Indigenous Nutritional Supplements for Pregnancy to Improve Resilience in Environmental Heat (INSPIRE)

The purpose of this study is to learn whether a simple, traditional, and balanced meal made from local foods, eaten once a day during pregnancy, can help women in rural Pakistan stay healthier in hot weather and give birth to healthier babies. Climate change has made heat a serious challenge for pregnant women, especially in areas with limited resources. This study will explore whether an indigenous meal that is culturally acceptable and easy to prepare can improve resilience to heat stress and support better outcomes for both mothers and newborns.

The study will focus on two main questions:

• Can this daily balanced meal reduce the harmful effects of heat stress during pregnancy?
• Does it improve newborn health, especially birth weight?

Researchers will compare women who eat the balanced local meal every day with women who continue their usual meals. They will check changes in women's health, levels of key vitamins and nutrients, and their babies' birth outcomes.

During the study, participants will:

• Either eat the balanced local meal daily or continue their usual meals.
• Share information on their health, diet, and heat exposure.
• Provide small samples, such as blood and stool, to study nutrient levels and gut health.
• Have their newborns' health and growth measured at birth.

Study Overview

• Status: Not yet recruiting
• Conditions: Pregnancy; Heat Stress; Nutrition Status; Women of Reproductive Age
• Intervention / Treatment: Dietary supplement: Indigenous Balanced Diet Arm

Detailed Description

This study will use a quasi-experimental design to study if the effects of an indigenous heat-mitigating balanced dietary intervention on maternal health and neonatal development when implemented from preconception to delivery in a region with high temperatures.

The study will recruit 292 women of reproductive age who plan to become pregnant and assign them to either the intervention group or the comparison group in a 1:1 ratio. The intervention group will receive one customized indigenous heat-mitigating balanced diet as daily lunch meal (~1,000 kilocalories). The comparison group will continue their usual dietary practices while receive routine antenatal care and dietary counseling services according to national guidelines.

The intervention diet plans have been designed through review of dietary recommendations and published evidence, combined with community consultations to ensure feasibility and cultural acceptability. The food choices were established according to three criteria which required foods to have high nutrient content and be affordable and accessible within the local area. The meal composition includes whole grains, lentils, legumes, green leafy vegetables, dairy products, fermented foods, fish, and other culturally acceptable animal-source foods. A 14-day rotating menu will be implemented. The intervention will begin at least one month prior to conception and continue until delivery.

Meals will be prepared in kitchen in field site's office set up specially for meals preparation. Local chefs will be hired and counselled to prepare meals ensuring proper hygiene and following study's diet plans. Study data collectors will distribute meals to the participants. The team will use attendance records, intervention adherence forms, telephone follow-up and home visits to monitor intervention delivery. The team will organize home delivery services when they become essential.

The research team will evaluate maternal health at the end of each trimester starting from the time of conception until the end of pregnancy. Data will be collected through three different methods which include anthropometer, vitals assessments and testing blood samples for hemoglobin levels using point of care testing device (HemoCue 301+) and specific micronutrients & inflammatory markers (Vitamin A, D, B9, B12, Zinc, Ferritin and CRP). The research team will collect stool samples to investigate gut microbiome composition through molecular techniques. The study will use weather stations, thermal drone cameras and wearable devices (FitBit) to measure heat exposure while linking those measurements to local weather patterns.

At delivery, neonatal anthropometric measurements will be obtained using standardized procedures. Study staff will collect cord blood samples which will then undergo biomarker analysis. Moreover, placental tissues will be collected for both gross examination and transcriptomic analysis.

For safety purposes, all individuals will be monitored carefully for food allergies by conducting regular assessments and establishing health facility connections to treat any medical complications. The study allows participants to join voluntarily while they maintain their right to leave at any moment without losing access to standard medical treatment.

The study has received ethical approval from the Aga Khan University Ethical Review Committee (Reference: 2024-10697-3239) and the National Bioethics Committee of Pakistan (Reference: 4-87/NBCR-1220/24-25/836). Written informed consent will be obtained prior to enrollment. Data will be managed in accordance with institutional confidentiality and data protection policies.

