. 1971; 64(1): 10–2. ternal dietary patterns and risk of adverse pregnancy (hypertensive disorders of pregnancy and gestational diabetes mellitus) and 33 Brazle AE, Johnson BJ, Webel SK, Rathbun TJ, Davis DL. Omega-3

birth (preterm birth and low birth weight) outcomes: a systematic fatty acids in the gravid pig uterus as affected by maternal supple-

review and meta-analysis. Public Health Nutr . 2019; 22(3): 506–20. mentation with omega-3 fatty acids. J Anim Sci. 2009; 87(3): 994– 1002. 18 Raghavan R, Dreibelbis C, Kingshipp BL, Wong YP, Abrams B, Ger- nand AD, et al. Dietary patterns before and during pregnancy and 34 Ramsden CE, Makrides M, Yuan Z-X, Horowitz MS, Zamora D, Yel-

maternal outcomes: a systematic review. Am J Clin Nutr. 2019; land LN, et al. Plasma oxylipins and unesterified precursor fatty

109(Suppl 7): 705S–28S. acids are altered by DHA supplementation in pregnancy: can they help predict risk of preterm birth? Prostaglandins Leukot Essent 19 Olsen SF, Hansen HS, Sørensen TI, Jensen B, Secher NJ, Sommer

Fatty Acids. 2020; 153: 102041. S, et al. Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation. Lancet . 35 Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR.

1986; 2(8503): 367–9. Dietary intakes and food sources of omega-6 and omega-3 poly-

unsaturated fatty acids. Lipids . 2003; 38(4): 391–8.

38 Reprint with permission from: Best/Gomersall/Makrides Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 36 Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin 40 Simmonds LASTR, Skubisz M, Middleton PF, Best KP, Yelland LN, precursor, supplementation for pregnancy uncomplicated by Quinlivan J, et al. Omega-3 fatty acid supplementation in preg-

pre-eclampsia or intrauterine growth restriction. Cochrane Data- nancy: baseline omega-3 status and early preterm birth: explor-

base Syst Rev. 2006; 3(3): CD003402. atory analysis of a randomised controlled trial. BJOG . 2020 Jul;

127: 975–81. 37 Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, Ryan P, et al. Effect of DHA supplementation during pregnancy on ma- 41 Olsen SF, Halldorsson TI, Thorne-Lyman AL, Strøm M, Gørtz S,

ternal depression and neurodevelopment of young children: a Granstrøm C, et al. Plasma concentrations of long chain N-3 fat-

randomized controlled trial. JAMA . 2010; 304(15): 1675–83. ty acids in early and mid-pregnancy and risk of early preterm birth.

EBioMedicine. 2018; 35: 325–33. 38 Zhou SJ, Best K, Gibson R, McPhee A, Yelland L, Quinlivan J, et al. Study protocol for a randomised controlled trial evaluating the ef- 42 Klebanoff MA, Harper M, Lai Y, Thorp J Jr., Sorokin Y, Varner MW, fect of prenatal omega-3 LCPUFA supplementation to reduce the et al. Fish consumption, erythrocyte fatty acids, and preterm birth.

incidence of preterm birth: the ORIP trial. BMJ Open. 2017; 7(9): Obstet Gynecol. 2011; 117(5): 1071–7. e018360. 43 Mulholland CA, Benford DJ. What is known about the safety of 39 Makrides M, Best K, Yelland L, McPhee A, Zhou S, Quinlivan J, et multivitamin-multimineral supplements for the generally healthy

al. A randomized trial of prenatal n-3 fatty acid supplementation population? Theoretical basis for harm. Am J Clin Nutr . 2007;

and preterm delivery. N Engl J Med. 2019; 381(11): 1035–45. 85(1): 318S–22S.

Nutritional Strategies to Reduce Risk of Reprint with permission from: 39 Prematurity Ann Nutr Metab 2020;76(suppl 3):31–39 DOI: 10.1159/000509901 Focus

Care for women includes women having adequate access to food and health care to prevent illness, availability of fertility regulation and birth spacing options, sufficient time for rest, and protection from abuse

Reprinted with permission from: Ann Nutr Metab 2020;76(suppl 3):36–49 Maternal Undernutrition before and during Pregnancy and Offspring Health and Development Melissa F. Young and Usha Ramakrishnan

Key Insights ଶ Food insecurity ଶ Poverty ଶ Lack of access Maternal undernutrition remains a critical public health to services Diet quality, Adverse problem with large regional and intra-country disparities in (health, water, nutrition maternal and sanitation) status child outcomes the prevalence of underweight, anemia, and micronutrient ଶ Lack of education deﬁciencies. The greatest burden is seen among the poorest ଶ Social and political environment Maternal undernutrition women in poor countries. While the obesity epidemic is growing, the persistence of underweight in some countries in South Asia and Africa remains unacceptably high. Another Maternal undernutrition is highly prevalent among the poorest women major problem that disproportionately affects women of and is driven by a complex series of factors. reproductive age is anemia, which is also associated with an increased risk of poor maternal and infant outcomes. A key driver of poor nutrition is food insecurity. Despite the existence Practical implications of evidence-based strategies for improving maternal nutrition during pregnancy, there are still large gaps in program At the political level, women’s nutrition has not received suf- implementation and outreach. ficient prioritization. Furthermore, restricting the focus of women’s nutrition to pregnancy places a significant limit on the effectiveness of interventions. For women who live in conditions of extreme food insecurity (with anemia, micronutrient Current knowledge deficiencies, and undernutrition), maternal nutrition interventions during pregnancy may arrive too late. We urgently need Globally, 9.7% of women are underweight and 14.9% are to reach women earlier, in order to provide preconception obese. The nutritional and health status of women as they care and family planning services. Programs focused on enter pregnancy is known to play a key role in placental func- school-aged or adolescent girls have been identified as prom- tion and the subsequent growth and development of the fe- ising strategies in this context. Future efforts need to ensure tus. The placenta regulates nutrient availability for fetal growth that programs reach vulnerable and marginalized communi- and ultimately influences the long-term health of the new- ties in order to address regional disparities in maternal under- born. Micronutrients, including iron, zinc, folic acid, and oth- nutrition. er vitamins, contribute to genome-wide alterations and/or epigenetic modifications during the critical period of organogenesis. These changes influence subsequent outcomes, Recommended reading such as body composition, metabolism, immunity, and cognitive function, in the offspring. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al.; Maternal and Child Nutrition Study Group. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427–51.

