Effect of the WHEY protein on pregnancyneonatal outcomes and prophylactic effect on fetal growth restriction cases: A randomized clinical trial

Research

HJOG 2024, 23 (4), 267-275| doi: 10.33574/hjog.0575

Samir Abdallah Ali1, Emad Mohamed Ibrahim Attallah1, Mostafa Mahmoud Mohamed El-Abd2

1Department of Obstetrics and Gynecology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2Resident of Obstetrics and Gynecology, Alexandria University, New Cairo Hospital, Alexandria, Egypt

Correspondence: Mostafa Mahmoud Mohamed El-Abd, mobile: 01227960980, email: mostafamahmoudelabd1@gmail.com

Abstract

Background: WHEY protein is a high-quality protein source that is easily absorbed and utilized by the body. It has a beneficial effect on pregnancy and neonatal outcomes.

Aim: To evaluate the impact of WHEY protein on pregnancy-neonatal outcomes and its prophylactic effect on Fetal growth restriction (FGR) cases.

Patients and methods: This study was a prospective randomized, controlled clinical trial conducted on 300 pregnant females from attendees of obstetrics and gynecology clinics of Al Azhar University Hospitals. They were randomly divided into two groups: Case group: The intervention group (150 cases) received a daily WHEY protein supplement containing 25 grams of protein, and the Control Group: 150 cases received a placebo supplement.

Results: There was no statistically significant difference between the studied groups regarding demographic criteria (P>0.01), and the prevalence of FGR was (20% vs 18.75) in the studied groups. According to fetal biometry at birth, there was no statistically significant difference regarding sonographic parameters between the appropriate gestational age (AGA) in the studied groups (P>0.01). There was no statistically significant difference between the two groups regarding complete blood parameters, platelets, or PTT (P>0.01). There was a highly statistically significant difference regarding PT between the studied groups (P<0.001). There was no statistically significant difference between the two groups regarding liver and kidney function tests (P>0.01). There was a highly statistically significant difference regarding total proteins and serum calcium between the studied groups (P<0.001).

Conclusion: WHEY protein supplementation did not affect fetal growth, but it improved some maternal parameters, such as total protein and PT.

Key words: WHEY Protein, FGR, Gestational age

Introduction

WHEY protein is a high-quality source that is easily absorbed and utilized by the body. Whey proteins are rich sources of Essential amino acids, including branched-chain amino acids such as isoleucine, valine, and leucine. The amino acid profile of whey protein is similar to that of muscle proteins, with almost all the AAs of comparable magnitudes. The whey protein bioactive peptides contain approximately 3–20 amino acids and might exhibit antihypertensive, immunomodulatory, antithrombotic, antimicrobial, and opioid activities; they can modulate the mood and intestinal microbiota and show action against allergies, infections, and atopic dermatitis1.

Fetal growth restriction (FGR) is a common complication of pregnancy that is characterized by slowed fetal growth and development during pregnancy. It is associated with an increased risk of adverse neonatal outcomes, including low birth weight, preterm delivery, and neonatal morbidity2.

Maternal nutrition, including protein intake, has been identified as a potential factor in developing FGR. Adequate maternal nutrition, including sufficient intake of high-quality protein, may protect against FGR3.

Several studies have investigated the potential role of WHEY protein in pregnancy and neonatal outcomes. Supplementation with WHEY protein in pregnant women at risk for FGR was associated with an increase in maternal weight gain and a reduction in the incidence of preterm delivery. WHEY protein supplementation during pregnancy was associated with a decreased incidence of low birth weight and improved neonatal morbidity4,5.

WHEY protein supplementation during pregnancy in women with low body mass index (BMI) leads to an increase in birth weight and a decrease in the incidence of low birth weight. Some research has suggested that WHEY protein may improve placental function and increase fetal growth and development. Although WHEY protein consumption has shown increased muscle growth, it’s not a steroid as it holds no anabolic properties6,7.