• Study Type: Interventional
• Enrollment (Estimated): 292
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Junaid Iqbal, PhD; Phone Number: +923353189185; Email: junaid.iqbal@aku.edu
• Study Contact Backup: Name: Kehkashan Begum Hussain, MS; Phone Number: +923368906517; Email: kehkashan.begum@aku.edu

Study Locations

• Pakistan
  • Karachi, Pakistan, 74800
    • Aga Khan University
    • Contact: Junaid Iqbal, PhD; Phone Number: 00922134861648; Email: junaid.iqbal@aku.edu
    • Contact: Kehkashan Begum, MS; Phone Number: 00922134864088; Email: kehkashan.begum@aku.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Women aged 18-45 years belonging to a low to middle socioeconomic status, residing in Mithi, Districts in Sindh.
2. Planning to conceive within the study time frame and expect to become pregnant within four months of starting nutritional intervention.
3. Women who confirm their pregnancy during the first trimester i.e., before 8 weeks of gestational age.

Exclusion Criteria:

1. Women using long-lasting contraceptives such as IUDs, implants, and injectable methods like Depo-Provera.
2. Women with a history of multiple miscarriage or stillbirths.
3. Women with known chronic diseases, such as cardiovascular disorders, hepatic disorders, renal disorders, and infectious diseases.
4. Women suffering from severe malnutrition (WHO: Underweight i.e., having BMI < 16 Kg/m2 or obese having BMI ≥ 30 Kg/m2).
5. Women having severe anemia (WHO: Severe anemia i.e., Hb < 7g/dL).
6. Women currently enrolled in BISP supplementation programs or taking any supplements other than iron and folic acid (IFA) will be excluded from the study.
7. Those who do not become pregnant within three months of supplementation during pre-conception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Indigenous Balanced Diet Arm; Participants in this arm will receive minimally modified culturally-tailored indigenous heat-mitigating balanced diet as once a day meal starting from at least one month before conception and throughout the pregnancy till delivery.	Dietary supplement: Indigenous Balanced Diet Arm; The uniqueness of this intervention lies in its culturally-preservative approach, its novel target of heat stress, its timing (preconception), and its integrated process (nutritionist collaboration + overall dietary counseling). It specifically targets heat resilience in pregnancy through a holistic approach of adapting dietary intervention as mitigating strategy for providing resilience to heat stress and evaluating key hypothesized pathways responsible for combating adverse pregnancy outcomes by this intervention.
No Intervention: Usual Diet Arm; Pregnant women in this arm will continue with their usual diet, and receives standard antenatal care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in proportion of neonates with low Weight-for-Gestational-Age Z-score (WGAZ< -2 SD) at birth between intervention and control arms.	Neonatal birth weight (grams) will be measured using a digital infant weighing scale within 24 hours of birth. Birth weight will be converted into WGAZ using WHO 2013 sex- and gestational age-specific reference standards. The percentage of neonates with low WGAZ (< -2 SD) will be calculated for both supplemented and non-supplemented groups, and comparisons between groups will be made using appropriate statistical methods, adjusting for maternal heat stress exposure. Unit of Measure: % of neonates with WGAZ < -2 SD	Within 24 hours of delivery
Difference in proportion of neonates with low height-for-Gestational-Age Z-score (LGAZ< -2 SD) at birth between intervention and control arms.	Neonatal birth height (cm) will be measured using a standardized neonate's height scale within 24 hours of birth. Birth height will be converted into LGAZ using WHO 2013 sex- and gestational age-specific reference standards. The percentage of neonates with low LGAZ (< -2 SD) will be calculated for both supplemented and non-supplemented groups, and comparisons between groups will be made using appropriate statistical methods, adjusting for maternal heat stress exposure. Unit of Measure: % of neonates with LGAZ < -2 SD	Within 24 hours of delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age at delivery	Gestational age will be determined based on first-trimester ultrasound and/or last menstrual period (LMP). Unit of Measure: Weeks	At delivery date
Mode of delivery	Mode of delivery will be recorded as vaginal or cesarean section. Unit of Measure: Percentage (%) of cesarean deliveries	At delivery
Maternal serum ferritin concentration	Maternal serum ferritin will be measured using standardized immunoturbidimetric assay on an automated chemistry analyzer. Unit of Measure: ng/mL	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Maternal serum folate concentration	Maternal serum folate will be measured using standardized laboratory assay on automated immunoassay analyzer.	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Maternal serum 25-hydroxyvitamin D concentration	Maternal serum 25-hydroxyvitamin D concentration will be measured using standardized laboratory assay on automated immunoassay analyzer. Unit of Measure: ng/mL	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Generalized anxiety symptoms	Maternal mental health will be assessed using a validated psychological questionnaires Generalized Anxiety Disorder-7 (GAD-7) for assessing generalized anxiety symptoms over the past two weeks. Unit of Measure: The scale comprises 7 items, each rated on a 4-point Likert scale from 0 (not at all) to 3 (almost every day), with a total score ranging from 0 to 21. Interpretation: A score of 15 or higher is indicative of severe anxiety.	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Maternal gut microbiome alpha diversity	Alpha diversity of maternal gut microbiome will be assessed using 16S rRNA gene sequencing of stool samples. Unit of Measure: Shannon diversity index	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Placental gene expression levels	Placental gene expression will be quantified using RNA sequencing. Expression levels will be reported as normalized transcript counts. Unit of Measure: Normalized transcript counts	At delivery
Estimated fetal weight during pregnancy	Estimated fetal weight will be calculated using ultrasound biometric measurements according to standard obstetric formulas. Unit of Measure: Grams	Evaluated at the end of each trimester (within one week before or after the scheduled time point), from enrollment until delivery.
Perceived stress score	Perceived Stress Scale-10 (PSS-10) to assess perceived stress over the past month. Unit of Measure: The scale consists of 10 items, each rated on a 5-point Likert scale from 0 (never) to 4 (very often), with a total score ranging from 0 to 40. Interpretation: A score of 27 or higher indicates higher perceived stress.	Assessed at enrollment (baseline), monthly during pregnancy, and postpartum (after 2 weeks of delivery).
Postnatal depression symptoms	Edinburgh Postnatal Depression Scale (EPDS) to assess postnatal depression symptoms over the past week. Unit of Measure: The scale comprises 10 items, each rated on a 4-point Likert scale from 0 (no) to 3 (yes), with a total score ranging from 0 to 30. Interpretation: A score of 13 or greater is indicative of postnatal depression.	Assessed at enrollment (baseline), monthly during pregnancy, and postpartum (after 2 weeks of delivery).
Depression symptoms	Patient Health Questionnaire-9 (PHQ-9) to assess depression symptoms over the past two weeks. Unit of Measure: The scale consists of 9 items, each rated on a 4-point Likert scale from 0 (not at all) to 3 (nearly every day), with a total score ranging from 0 to 27. Interpretation: A score of 10 or greater indicates moderate to severe depression.	Assessed at enrollment (baseline), monthly during pregnancy, and postpartum (after 2 weeks of delivery).
Combined Depression, Anxiety, and Stress score	Depression, Anxiety, and Stress Scale-21 (DASS-21) to Assesses depression, anxiety, and stress over the past week. Unit of Measure: The scale consists of 21 items, divided into three subscales, each rated on a 4-point Likert scale from 0 (did not apply to me at all) to 3 (applied to me most of the time). Each subscale score is multiplied by 2 to match the original DASS-42 format. Interpretation: A score of 14 or greater is indicative of moderate to severe depression, anxiety, and stress.	Assessed at enrollment (baseline), monthly during pregnancy, and postpartum (after 2 weeks of delivery).