Reprint with permission from: Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595

Maternal Undernutrition before and during Pregnancy and Offspring Health and Development

Melissa F. Young Usha Ramakrishnan

Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta , GA , USA

Key Messages context. Women’s health, nutrition, and wellbeing across the continuum of preconception to pregnancy are critical for en- • Maternal undernutrition remains a critical public health suring positive pregnancy and long-term outcomes for both problem with large regional and within-country disparities in the mother and child. In this review, we summarize the evi- the burden of underweight, anemia, and micronutrient deficiencies across the globe. dence base for nutrition interventions before and during • Maternal preconception nutrition may influence birth pregnancy that will help guide programs targeted towards outcomes and merits further research and program focus. women’s nutrition. Growing evidence from preconception • Several evidence-based strategies exist to improve maternal nutrition trials demonstrates an impact on offspring size at nutrition during pregnancy; however, there remain key gaps birth. Preconception anemia and low preconception weight in program implementation and equity. are associated with an increased risk of low birth weight and small for gestational age births. During pregnancy, several evidence-based strategies exist, including balanced-energy protein supplements, multiple micronutrient supplements, Keywords and small-quantity lipid nutrient supplements for improving Maternal undernutrition · Micronutrients · Child growth and birth outcomes. There, however, remain several important development priority areas and research gaps for improving women’s nutrition before and during pregnancy. Further progress is needed to prioritize preconception nutrition and access to health and Abstract family planning resources. Additional research is required to Maternal undernutrition remains a critical public health prob- understand the long-term effects of preconception and lem. There are large regional and within-country disparities pregnancy interventions particularly on offspring develop- in the burden of underweight, anemia, and micronutrient de- ment. Furthermore, while there is a strong evidence base for ficiencies across the globe. Driving these disparities are com- maternal nutrition interventions, the next frontier requires a plex and multifactorial causes, including access to health ser- greater focus on implementation science and equity to de- vices, water and sanitation, women’s status, and food insecu- crease global maternal undernutrition disparities. rity as well as the underlying social, economic, and political © 2021 Nestlé Nutrition Institute, Switzerland/ S. Karger AG, Basel

[email protected] © 2021 Nestlé Nutrition Institute, Switzerland/ Usha Ramakrishnan S. Karger AG, Basel Hubert Department of Global Health, Rollins School of Public Health Emory University, 1518 Clifton Road, NE Atlanta, GA 30322 (USA)

uramakr @ emory.edu Introduction women in the poor countries [2] . This is concerning given that both over- and undernutrition are associated with poor birth Maternal undernutrition remains a critical public health prob- outcomes [3] . Maternal overweight and obesity are associated lem across the globe. While there is growing recognition of with increased maternal morbidity, preterm birth (PTB), and the importance of maternal nutrition for child health and de- infant mortality [3] . Maternal underweight is likewise associ- velopment, women’s nutrition has historically not received ated with offspring growth and development, including in- the political or program prioritization required to make mean- creased risk for PTB, low birth weight (LBW), under-ﬁve mor- ingful progress. In this review, we summarize the current tality, and poor mental and physical development [3] . Anoth- global status of women’s nutrition, provide an overview of the er major public health problem that affects women of driving causes and consequences of maternal undernutrition, reproductive age disproportionately is anemia, which has and summarize the evidence base for nutrition interventions been associated with an increased risk of poor birth outcomes before and during pregnancy that will help guide programs (LBW, PTB, small for gestational age, stillbirth, and perinatal targeted towards women’s nutrition. and neonatal mortality) and adverse maternal outcomes (maternal mortality, postpartum hemorrhage, preeclampsia, and blood transfusion) [4] . Globally, 29% of nonpregnant women Global Status of Maternal Undernutrition and 38% of pregnant women are anemic [5] . Similar to underweight, there are large disparities in the global burden of ane- Globally, 9.7% of women are underweight and 14.9% are mia, particularly across South Asia and Central and West Af- obese [1] . While the obesity epidemic is growing, the persis- rica (Fig. 1 ). The etiology of anemia is diverse and context spe- tence of underweight in some countries in South Asia and cific, but a high burden of anemia may be an indicator of an central and east Africa remains unacceptably high. There are even greater burden of micronutrient deficiencies among large regional and within-country disparities in the burden of women. It is estimated that approximately 50% of anemia underweight, with the highest burden among the poorest among nonpregnant and pregnant women is amenable to

Prevalence of anemia in pregnant women, 2016 Prevalence of anemia in pregnant women, measured as the percentage of pregnant women with a hemoglobin level less than 110 g per liter at sea level

No data 0% 10% 20% 30% 40% 50% 60% 70%

Source: World Bank OurWorldInData.org/micronutrient-deficiency/ •CC BY

Fig. 1. Global prevalence of anemia in pregnant women. Reproduced from World Bank [92] .

42 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 iron supplementation; however, at the national and sub-na- ly age at marriage, limited maternal empowerment, and gen- tional level, the role of iron deficiency in anemia has been der inequality, remain critical barriers across the globe. In ad-

shown to be extremely variable from < 1 to 75% [6] and may dition, 9.3% of the population are affected by severe food in- be influenced by many conditions, including malaria, infec- security, with a slightly higher prevalence among women. tion, hemoglobinopathies, or other micronutrient deficien- Food insecurity is a key driver of poor nutrition across the cies (folate, vitamins B12 and B6 , riboflavin, vitamins A and C). globe and can be influenced by food affordability, availability, The World Health Organization (WHO) estimates that over and distribution of food among household members [19] . two billion people are at risk for micronutrient deficiencies [7] . Collectively, these factors influence the conditions (inade- Micronutrients deficiencies of public health concern include quate dietary intake, care for women, and disease) before iron, vitamin A, iodine, zinc, folate, and B vitamins. Figure 2 il- pregnancy and during pregnancy. Diet quality remains a ma- lustrates the current regional estimates of micronutrient de- jor concern globally [20] , and women are particularly vulner- ficiencies and anemia among women of reproductive age able. The vicious cycle of inadequate dietary intake and dis- across the globe [8] . ease is well known. Poor nutrition lowers immunity and increases susceptibility to disease; disease in turn perpetuates poor nutrition by decreasing appetite, inhibiting nutrient ab- Conceptual Framework sorption and increasing risk for micronutrient deficiencies and undernutrition. The conceptual framework shown in Figure 3 provides an Care for women includes women having adequate access overview of the underlying complex and multifactorial causes to food and health care to prevent illness, availability of fertil- and consequences of maternal undernutrition. This concep- ity regulation and birth spacing options, sufficient time for tual framework has been adapted based on the current un- rest, and protection from abuse [11, 21] . Women who marry derstanding of the causes of child malnutrition [9–14] . Distal early are more likely to have children at a young age, when causes of malnutrition include social, economic, and political they are still growing and developing themselves. Adolescent context and lack of capital (financial, human, physical, social, pregnancy can adversely affect both maternal health and nu- and natural). These factors may affect maternal and child trition and increase the risk for poor birth outcomes [22] . In health either directly or indirectly, through more proximal fac- some contexts, women may have limited decision-making tors, including access to health services, water and sanitation, authority on the number of children or when they have them women’s status, and food insecurity. Poor water and sanita- [23] . Early age at pregnancy and short interpregnancy intervals

tion increase the risk for infectious diseases, malnutrition, and (< 6 months) have been associated with increased risks for ad- mortality and may disproportionately affect women [15–18] . verse pregnancy outcomes (PTB, LBW, stillbirth, and early Women’s status, including reduced access to education, ear- neonatal death), highlighting the importance of women’s

100 ଶVitamin A ଶFolate ଶVitamin B12 80 ଶVitamin D ଶIodine ଶZinc ଶAnemia Fig. 2. Regional estimates of micronutri- 60 ଶIDA ent deficiencies and anemia among women of reproductive age. Reproduced from Bourassa et al. [8] , 2019. Data calcu- 40 lated from 52 national and regional sur- % Deficiency veys, published between 2013 and July 2017 using the World Health Organization 20 VMNIS database. Missing bars means no data were found for that micronutrient in the specific region. LMIC, low- and mid- 0 dle-income countries; IDA, iron deficien- Africa Americas Eastern- European South-East Western LMIC cy anemia. Black circles are not represen- Mediterranean Asian Pacific tative (<3 countries).