Additionally, WHEY protein may have a prophylactic effect against FGR, a condition in which the fetus does not grow normally in the womb. This can have severe consequences for the baby’s health, including an increased risk of preterm birth, low birth weight, and developmental delays. Some studies have found that WHEY protein supplementation during pregnancy may reduce the incidence of FGR and improve fetal growth8.

This work aimed to evaluate the effect of WHEY protein on pregnancy-neonatal outcomes and its prophylactic effect on FGR cases.

Patients and methods

This study was a prospective randomized, controlled clinical trial conducted on 300 pregnant females attending obstetrics and gynecology clinics of Al Azhar University Hospitals.

They were divided into two groups: Case group: The intervention group (150 cases) received a daily WHEY protein supplement containing 25 grams (Deron manufactured by Pharmazad, Egypt,) and Control Group: 150 cases received a placebo supplement (supplied by the same manufacturer).

Sample Size Justification

This study, based on a study carried out by Liberato et al., 2013 Epi Info STATCALC, was used to calculate the sample size by considering the following assumptions: 95% two-sided confidence level, with a power of 80% & α error of 5%. The final maximum sample size from the Epi-Info output was 120. Thus, the sample size was increased to 150 subjects to assume any dropout cases during follow-up.

Randomization

Using the sequentially numbered, opaque sealed envelopes (SNOSE) technique, we ensured that the randomization sequence was effectively allocated and concealed. The randomization groups were written on paper and kept in a sealed, opaque envelope with a serial number. As soon as the patient gives consent to participate, the researcher opens the sealed envelope and assigns the patient to the treatment group accordingly: Group A: WHEY protein supplement Group B: placebo.

Ethical approval

The Local Ethics Committee approved the study protocol and obtained written informed consent MS 555/2024. The protocol was registered in the Pan-African clinical registry.

Inclusion criteria

Pregnant women, singleton pregnancy, gestational age of 24 -36 weeks, gestational age determined by the sure date of last menstrual period confirmed by ultrasound examination at < 20 weeks gestation, and pregnant women at risk for FGR

Exclusion criteria: Allergy or intolerance to milk or milk products, chronic illness such as diabetes or hypertension, and multiple gestations

Methods

All patients underwent Complete history taking, physical examination, and lab investigations. The supplements were provided as a powder that could be mixed with water or other beverages. The intervention began in the second trimester of pregnancy and continued until delivery.

Ultrasonography Abdominopelvic ultrasound examination: fetal biometry, weight, biophysical profile, and amniotic fluid index. US investigations repeated every week till delivery. FGR is diagnosed based on Estimated fetal weight below the 10th percentile for gestational age and fetal abdominal circumference or head circumstance < 5th percentile, presence of oligohydramnios, and uterine artery doppler changes (end diastolic flow). Patients diagnosed were terminated at 34 weeks or 36 weeks according to our hospital protocol after giving dexamethasone for lung maturity.

After delivery, we collected data about birth outcomes, including gestational age and neonatal anthropometric measurements (weight, height, and head circumference at birth) to compare the mean scores. Also, maternal anthropometric measurements, labs, and vitals were re-evaluated after delivery. The normal range of weight, height, and head circumstance at birth is 2500 to 4000 grams, 45 to 55 cm, and 33 to 37 cm, respectively.9

Results

According to demographic data, there was no statistically significant difference between the studied groups regarding age, residence, and BMI (Table 1).

According to Table (2), 14 patients were diagnosed with FGR, ten were delivered at 36 weeks, and four were delivered at 34 weeks. In the control group, 11 were delivered at 36 weeks, and four were delivered at 34 weeks, with no statistically significant difference between the two groups (data not tabulated).

No statistically significant difference in gestational age at birth between the appropriate gestational age (AGA) in the studied groups (Table 3).

According to fetal biometry at birth, there was no statistically significant difference between the appropriate gestational age (AGA) in studied groups regarding BPD, HC, FL, fetal birth weight, fetal birth height, fetal birth head circumference, and mode of delivery (Table 4).

According to the CBC and coagulation profile, there was no statistically significant difference regarding Hgb, WBCs, Plt, and bleeding time between the studied groups, while there was a statistically significant difference regarding RBCs and PTT and a highly statistically significant difference regarding PT (Table 5).