Collaborators and Investigators

• Sponsor: Aga Khan University
• Collaborators: Bill and Melinda Gates Foundation
• Investigators: Principal Investigator: Junaid Iqbal, PhD, Aga Khan University

Publications and helpful links

General Publications

• Brett KE, Ferraro ZM, Yockell-Lelievre J, Gruslin A, Adamo KB. Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta. Int J Mol Sci. 2014 Sep 12;15(9):16153-85. doi: 10.3390/ijms150916153.
• Bremner JD, Moazzami K, Wittbrodt MT, Nye JA, Lima BB, Gillespie CF, Rapaport MH, Pearce BD, Shah AJ, Vaccarino V. Diet, Stress and Mental Health. Nutrients. 2020 Aug 13;12(8):2428. doi: 10.3390/nu12082428.
• Ebi KL, Vanos J, Baldwin JW, Bell JE, Hondula DM, Errett NA, Hayes K, Reid CE, Saha S, Spector J, Berry P. Extreme Weather and Climate Change: Population Health and Health System Implications. Annu Rev Public Health. 2021 Apr 1;42:293-315. doi: 10.1146/annurev-publhealth-012420-105026. Epub 2021 Jan 6.
• Bonell A, Sonko B, Badjie J, Samateh T, Saidy T, Sosseh F, Sallah Y, Bajo K, Murray KA, Hirst J, Vicedo-Cabrera A, Prentice AM, Maxwell NS, Haines A. Environmental heat stress on maternal physiology and fetal blood flow in pregnant subsistence farmers in The Gambia, west Africa: an observational cohort study. Lancet Planet Health. 2022 Dec;6(12):e968-e976. doi: 10.1016/S2542-5196(22)00242-X.
• Gonzalez-Fernandez D, Muralidharan O, Neves PA, Bhutta ZA. Associations of Maternal Nutritional Status and Supplementation with Fetal, Newborn, and Infant Outcomes in Low-Income and Middle-Income Settings: An Overview of Reviews. Nutrients. 2024 Oct 31;16(21):3725. doi: 10.3390/nu16213725.
• Unger HW, Ashorn P, Cates JE, Dewey KG, Rogerson SJ. Undernutrition and malaria in pregnancy - a dangerous dyad? BMC Med. 2016 Sep 19;14(1):142. doi: 10.1186/s12916-016-0695-2.
• Lakhoo DP, Brink N, Radebe L, Craig MH, Pham MD, Haghighi MM, Wise A, Solarin I, Luchters S, Maimela G, Chersich MF; Heat-Health Study Group; HIGH Horizons Study Group. A systematic review and meta-analysis of heat exposure impacts on maternal, fetal and neonatal health. Nat Med. 2025 Feb;31(2):684-694. doi: 10.1038/s41591-024-03395-8. Epub 2024 Nov 5.
• Taylor A. ABC of subfertility: extent of the problem. BMJ. 2003 Aug 23;327(7412):434-6. doi: 10.1136/bmj.327.7412.434. No abstract available.
• Sheikh S, Qureshi RN, Raza F, Memon J, Ahmed I, Vidler M, Payne BA, Lee T, Sawchuck D, Magee L, von Dadelszen P, Bhutta Z; CLIP Working Group. Self-reported maternal morbidity: Results from the community level interventions for pre-eclampsia (CLIP) baseline survey in Sindh, Pakistan. Pregnancy Hypertens. 2019 Jul;17:113-120. doi: 10.1016/j.preghy.2019.05.016. Epub 2019 May 17.
• Kuehn L, McCormick S. Heat Exposure and Maternal Health in the Face of Climate Change. Int J Environ Res Public Health. 2017 Jul 29;14(8):853. doi: 10.3390/ijerph14080853.
• Shankar K, Ali SA, Ruebel ML, Jessani S, Borengasser SJ, Gilley SP, Jambal P, Yazza DN, Weaver N, Kemp JF, Westcott JL, Hendricks AE, Saleem S, Goldenberg RL, Hambidge KM, Krebs NF. Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition. PNAS Nexus. 2023 Jan 27;2(1):pgac309. doi: 10.1093/pnasnexus/pgac309. eCollection 2023 Jan.
• Ramirez JD, Maldonado I, Mach KJ, Potter J, Balise RR, Santos H. Evaluating the Impact of Heat Stress on Placental Function: A Systematic Review. Int J Environ Res Public Health. 2024 Aug 22;21(8):1111. doi: 10.3390/ijerph21081111.
• Grzeszczak K, Lanocha-Arendarczyk N, Malinowski W, Zietek P, Kosik-Bogacka D. Oxidative Stress in Pregnancy. Biomolecules. 2023 Dec 9;13(12):1768. doi: 10.3390/biom13121768.