Undernutrition before and during Pregnancy and Reprint with permission from: 43 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 Child Child health and nutrition consequences Birth Morbidity/ Growth & Brain & cognitive outcomes mortality body composition development

Maternal Micronutrient Pre-pregnant Gestational Micronutrient Morbidity/ Short stature consequences deficiencies BMI weight gain deficiencies mortality

Before pregnancy During pregnancy

Inadequate Inadequate Care for womenDisease Care for women Disease dietary intake dietary intake

Women’s status Proximal Access to health services & (education/age at marriage, gender Foody insecurity causes water/sanitation equality)

Distal Lack of capital: Social, economic & political context causes financial, human, physical, social and natural

Fig. 3. Conceptual framework of the causes and consequences of maternal undernutrition. The conceptual framework provides an overview of the underlying complex and multifactorial causes and consequences of maternal undernutrition. This conceptual framework has been adapted based on the current understanding of the causes of child malnutrition [9–14] .

health and nutritional status prior to conception [24–26] . and child health and nutrition [37] . Collectively, women’s Women who experience interpersonal violence may also be health, nutrition, and wellbeing across the continuum of pre- at increased risk of poor pregnancy outcomes [27] . The im- conception through pregnancy are critical for ensuring posi- portance of a woman’s nutrition before pregnancy, especial- tive pregnancy and long-term outcomes for both the mother ly during adolescence and preconception, on infant and ma- and child. ternal outcomes is gaining recognition [28–31] ; and this con- nection is both through the direct effect on outcomes as well as indirectly though influencing a women’s nutritional status Importance of Maternal Nutritional Status during pregnancy. before and during Pregnancy Maternal short stature is a risk factor for caesarean delivery and complications at childbirth [32] . A woman’s height is a The nutritional and health status of women as they enter product of her poor nutritional status as a child and is an im- pregnancy may play a key role in placental function and sub- portant predictor of her own child’s health as well. For ex- sequent growth and development of the fetus [38, 39] . The ample, in India, maternal height has been associated with placenta regulates nutrient availability for fetal growth and ul- child mortality, growth failure, and anemia [33] . Likewise, oth- timately influences the long-term health of the newborn. er measures of maternal nutritional status, such as her body Periconceptional nutrition may also influence offspring health mass index (BMI) or weight gain during pregnancy, are associ- and cognitive outcomes by affecting the growth and develop- ated with adverse birth outcomes, such as LBW, PTB, and in- ment of the brain, liver, and pancreas during the first few trauterine growth restriction [30, 34–36] . As described in fur- weeks of pregnancy [29] . Animal studies have shown that fe- ther depth below, maternal anemia and micronutrient status tal growth and development are sensitive to maternal nutri- are likewise powerful determinants of pregnancy outcomes tion during implantation [38, 40] . Dietary restriction studies in

44 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 Table 1. Preconception nutrition interventions and impact on maternal and child health outcomes

Setting Design Impact First author [ref.], year

Mumbai, India RCT of micronutrient- Women with a BMI >21.5 kg/m2, who took the snack for at Potdar [49], and energy-dense snack least 90 days prior to conception, gave birth to heavier 2014 before and/or during babies (~113 g) when compared to those who received the pregnancy intervention only during pregnancy Vietnam RCT of preconception No differences in birth outcomes in the intent-to-treat Ramakrishnan weekly supplements analysis; however, birthweight was ~60 g higher for [50], 2016 containing multiple offspring born to women who received the weekly MM micronutrients, iron- supplement for at least 6 months compared to the other 2 folate, or folic acid groups (PRECONCEPT; NCT 1665378) India, Pakistan, Guatemala, Multisite RCT of lipid- Significant increases in mean birth length of offspring born Hambidge [51, and the Democratic based micronutrient to women who received lipid-based micronutrient 52], 2014, 2019 Republic of Congo supplement (WOMENS supplements daily for at least 3 months before conception First trial) through pregnancy when compared to those born to women who received only routine prenatal care

normal and overweight sheep have demonstrated the pro- idence based on intervention studies that have been con- gramming effects of periconceptional nutrition on fetal adi- ducted before and during pregnancy is summarized in the pose tissue development and regulation of IGF1R signaling following sections. pathway postnatally [41, 42] . Findings from the Dutch Famine Study have also documented alterations in epigenetic signatures among offspring born to women exposed to acute mal- Maternal Nutrition Interventions and Birth nutrition during the periconceptional period [43] . Micronutri- Outcomes ents, including iron, zinc, folic acid (FA), and other vitamins, contribute to genome-wide alterations and/or epigenetic In a systematic review that evaluated the role of nutrition in- modifications during the crucial period of organogenesis [29] . terventions or exposures that were measured before 12 weeks’ These changes influence subsequent outcomes, such as body gestation but did not continue through pregnancy, Ramak- composition and cognitive function [44, 45] . rishnan et al. [30] found that most studies were observational Evidence, primarily from observational studies, shows that and focused primarily on perinatal outcomes, including birth fetal growth during the first trimester is especially sensitive to defects, pregnancy loss, or stillbirths. The quality of the evi- preconceptional nutrition [38] . A systematic review by Young dence was also low to very low, with the exception of inter- et al. [4] has shown that preconception anemia was associ- vention trials that demonstrated the benefits of providing ated with an increased risk of LBW and small for gestational periconceptional FA to reduce the risk of birth defects, espe- age (SGA) births, while anemia in the first trimester of preg- cially neural tube defects [48] . More recently, a few random- nancy was associated with LBW, PTB, and neonatal mortality. ized controlled trials (RCTs) have evaluated the benefits of Studies have also demonstrated the role of maternal precon- preconception nutrition interventions on maternal and child ception nutrition on child linear growth from conception health outcomes as summarized in Table 1 [49–51] . In a trial through the child’s second birthday (the “first 1,000 days”) conducted in Mumbai, India, low-income urban women were [46, 47] . Women with a preconception weight less than 43 kg recruited prior to conception and randomized to receive a or a gestational weight gain less than 8 kg were around 3 micronutrient and energy-dense snack before and/or during times more likely to give birth to a SGA or LBW infant. Fur- pregnancy [49] . This study found that among women with a 2 thermore, women with preconception height less than 150 BMI > 21.5 kg/m , those who took the snack for at least 90 days cm or a weight less than 43 kg were at nearly twice the in- prior to conception gave birth to heavier babies (∼ 113 g) when creased risk of having a stunted child at age 2 years. The ev- compared to those who received the intervention only during