According to the liver and kidney function test, there was no statistically significant difference between the studied groups regarding bilirubin, albumin, AST, ALT, urea, and creatinine. However, there was a statistically significant difference between the studied groups regarding eGFR, and there was a highly statistically significant difference between the studied groups regarding total proteins and serum calcium (Table 6).

Discussion

The whey protein comprises a protein mixture obtained from whey, the liquid milk component that separates during the production of cheese. During the production of cheese, there is coagulation of the fats in the milk, resulting in the separation of whey as a by-product. Whey can also be considered as the liquid part of milk remaining after the curdling and straining of the milk. As a byproduct of cheese or casein production, whey, along with whey proteins, has many commercial and nutraceutical applications5

Our Results and their interpretation

We randomized 300 patients into two groups. The first group contained the Whey protein patients, and the second group received the placebo. 70 patients in group A and 80 in group B finalized the consort flow chart.

Figure 1. CONSORT Flow Diagram

Twenty percent of cases had FGR in both groups, with no statistically significant difference between the two groups and no effect of supplementation with Whey protein.

According to demographic data, there was no statistically significant difference between the studied groups regarding age, residence, and BMI.

There were no differences between patients with Appropriate gestational age in both groups regarding delivery time or fetal or neonatal assessment, indicating that Whey protein did not affect these measures. This can be explained by the fact that Whey was supplementary to iron and calcium supplementations already prescribed for the patients from their first trimester.

Comparison of our results to the same studies

Our results are consistent with Argaw et al.,10 who evaluated the effects of micronutrient-fortified balanced energy protein supplementation during pregnancy on the body composition of mothers and their newborns. They reported that the mean maternal age of the intervention group was 24.7 ± 5.97 years, while the mean maternal age of the control group was 25.1 ± 5.99 years. They found no statistically significant difference between the two studied groups regarding maternal age and BMI.

Also, our findings are in line with Tabrizi et al.,11 , who evaluated the effects of food supplementation during pregnancy on maternal weight gain, hemoglobin levels, and pregnancy outcomes. They demonstrated that the mean maternal age of the supplemented group was 24.7±5.5 years, while the mean maternal age of the control group was 25.8 ± 5.9 years. They found no statistically significant difference between the two studied groups regarding maternal age and BMI.

Similarly, our results are in concordance with Prameswari et al.,12  , who illustrated that the mean gestational age in the intervention group was 19.7±4.1 weeks while the mean gestational age in the control group was 20.9±3.8 weeks. They found no statistically significant difference between the studied groups regarding the initial gestational age assessment.

As regards fetal biophysical profile, our results revealed that there was no statistically significant difference between the studied groups regarding FGR

Our findings are in line with Prameswari et al.,12 ,  who demonstrated no statistically significant difference between the intervention and control groups regarding fetal growth, including femur length and estimated fetal weight.

The present study reported that the mean gestational age at birth in the study group with appropriate gestational age was 38.8 ± 1.17 weeks. The mean gestational age in the control group with appropriate gestational age was 38.9 ± 1.4 weeks. There was no statistically significant difference between the studied groups regarding gestational age at birth.

Tabrizi et al.,11, reported that preterm births (births that happen before 37 weeks gestational age) were 12%, 0.3%, and 2.1% in the supplemented group and 40%, 0.6%, and 6.3% in the control group. There were statistically significant differences between the two studied groups regarding preterm births (p =0.013).

According to fetal biometry at birth, there was no statistically significant difference between the studied groups regarding BPD, HC, FL, fetal birth weight, fetal birth height, fetal birth head circumference, and mode of delivery.

Also, our results are in line with the systematic review of Imdad & Bhutta,13  They reported that the effect of balanced protein energy supplementation seemed more pronounced in malnourished women. Their pooled results for mean change in birth weight showed that malnourished women benefited the most from balanced protein energy supplementation, and there was no statistically significant effect in adequately nourished women. Our study showed that most of the women who participated had average BMIs.