• Torheim LE, Ferguson EL, Penrose K, Arimond M. Women in resource-poor settings are at risk of inadequate intakes of multiple micronutrients. J Nutr. 2010 Nov;140(11):2051S-8S. doi: 10.3945/jn.110.123463. Epub 2010 Sep 29.
• Chauhan A, Potdar J. Maternal Mental Health During Pregnancy: A Critical Review. Cureus. 2022 Oct 25;14(10):e30656. doi: 10.7759/cureus.30656. eCollection 2022 Oct.
• Wang J, Liu X, Dong M, Sun X, Xiao J, Zeng W, Hu J, Li X, Guo L, Rong Z, He G, Sun J, Ning D, Chen D, Zhang Y, Zhang B, Ma W, Liu T. Associations of maternal ambient temperature exposures during pregnancy with the placental weight, volume and PFR: A birth cohort study in Guangzhou, China. Environ Int. 2020 Jun;139:105682. doi: 10.1016/j.envint.2020.105682. Epub 2020 Apr 2.
• Ranciere F, Wafo O, Perrot X, Momas I. Associations between heat wave during pregnancy and term birth weight outcomes: The PARIS birth cohort. Environ Int. 2024 Jun;188:108730. doi: 10.1016/j.envint.2024.108730. Epub 2024 May 9.
• Lakhani S, Ambreen S, Padhani ZA, Fahim Y, Qamar S, Meherali S, Lassi ZS. Impact of ambient heat exposure on pregnancy outcomes in low- and middle-income countries: A systematic review. Womens Health (Lond). 2024 Jan-Dec;20:17455057241291271. doi: 10.1177/17455057241291271.
• Chersich MF, Pham MD, Areal A, Haghighi MM, Manyuchi A, Swift CP, Wernecke B, Robinson M, Hetem R, Boeckmann M, Hajat S; Climate Change and Heat-Health Study Group. Associations between high temperatures in pregnancy and risk of preterm birth, low birth weight, and stillbirths: systematic review and meta-analysis. BMJ. 2020 Nov 4;371:m3811. doi: 10.1136/bmj.m3811.
• Asakura H. Fetal and neonatal thermoregulation. J Nippon Med Sch. 2004 Dec;71(6):360-70. doi: 10.1272/jnms.71.360.
• Carlson JM, Zanobetti A, Ettinger de Cuba S, Poblacion AP, Fabian PM, Carnes F, Rhee J, Lane KJ, Sandel MT, Janulewicz PA. Critical windows of susceptibility for the effects of prenatal exposure to heat and heat variability on gestational growth. Environ Res. 2023 Jan 1;216(Pt 2):114607. doi: 10.1016/j.envres.2022.114607. Epub 2022 Oct 22.
• Samuels L, Nakstad B, Roos N, Bonell A, Chersich M, Havenith G, Luchters S, Day LT, Hirst JE, Singh T, Elliott-Sale K, Hetem R, Part C, Sawry S, Le Roux J, Kovats S. Physiological mechanisms of the impact of heat during pregnancy and the clinical implications: review of the evidence from an expert group meeting. Int J Biometeorol. 2022 Aug;66(8):1505-1513. doi: 10.1007/s00484-022-02301-6. Epub 2022 May 12.
• Aziz M, Anjum G. Transformative strategies for enhancing women's resilience to climate change: A policy perspective for low- and middle-income countries. Womens Health (Lond). 2024 Jan-Dec;20:17455057241302032. doi: 10.1177/17455057241302032.
• Rylander C, Odland JO, Sandanger TM. Climate change and the potential effects on maternal and pregnancy outcomes: an assessment of the most vulnerable--the mother, fetus, and newborn child. Glob Health Action. 2013 Mar 11;6:19538. doi: 10.3402/gha.v6i0.19538.
• Tollefson J. How hot will Earth get by 2100? Nature. 2020 Apr;580(7804):443-445. doi: 10.1038/d41586-020-01125-x. No abstract available.
• Anjum G, Aziz M. Climate change and gendered vulnerability: A systematic review of women's health. Womens Health (Lond). 2025 Jan-Dec;21:17455057251323645. doi: 10.1177/17455057251323645. Epub 2025 Mar 12.
• Cooper MW, Brown ME, Hochrainer-Stigler S, Pflug G, McCallum I, Fritz S, Silva J, Zvoleff A. Mapping the effects of drought on child stunting. Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17219-17224. doi: 10.1073/pnas.1905228116. Epub 2019 Aug 12.