Undernutrition before and during Pregnancy and Reprint with permission from: 45 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 pregnancy; effects on offspring growth and development Another promising intervention are small-quantity lipid-based have not been reported. Ramakrishnan et al. [50] evaluated nutrient supplements that have shown improved birth weight the benefits of providing preconceptional weekly supple- (53.3 g) and birth length (0.24 cm) compared to IFA supplements containing multiple micronutrients (MMs), iron-folate ments [61] . (IFA), or FA in a large RCT (PRECONCEPT) that was conducted in rural Vietnam. All women who conceived received daily Maternal Nutrition and Offspring Growth and Body prenatal IFA supplements. Although there were no differenc- Composition es in birth outcomes in the intent-to-treat analysis, birth- To our knowledge, very few studies have examined the role weight was ∼ 60 g higher for offspring born to women who of preconception micronutrient status on later offspring received the weekly MM supplement for at least 6 months growth and body composition, including fat mass (FM), lean compared to the other 2 groups [50] . Finally, findings from the body mass, bone mineral content (BMC), and bone mineral WOMENS First trial, a large multisite RCT conducted in India, density. The PRECONCEPT trial showed differences in off- Pakistan, Guatemala, and the Democratic Republic of Congo, spring linear growth during the first 2 years of life. At age 2 showed significant increases in mean birth length of offspring years, children in the IFA group had significantly higher length- born to women who received lipid-based micronutrient sup- for-age z scores (LAZ; 0.14; 95% CI: 0.03, 0.26), reduced risk plements daily for at least 3 months preconception through of being stunted (0.87; 95% CI: 0.76, 0.99), and smaller decline pregnancy when compared to those born to women who re- in LAZ from birth (0.10; 95% CI: 0.04, 0.15) than the children ceived only routine prenatal care [52] . in the FA group. Similar trends were found for the children in In contrast to the dearth of evidence for preconception the MM group compared with the FA group for LAZ (0.10; 95% interventions, considerable evidence has accumulated over CI: 20.02, 0.22) and the risk of being stunted (0.88; 95% CI: the past few decades on the benefits of improving maternal 0.77, 1.01) [62] . Although data on the effect of preconception nutrition during pregnancy. Several evidence-based interven- nutrition on body composition are lacking, there is some evi- tions for improving maternal and child nutrition across the dence suggesting that micronutrient intakes during pregnan- lifecycle have been reviewed, including a range of approach- cy may affect later offspring body size and composition as es from population-level fortification, nutrition education, described below. and targeted supplementation for vulnerable populations [53] . Although prenatal IFA supplementation has been standard of care for over 50 years, recent evidence has demonstrated a Micronutrient intakes during promising impact of prenatal balanced energy protein supplements, MM supplements, and small-quantity lipid nutrient pregnancy may affect later supplements for improving birth outcomes. Balanced protein offspring body size and and energy supplements reduced the risk of stillbirth by 40% and of SGA by 21%, and mean birth weight was increased by composition 41 g [54] . Several recent reviews of prenatal MM supplements have demonstrated clear benefits for cost-effectively improving birth outcomes; thus, leading to calls for revised WHO Several studies have evaluated the effects of prenatal nutri- guidelines to support widescale adoption and replacement tion on offspring growth during early childhood and beyond. over traditional IFA supplementation programs [8, 55–60] . Most notably, follow-up studies of the food-based supplemen- MM supplementation in pregnancy reduced the risk of LBW tation trials that were conducted in the 1970s to 1980s have by 12–14%, PTB by 8–4%, and being born SGA by 8–3%, de- shown improved child growth and attained adult height among pending on the analytic approach used in a Cochrane Review the offspring, but many of these interventions were not restrict- meta-analysis versus an individual participant data meta- ed to the prenatal period [63] . Devakumar et al. [64] (2016) con- analysis [8, 55, 56] . Although some concerns about a potential ducted a systematic review of studies that included follow-up increase in the risk of neonatal mortality associated with MM data from 6 RCTs and found no differences in weight-for-age supplementation have been raised in the past, updated analy- z score (0.02; 95% CI: –0.03 to 0.07), height-for-age z score ses indicate no adverse risk. Results from the Smith et al. [56] (0.01; 95% CI: –0.04 to 0.06), or head circumference (0.11 cm; seminal paper on modifiers of the effect of prenatal MMs 95% CI: –0.03 to 0.26) among offspring born to women who ( Fig. 4) demonstrated improved survival of female offspring received antenatal MM supplements compared to routine IFA. and increased benefits of micronutrient supplementation Some of the limitations of these studies, however, are the varia- among infants born to undernourished or anemic mothers. tion in the age at follow-up and loss to follow-up.

46 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 a Stillbirth b Neonatal mortality c Infant mortality Infant sex Male Female Gestational age at enrolment <20 weeks 20 weeks Maternal adherence to regimen <95% adherence DGKHUHQFH Maternal age <20 years \HDUV Parity First birth Second+ birth Maternal underweight at enrolment BMI <18.5 kg/m2 %0,NJP2 Maternal stature Height <150 cm +HLJKWFP Maternal haemoglobin at enrolment Anaemic (haemoglobin >110 g/L) 1RQDQDHPLF KDHPRJORELQJ/ Maternal education None \HDUIRUPDOHGXFDWLRQ Skilled birth attendant Yes No Overall

0.5 0.75 1 1.25 1.5 0.5 0.75 1 1.25 1.5 0.5 0.75 1 1.25 1.5

d Low birthweight e Preterm birth f Small-for-gestational age Infant sex Male Female Gestational age at enrolment <20 weeks 20 weeks Maternal adherence to regimen <95% adherence DGKHUHQFH Maternal age <20 years \HDUV Parity First birth Second+ birth Maternal underweight at enrolment BMI <18.5 kg/m2 %0,NJP2 Maternal stature Height <150 cm +HLJKWFP Maternal haemoglobin at enrolment Anaemic (haemoglobin >110 g/L) 1RQDQDHPLF KDHPRJORELQJ/ Maternal education None \HDUIRUPDOHGXFDWLRQ Overall

0.6 0.7 0.8 0.9 1 1.1 1.2 0.6 0.7 0.8 0.9 1 1.1 1.2 0.6 0.7 0.8 0.9 1 1.1 1.2 Pooled relative risk with 95% CI

Fig. 4. Modifiers of the effects of prenatal MM supplementation on birth outcomes. Reproduced from Smith et al. [56] , 2017.

Undernutrition before and during Pregnancy and Reprint with permission from: 47 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 In Nepal, antenatal supplementation with FA, iron, and zinc countries in Asia and Africa, but important limitations includ- resulted in lower offspring adiposity as assessed by skinfold ed sample size/power and sensitivity of tests to assess men- thicknesses at age 6–8 years [65] . Maternal multivitamin use tal development in children under 2 years. Findings from the was also associated with a slower rate of FM accretion during PRECONCEPT trial showed that children in the IFA group had infancy compared to offspring of control women (non-users) improved motor development assessed by the Bayley Scales in the United States [66] . Regarding bone density, increased of Infant Development (BSID), especially fine motor develop- maternal intake of calcium-rich foods and higher folate status ment (IFA vs FA: 0.41; 95% CI: 0.05, 0.77), but there were no during mid-pregnancy were associated with greater offspring significant differences in Bayley mental or language scores BMC and bone mineral density at age 6 years in India [67] . [62] . Both early nutritional status and home learning environ- Findings from a Dutch cohort study (median age, 6 years) ment were also associated with child development in this showed that vitamin B12 status sample [79] . Preliminary results during the first trimester was as- from the most recent follow-up sociated with greater offspring As women may not realize that was conducted when the BMC, adjusted for total bone offspring were aged 6–7 years area [68] . Overall, there is a lack they are pregnant during the show promising differences by of consistent and robust data on ﬁrst 1–2 months, optimal treatment group. The Wechsler the influence of maternal mi- Intelligence Scale for Children cronutrient intake, either before nutrition prior to pregnancy is IVth edition (WISC-IV ® ) was or during pregnancy, on off- critical used to measure global intelli- spring body composition. Addi- gence, verbal comprehension, tionally, the effects of precon- memory, and executive func- ceptional micronutrient intakes may only emerge during the tioning and compared to the FA group; offspring in the MM pre-pubertal years of 9–14 years when rapid adipose tissue group had higher IQ scores as well as working memory and deposition occurs [69] . Potential mechanisms include epi- processing speed. These differences were also stronger genetic modifications that may occur early in pregnancy and among the subgroup of children born to women who re- influence offspring body composition in late childhood. For ceived the preconception intervention for at least 6 months, example, hypermethylation of the umbilical retinoic acid X- and there is also evidence of effect modification by baseline receptor, a key regulator of adipocyte proliferation, has been socioeconomic status (SES), indicating that MM attenuated associated with increased offspring FM at 9 years of age [70] . the effects of SES on perceptual reasoning and IQ [80] . Im- portant strengths of this study include the low rates of attri-

Maternal Nutrition before and during Pregnancy Is Important tion (< 10%) and that the groups were balanced on several for Brain Development and Cognitive Functioning baseline characteristics including SES and maternal educa- Brain development begins shortly after conception [71, 72] . tion. Most of the structural features of the brain appear during the Two large studies, from Nepal and Indonesia, have also embryonic period (about the first 8 weeks after fertilization); documented the impact of maternal micronutrient supple- these structures then continue to grow and develop through- mentation on cognitive functioning in school-age children out pregnancy [71, 72] . Iron, in particular, plays an important [81, 82] . In Nepal, working memory, inhibitory control, and role in early fetal brain development [73] , and other micronu- fine motor functioning at age 7–9 years were positively as- trients, such as vitamin B6 , B12 , FA, and zinc, are influential [74] . sociated with prenatal IFA supplementation [81] . In Indonesia,

FA, vitamin B12 , and zinc participate in brain DNA and RNA MM supplementation that began early in pregnancy had long- synthesis, which begins early in gestation [75] . Vitamin B12 has term benefits for cognitive development at age 9–12 years also been shown to affect myelination, which begins during compared to IFA, including positive associations with proce- gestation and may affect cognitive functioning [76, 77] . As dural memory and general intellectual ability (for children of women may not realize they are pregnant during the first 1–2 anemic mothers) [82] . This study also noted the importance months, optimal nutrition prior to pregnancy is critical. of measuring socio-environmental determinants, such as A systematic review by Larson and Yousafzai [78] that in- home environment and maternal depression, which were cluded 10 prenatal trials that evaluated a variety of nutrition strongly associated with school-age cognitive, motor, and interventions (macro- and/or micronutrients) did not find a socio-emotional scores. However, concerns about the limit- significant impact on young child mental development. Most ed findings and null results from follow-up studies in other of these studies were conducted in low- to middle-income settings like China and Tanzania have been raised, and further

48 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 Table 2. Program priority areas and research gaps for improving women’s nutrition before and during pregnancy

Key priority areas for research and programs

⚫ Program prioritization is needed to improve access and counseling on family planning (delayed age at first pregnancy, inter-pregnancy interval) and preconception care ⚫ Additional research is required to understand the long-term effects of periconceptional nutritional supplementation on later cognitive outcomes, including aspects of intellectual functioning, executive function, and academic achievement ⚫ Greater research and program focus on implementation science is required to develop effective strategies to scale up evidence-based maternal nutrition interventions ⚫ Political and program support is needed for the promotion and scale up of multiple micronutrient supplement programs among women ⚫ Research on long-term impact of multiple micronutrient supplementation during pregnancy ⚫ Strong formative research is needed to contextualize and develop multiple micronutrient supplementation programs to help overcome prior barriers with iron and folic acid programs ⚫ An enhanced program focus on equity is required to ensure programs are reaching vulnerable and marginalized communities in order to decrease global maternal undernutrition disparities

research is needed to better understand the long-term health women’s nutrition to the pregnancy window may limit the ef- effects on maternal and child health [60, 83] . fectiveness of interventions. This is particularly critical in set- Finally, long-term studies from Guatemala have demon- tings of severe food insecurity with high rates of anemia, mi- strated the benefits of nutritional supplementation during the cronutrient deficiencies, and undernutrition and where wom- first 1,000 days of life on cognitive outcomes in later child- en may not enter antenatal care until into the second or third hood and adolescence, effects which were considerably larg- trimester. Simply put, maternal nutrition interventions in these er than those seen in early childhood [84–88] . At ages 3–7 settings may be too little, too late . Table 2 outlines several

years, there was only a small effect (< 0.2 standard deviation) program priorities areas and research gaps for improving of the Atole-Fresco differences compared to medium to large women’s nutrition. While efforts to improve timely and qual- effects (0.6 standard deviation) during adolescence/young ity antenatal care that includes interventions that effectively adulthood (11–26 years). Although the findings are mixed for address the nutrient gaps during pregnancy need strengthen- the influence of prenatal docosahexaenoic acid (DHA) on ing, greater program prioritization is needed to reach women cognitive outcomes, especially during the first 2 years of life earlier to provide preconception care and family planning ser- [89] , there is evidence of a small but significant effect of pre- vices. Programs focused on school-age or adolescent girls natal DHA on measures of attention in the offspring at age 5 have also been identified as promising strategies for reaching years in Mexico, and higher global scores of intelligence women earlier. A notable gap in the field includes research among those from poorer home environments when com- examining the long-term effects of periconceptional nutri- pared to those in the placebo group [90] . Results from the tional supplementation on later cognitive outcomes, includ- MAL-ED longitudinal cohort corroborate the importance of a ing aspects of intellectual functioning, executive function, and nurturing home environment, adequate micronutrient status, academic achievement. Examining these effects during early and maternal reasoning on child cognitive function at age 5 adolescence is particularly important as effects of early-life years [91] . These studies highlight the importance of assessing experiences may become more pronounced at later ages. the impact of maternal nutrition interventions on cognitive Further, the role of improving maternal nutrition right before outcomes in later childhood and adolescence. and during the periconceptional period, along with the home environment, on later cognitive outcomes can provide much needed information on the relative importance of early nutri- Priority Areas and Research Gaps for Improving tion and socio-environmental factors on cognitive outcomes. Women’s Nutrition before and during Pregnancy During pregnancy, we have several evidence-based maternal nutrition interventions. However, while it is clear we Despite recent progress and shifts in global agenda, women’s know what to do , challenges remain in knowing how to do it nutrition has historically not received sufficient political or at scale? Research and program focus on implementation sci- program prioritization. Furthermore, narrowing the focus of ence is required to develop effective strategies to scale up

Undernutrition before and during Pregnancy and Reprint with permission from: 49 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 evidence-based maternal nutrition interventions. For exam- quired to ensure programs are reaching vulnerable and mar- ple, providing MM supplements during pregnancy is a highly ginalized communities in order to decrease global maternal effective strategy for improving birth outcomes; however, undernutrition disparities. there is limited national policy adoption and evidence of impact at scale. Further political and program advocacy is needed for the promotion and scale up of multiple micronutrient Conflict of Interest Statement supplement programs among women. In addition, strong for- The writing of this article was supported by Nestlé Nutrition Institute mative research is needed to contextualize and develop MM and the authors declare no other conflicts of interest. supplementation programs to help overcome prior barriers with IFA programs. Finally, an enhanced focus on equity is re-