Helpful Links

• Trends in maternal mortality 2000 to 2020: estimates by WHO, UNICEF, UNFPA, World Bank Group and UNDESA/Population Division
• Climate change impacts on health
• Climate Change Profile of Pakistan
• Key findings report of National Nutrition Survey of Pakistan 2018
• Malnutrition in women
• Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity
• What are the chances of getting pregnant the first time trying?
• Deaths mount as Pakistan swelters in heatwave

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: November 28, 2025
• First Submitted That Met QC Criteria: March 19, 2026
• First Posted (Actual): March 24, 2026

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: microbiome; maternal depression; Local Food-Based Diet to Improve Birth Outcomes and Heat Resilience in Pregnant Women; placental transcriptomics
• Additional Relevant MeSH Terms: Wounds and Injuries; Heat Stress Disorders
• Other Study ID Numbers: 10697-33069; 074884 (Other Grant/Funding Number: Bill & Melinda Gates Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual Participant Data (IPD) will not be made available to anyone including other researchers. Participant confidentiality and privacy protection will be given utmost importance as even anonymized data could have potential indirect identifiers due to the particular locality of the study in a specific rural community, which may lead to the re-identification of participants and may damage the reputation of the community, or stigmatize the participants. Informed consent was also not obtained from the participants regarding sharing of personal data with the public. Thus, we will prioritize our ethical commitment by only making available results of the study in aggregated group format.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No