References

1 Collaboration NC; NCD Risk Factor Collaboration (NCD-RisC). 11 Smith LC, Ramakrishnan U, Ndiaye A, Haddad L, Martorell R. The Trends in adult body-mass index in 200 countries from 1975 to Importance of Women’s status for Child Nutrition in Developing 2014: a pooled analysis of 1698 population-based measurement Countries. Research Report 131. International Food Policy Re-

studies with 19.2 million participants. Lancet . 2016 Apr; 387(10026): search Institute; 2003. 1377–96. 12 Young M, Ramakrishnan U. Adolescent girls and women’s nutri- 2 Matos UR, Mesenburg MA, Victora CG. Socioeconomic inequali- tional status in India: A critical review of current understanding, ties in the prevalence of underweight, overweight, and obesity gaps and challenges. India Health Report: Nutrition 2016. New among women aged 20–49 in low- and middle-income coun- Delhi, India: Public Health Foundation of India; 2016.

tries. Int J Obes (London). 2020 Mar; 44(3): 609–16. 13 Cheng JJ, Schuster-Wallace CJ, Watt S, Newbold BK, Mente A. An 3 Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis ecological quantification of the relationships between water, san- M, et al.; Maternal and Child Nutrition Study Group. Maternal and itation and infant, child, and maternal mortality. Environ Health.

child undernutrition and overweight in low-income and middle- 2012 Jan; 11: 4.

income countries. Lancet . 2013 Aug; 382(9890): 427–51. 14 Kayser GL, Rao N, Jose R, Raj A. Water, sanitation and hygiene: 4 Young MF, Oaks BM, Tandon S, Martorell R, Dewey KG, Wendt AS. measuring gender equality and empowerment. Bull World Health

Maternal hemoglobin concentrations across pregnancy and ma- Organ. 2019; 97(6): 438–40. ternal and child health: a systematic review and meta-analysis. 15 Merchant AT, Jones C, Kiure A, Kupka R, Fitzmaurice G, Herrera Ann N Y Acad Sci. 2019 Aug; 1450(1): 47–68. MG, et al. Water and sanitation associated with improved child

5 Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, growth. Eur J Clin Nutr. 2003 Dec; 57(12): 1562–8. Branca F, et al. Global, regional, and national trends in haemoglo- 16 World Health Organization; UNICEF. Progress on drinking water bin concentration and prevalence of total and severe anaemia in and sanitation: Joint Monitoring Programme update 2012. WHO, children and pregnant and non-pregnant women for 1995–2011: UNICEF; 2012. a systematic analysis of population-representative data. Lancet

Glob Health. 2013 Jul; 1(1):e16–25. 17 Inter-agency Task Force on Gender and Water (GWTF). Gender, Water and Sanitation: A Policy Brief. UN-Water Task Force on 6 Petry N, Olofin I, Hurrell RF, Boy E, Wirth JP, Moursi M, et al. The Gender and Water; 2006. Proportion of Anemia Associated with Iron Deficiency in Low, Me- dium, and High Human Development Index Countries: A System- 18 Pratley P. Associations between quantitative measures of wom-

atic Analysis of National Surveys. Nutrients . 2016 Nov; 8(11): 8. en’s empowerment and access to care and health status for mothers and their children: A systematic review of evidence from the 7 World Health Organization. World Health Report 2000. Geneva:

developing world. Soc Sci Med . 2016 Nov; 169: 119–31. WHO; 2000. 19 FAO, IFAD, UNICEF, WFP, WHO. The State of Food Security and 8 Bourassa MW, Osendarp SJM, Adu-Afarwuah S, Ahmed S, Ajello C, Nutrition in the World 2017. Building resilience for peace and food Bergeron G, et al. Review of the evidence regarding the use of security. Rome: FAO; 2017. Available from: http://www.fao.org/3/ antenatal multiple micronutrient supplementation in low- and a-i7695e.pdf middle-income countries. Ann N Y Acad Sci. 2019 May; 1444(1): 6–21. 20 Wang DD, Li Y, Afshin A, Springmann M, Mozaffarian D, Stampfer MJ, et al. Global Improvement in Dietary Quality Could Lead to 9 Black RE, Allen LH, Bhutta ZA, Caulfield LE, de Onis M, Ezzati M, et

Substantial Reduction in Premature Death. J Nutr . 2019 Jun; al.; Maternal and Child Undernutrition Study Group. Maternal and

149(6): 1065–74. child undernutrition: global and regional exposures and health

consequences. Lancet . 2008 Jan; 371(9608): 243–60. 21 Engle PL, Menon P, Haddad L. Care and nutrition: Concepts and

measurement. World Dev. 1999 Aug; 27(8): 1309–37. 10 World Health Organization. Physical status: the use and interpre- tation of anthropometry, report of a WHO expert committee. 22 Christian P, Smith ER. Adolescent Undernutrition: Global Burden, WHO Technical Report Series, No. 854. Geneva: World Health Or- Physiology, and Nutritional Risks. Ann Nutr Metab. 2018; 72(4): ganization; 2005. 316–28.

50 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 23 Ramakrishnan U, Lowe A, Vir S, Kumar S, Mohanraj R, Chaturvedi 39 Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, Prentice AM, A, et al. Public health interventions, barriers, and opportunities for Stephenson J, et al. Origins of lifetime health around the time of

improving maternal nutrition in India. Food Nutr Bull. 2012 Jun; conception: causes and consequences. Lancet. 2018 May;

33(2 Suppl):S71–92. 391(10132): 1842–52. 24 Wendt A, Gibbs CM, Peters S, Hogue CJ. Impact of increasing 40 Wu G, Imhoff-Kunsch B, Girard AW. Biological mechanisms for inter-pregnancy interval on maternal and infant health. Paediatr nutritional regulation of maternal health and fetal development.

Perinat Epidemiol. 2012 Jul; 26 Suppl 1: 239–58. Paediatr Perinat Epidemiol. 2012 Jul; 26 Suppl 1: 4–26. 25 Ahrens KA, Nelson H, Stidd RL, Moskosky S, Hutcheon JA. Short 41 Zhang S, Morrison JL, Gill A, Rattanatray L, MacLaughlin SM, Klee- interpregnancy intervals and adverse perinatal outcomes in high- mann D, et al. Maternal dietary restriction during the periconcep- resource settings: An updated systematic review. Paediatr Perinat tional period in normal-weight or obese ewes results in adreno-

Epidemiol. 2019 Jan; 33(1):O25–O47. cortical hypertrophy, an up-regulation of the JAK/STAT and down-regulation of the IGF1R signaling pathways in the adrenal 26 Ramakrishnan U. Maternal nutrition and birth outcomes. In: de of the postnatal lamb. Endocrinology . 2013 Dec; 154(12): 4650– Pee S, Taren D, Bloem MW, editors. Nutrition and Health in a De- 62. veloping World. Springer; 2017. pp. 487–502. 42 Symonds ME, Pearce S, Bispham J, Gardner DS, Stephenson T. 27 Stöckl H, Filippi V, Watts C, Mbwambo JK. Induced abortion, preg- Timing of nutrient restriction and programming of fetal adipose nancy loss and intimate partner violence in Tanzania: a population tissue development. Proc Nutr Soc . 2004 Aug; 63(3): 397–403.

based study. BMC Pregnancy Childbirth. 2012 Mar; 12(1): 12. 43 Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, et al. 28 Lim SS, Dandona L, Hoisington JA, James SL, Hogan MC, Gakidou DNA methylation signatures link prenatal famine exposure to E. India’s Janani Suraksha Yojana, a conditional cash transfer pro- growth and metabolism. Nat Commun. 2014 Nov; 5: 5592. gramme to increase births in health facilities: an impact evalua-

tion. Lancet . 2010 Jun; 375(9730): 2009–23. 44 Waterland RA, Michels KB. Epigenetic epidemiology of the devel-

opmental origins hypothesis. Annu Rev Nutr. 2007; 27(1): 363–88. 29 Cetin I, Berti C, Calabrese S. Role of micronutrients in the pericon-

ceptional period. Hum Reprod Update. 2010 Jan-Feb; 16(1): 80– 45 Chandak GR, Silver MJ, Saffari A, Lillycrop KA, Shrestha S, Sahariah 95. SA, et al. Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children’s 30 Ramakrishnan U, Grant F, Goldenberg T, Zongrone A, Martorell R. health in India and Sub-Saharan Africa. BMC Nutr. 2017 Dec; 3(1): Effect of women’s nutrition before and during early pregnancy on 81. maternal and infant outcomes: a systematic review. Paediatr Per-

inat Epidemiol. 2012 Jul; 26 Suppl 1: 285–301. 46 Young MF, Nguyen PH, Gonzalez Casanova I, Addo OY, Tran LM, Nguyen S, et al. Role of maternal preconception nutrition on off- 31 Scholl TO. Maternal nutrition before and during pregnancy. Nestle spring growth and risk of stunting across the first 1000 days in

Nutr Workshop Ser Pediatr Program. 2008; 61: 79–89. Vietnam: A prospective cohort study. PLoS One. 2018; 32 Ronsmans C, Holtz S, Stanton C. Socioeconomic differentials in 13(8):e0203201. caesarean rates in developing countries: a retrospective analysis. 47 Young MF, Nguyen PH, Addo OY, Hao W, Nguyen H, Pham H, et

Lancet. 2006 Oct; 368(9546): 1516–23. al. The relative influence of maternal nutritional status before and 33 Subramanian SV, Ackerson LK, Davey Smith G, John NA. Associa- during pregnancy on birth outcomes in Vietnam. Eur J Obstet Gy-

tion of maternal height with child mortality, anthropometric fail- necol Reprod Biol. 2015 Nov; 194: 223–7.

ure, and anemia in India. JAMA . 2009 Apr; 301(16): 1691–701. 48 De-Regil LM, Pena-Rosas JP, Fernandez-Gaxiola AC, Rayco-So- 34 Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al.; lon P. Effects and safety of periconceptional oral folate supple- Maternal and Child Undernutrition Study Group. Maternal and mentation for preventing birth defects. Cochrane Database Syst child undernutrition: consequences for adult health and human Rev. 2015(12):CD007950.

capital. Lancet . 2008 Jan; 371(9609): 340–57. 49 Potdar RD, Sahariah SA, Gandhi M, Kehoe SH, Brown N, Sane H, et 35 Han Z, Mulla S, Beyene J, Liao G, McDonald SD; Knowledge Syn- al. Improving women’s diet quality preconceptionally and during thesis Group. Maternal underweight and the risk of preterm birth gestation: effects on birth weight and prevalence of low birth and low birth weight: a systematic review and meta-analyses. Int weight—a randomized controlled efficacy trial in India (Mumbai

Maternal Nutrition Project). Am J Clin Nutr. 2014 Nov; 100(5): J Epidemiol. 2011 Feb; 40(1): 65–101. 1257–68. 36 Kelly A, Kevany J, de Onis M, Shah PM. A WHO Collaborative Study of Maternal Anthropometry and Pregnancy Outcomes. Int J Gyn- 50 Ramakrishnan U, Nguyen PH, Gonzalez-Casanova I, Pham H, Hao W, Nguyen H, et al. Neither Preconceptional Weekly Multiple Mi- aecol Obstet. 1996 Jun; 53(3): 219–33. cronutrient nor Iron-Folic Acid Supplements Affect Birth Size and 37 Mousa A, Naqash A, Lim S. Macronutrient and Micronutrient Intake Gestational Age Compared with a Folic Acid Supplement Alone in during Pregnancy: An Overview of Recent Evidence. Nutrients. Rural Vietnamese Women: A Randomized Controlled Trial. J Nutr .

2019 Feb; 11(2): 443. 2016; 146(7): 1445S–52S. 38 King JC. A Summary of Pathways or Mechanisms Linking Precon- 51 Hambidge KM, Krebs NF, Westcott JE, Garces A, Goudar SS, Kod- ception Maternal Nutrition with Birth Outcomes. J Nutr. 2016 Jul; kany BS, et al. Preconception maternal nutrition: a multi-site ran-

146(7): 1437S–44S. domized controlled trial. BMC Pregnancy Childbirth. 2014; 14: 111.

Undernutrition before and during Pregnancy and Reprint with permission from: 51 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 52 Hambidge KM, Westcott JE, Garces A, Figueroa L, Goudar SS, 66 Sauder KA, Starling AP, Shapiro AL, Kaar JL, Ringham BM, Glueck Dhaded SM, et al. A multicountry randomized controlled trial of DH, et al. Exploring the association between maternal prenatal comprehensive maternal nutrition supplementation initiated be- multivitamin use and early infant growth: The Healthy Start Study.

fore conception: the Women First trial. Am J Clin Nutr. 2019; Pediatr Obes. 2016; 11(5): 434–41.

109(2): 457–69. 67 Ganpule A, Yajnik CS, Fall CH, Rao S, Fisher DJ, Kanade A, et al. 53 Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al.; Bone mass in Indian children—relationships to maternal nutrition- Lancet Nutrition Interventions Review Group, the Maternal and al status and diet during pregnancy: the Pune Maternal Nutrition

Child Nutrition Study Group. Evidence-based interventions for Study. J Clin Endocrinol Metab. 2006 Aug; 91(8): 2994–3001. improvement of maternal and child nutrition: what can be done 68 Heppe DH, Medina-Gomez C, Hofman A, Franco OH, Rivadenei-

and at what cost? Lancet . 2013 Aug; 382(9890): 452–77. ra F, Jaddoe VW. Maternal first-trimester diet and childhood bone

54 Ota E, Hori H, Mori R, Tobe-Gai R, Farrar D. Antenatal dietary edu- mass: the Generation R Study. Am J Clin Nutr . 2013 Jul; 98(1): cation and supplementation to increase energy and protein in- 224–32. take. Cochrane Database Syst Rev. 2015 Jun;(6):CD000032. 69 Baum D, Beck RQ, Hammer LD, Brasel JA, Greenwood MR. Adi-

55 Haider BA, Bhutta ZA. Multiple-micronutrient supplementation for pose tissue thymidine kinase activity in man. Pediatr Res. 1986 Feb;

women during pregnancy. Cochrane Database Syst Rev. 2017; 20(2): 118–21. 4:CD004905. 70 Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, 56 Smith ER, Shankar AH, Wu LS, Aboud S, Adu-Afarwuah S, Ali H, et McLean C, et al. Epigenetic gene promoter methylation at birth is

al. Modifiers of the effect of maternal multiple micronutrient sup- associated with child's later adiposity. Diabetes . 2011; 60(5): 1528– plementation on stillbirth, birth outcomes, and infant mortality: a 34. meta-analysis of individual patient data from 17 randomised trials 71 Marsh R, Gerber AJ, Peterson BS. Neuroimaging studies of normal in low-income and middle-income countries. Lancet Glob Health. brain development and their relevance for understanding child-

2017 Nov; 5(11):e1090–100. hood neuropsychiatric disorders. J Am Acad Child Adolesc Psy-

57 Kashi B, M Godin C, Kurzawa ZA, Verney AM, Busch-Hallen JF, De- chiatry . 2008; 47(11): 1233–51. Regil LM. Multiple Micronutrient Supplements Are More Cost-ef- 72 O’Rahilly R, Müller F. Significant features in the early prenatal de- fective Than Iron and Folic Acid: Modeling Results from 3 High-

velopment of the human brain. Ann Anat . 2008; 190(2): 105–18.

Burden Asian Countries. J Nutr . 2019 Jul; 149(7): 1222–9. 73 Georgieff MK. The role of iron in neurodevelopment: fetal iron 58 Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient deficiency and the developing hippocampus. Biochem Soc Trans. supplementation for women during pregnancy. Cochrane Data-

2008 Dec; 36(Pt 6): 1267–71.

base Syst Rev. 2019; 3:CD004905. 74 Stephenson J, Heslehurst N, Hall J, Schoenaker D, Hutchinson J, 59 Sudfeld CR, Smith ER. New Evidence Should Inform WHO Guide- Cade JE, et al. Before the beginning: nutrition and lifestyle in the lines on Multiple Micronutrient Supplementation in Pregnancy. J preconception period and its importance for future health. Lancet .

Nutr . 2019; 149(3): 359–61.

2018; 391(10132): 1830–41. 60 Bourassa MW, Osendarp SJM, Adu-Afarwuah S, Ahmed S, Ajello C, 75 Pfeiffer CC, Braverman ER. Zinc, the brain and behavior. Biol Psy- Bergeron G, et al. Antenatal multiple micronutrient supplementa-

chiatry . 1982 Apr; 17(4): 513–32. tion: call to action for change in recommendation. Ann N Y Acad

Sci. 2020; 1465(1): 5–7. 76 Black MM. Effects of vitamin B12 and folate deficiency on brain

development in children. Food Nutr Bull . 2008; 29(2 Suppl):S126–31. 61 Das JK, Hoodbhoy Z, Salam RA, Bhutta AZ, Valenzuela-Rubio NG, Weise Prinzo Z, et al. Lipid-based nutrient supplements for mater- 77 Deshmukh U, Katre P, Yajnik CS. Influence of maternal vitamin B12 nal, birth, and infant developmental outcomes. Cochrane Data- and folate on growth and insulin resistance in the offspring. Nes-

base Syst Rev. 2018; 8:CD012610. tle Nutr Inst Workshop Ser. 2013; 74: 145–54. 62 Nguyen PH, Gonzalez-Casanova I, Young MF, Truong TV, Hoang 78 Larson LM, Yousafzai AK. A meta-analysis of nutrition interven- H, Nguyen H, et al. Preconception Micronutrient Supplementation tions on mental development of children under-two in low- and

with Iron and Folic Acid Compared with Folic Acid Alone Affects middle-income countries. Matern Child Nutr. 2017 Jan; Linear Growth and Fine Motor Development at 2 Years of Age: A 13(1):e12229.

Randomized Controlled Trial in Vietnam. J Nutr . 2017 Aug; 147(8): 1593–601. 79 Nguyen PH, DiGirolamo AM, Gonzalez-Casanova I, Young M, Kim N, Nguyen S, et al. Influences of early child nutritional status and 63 Ramakrishnan U. Impact of Nutrition on the Next Generation: The home learning environment on child development in Vietnam.

INCAP Longitudinal Study. Food Nutr Bull. 2020; 41(1 suppl):S50–8. Matern Child Nutr. 2018 Jan; 14(1):e12468. 64 Devakumar D, Fall CH, Sachdev HS, Margetts BM, Osmond C, 80 Nguyen P, Young M, Khuong L, Duong TH, Nguyen HC, Truong Wells JC, et al. Maternal antenatal multiple micronutrient supple- TV, et al. Preconception Micronutrient Supplementation Positive- mentation for long-term health benefits in children: a systematic ly Affects Child Development at 6 Years of Age: A Randomized

review and meta-analysis. BMC Med. 2016; 14: 90. Controlled Trial in Vietnam. Curr Dev Nutr. 2020 Jun; 4(Suppl 2): 876. 65 Stewart CP, Christian P, LeClerq SC, West KP, Jr., Khatry SK. Ante- natal supplementation with folic acid + iron + zinc improves linear growth and reduces peripheral adiposity in school-age children in

rural Nepal. Am J Clin Nutr. 2009; 90(1): 132–40.

52 Reprint with permission from: Young/Ramakrishnan Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595 81 Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole 87 Pollitt E, Gorman KS, Engle PL, Rivera JA, Martorell R. Nutrition in PM, et al. Prenatal micronutrient supplementation and intellec- early life and the fulfillment of intellectual potential. J Nutr. 1995

tual and motor function in early school-aged children in Nepal. Apr; 125(4 Suppl): 1111S–8S.

JAMA. 2010 Dec; 304(24): 2716–23. 88 DiGirolamo AM, Ochaeta L, Flores RM. Early Childhood Nutrition 82 Prado EL, Sebayang SK, Apriatni M, Adawiyah SR, Hidayati N, Is- and Cognitive Functioning in Childhood and Adolescence. Food

lamiyah A, et al. Maternal multiple micronutrient supplementation Nutr Bull. 2020 Jun; 41(1_suppl suppl):S31–40. and other biomedical and socioenvironmental influences on chil- 89 Best KP, Goersall J, Makrides M. Prenatal nutritional strategies to dren’s cognition at age 9-12 years in Indonesia: follow-up of the reduce the risk of preterm birth. Ann Nutr Metab . doi: SUMMIT randomised trial. Lancet Glob Health. 2017 Feb; 5(2):e217– 10.1159/000509901. 28. 90 Ramakrishnan U, Gonzalez-Casanova I, Schnaas L, DiGirolamo A, 83 Devakumar D, Osrin D, Sachdev HS, Prost A. Antenatal multiple Quezada AD, Pallo BC, et al. Prenatal supplementation with DHA micronutrient supplementation: where are the long-term bene- improves attention at 5 y of age: a randomized controlled trial. Am fits? Ann N Y Acad Sci. 2020 Apr; 1465(1): 8–9.

J Clin Nutr. 2016 Oct; 104(4): 1075–82. 84 Pollitt E, Gorman KS, Engle PL, Martorell R, Rivera J. Early supple- 91 McCormick BJJ, Richard SA, Caulfield LE, Pendergast LL, Seidman mentary feeding and cognition: effects over two decades. Monogr JC, Koshy B, et al. Early Life Child Micronutrient Status, Maternal Soc Res Child Dev. 1993; 58(7): 1–99. Reasoning, and a Nurturing Household Environment have Persis- 85 Martorell R. Overview of long-term nutrition intervention studies tent Influences on Child Cognitive Development at Age 5 years:

in Guatemala, 1968-1989. Food Nutr Bull. 1993; 14(3): 270–7. Results from MAL-ED. J Nutr . 2019 Aug; 149(8): 1460–9. 86 Martorell R. Results and implications of the INCAP follow-up 92 Ritchie H, Roser M. Micronutrient deficiency. Our World in Data.

study. J Nutr . 1995 Apr; 125(4 Suppl): 1127S–38S. 2017 [cited 2020 July 10]. Available from: https://ourworldindata. org/micronutrient-deficiency

Undernutrition before and during Pregnancy and Reprint with permission from: 53 Child Outcomes Ann Nutr Metab 2020;76(suppl 3):41–53 DOI: 10.1159/000510595