Also, Huybregts et al.,14, investigated whether prenatal balanced energy and protein with fortified food supplement (FFS) improve anthropometric measures at birth compared with supplementation with a BEP pill alone. They demonstrated that balanced protein energy supplementation showed improved birth weight in infants.

In contrast, our results disagreed with Tabrizi et al.,11, who illustrated that there was a statistically significant difference between the supplemented and control groups regarding birth weight.

According to liver and kidney function test, there was no statistically significant difference between the studied groups regarding bilirubin, albumin, AST, ALT, urea, and creatinine. There was a statistically significant difference between the studied groups regarding eGFR, while there was a highly statistically significant difference between the studied groups regarding total proteins and serum calcium. According to the CBC and coagulation profile, there was no statistically significant difference in Hgb, WBCs, platelets, or bleeding time. At the same time, there was a statistically significant difference regarding RBCs and PTT and a highly statistically significant difference regarding PT between the studied groups.

Similarly, our study is inconsistent with Tabrizi et al.,11  who reported that the mean Hb decreased from 12 and 12.1 mg/dl in week ten at enrolment to 11.9 and 11.7 mg/dl in week 20 in the supplemented and control groups, respectively, which was significant only for the control group. Nineteen percent and 23.5 percent of participants were anemic at early pregnancy in the supplemented and control groups, respectively. These values increased to 25% and 32.5% in mid-pregnancy, which was significant in the control group. 

Strengths and limitations of our study

The strength of our research was the appropriate methodology and close follow-up of patients who took supplementations and placebo. Our study has several limitations, including the small number of patients, the self-funded study leading to the small number of patients, and finally, it was a single-center study.

Recommendation for further studies: Studies involving a large number of patients and multicentric designs should investigate the effect of Whey protein on maternal and neonatal outcomes.

Conclusion

WHEY protein supplementation and placebo supplementation showed similar effects on fetal growth. We found no statistically significant difference between the studied groups regarding fetal biometry and IUGR. More studies are needed to evaluate the effect of Whey protein.

References
  1. Baba WN, McClements DJ, Maqsood S. Whey protein-polyphenol conjugates and complexes: Production, characterization, and applications. Food Chem. 2021;365:130455. doi:10.1016/j.foodchem.2021.130455
  2. Aski SK, Akbari R, Hantoushzadeh S, Ghotbizadeh F. A bibliometric analysis of Intrauterine Growth Restriction research [published correction appears in Placenta. 2020 Sep 15;99:208]. Placenta. 2020;95:106-120. doi:10.1016/j.placenta.2020.03.010
  3. Sebastiani G, Herranz Barbero A, Borrás-Novell C, et al. The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring. Nutrients. 2019;11(3):557. Published 2019 Mar 6. doi:10.3390/nu11030557
  4. Abreu S, Santos PC, Montenegro N, Mota J. Relationship between dairy product intake during pregnancy and neonatal and maternal outcomes among Portuguese women. Obes Res Clin Pract. 2017;11(3):276-286. doi:10.1016/j.orcp.2016.07.001
  5. Lagrange V, Clark DC. Nutritive and therapeutic aspects of whey proteins. InWhey Proteins 2019 Jan 1 (pp. 549-577). Academic Press.doi.org/10.1016/B978-0-12-812124-5.00016-3
  6. Pimpin L, Kranz S, Liu E, et al. Effects of animal protein supplementation of mothers, preterm infants, and term infants on growth outcomes in childhood: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2019;110(2):410-429. doi:10.1093/ajcn/nqy348
  7. Lopes Gomes D, Moehlecke M, Lopes da Silva FB, Dutra ES, D’Agord Schaan B, Baiocchi de Carvalho KM. Whey Protein Supplementation Enhances Body Fat and Weight Loss in Women Long After Bariatric Surgery: a Randomized Controlled Trial. Obes Surg. 2017;27(2):424-431. doi:10.1007/s11695-016-2308-8
  8. Morise A, Sève B, Macé K, Magliola C, Le Huërou-luron I, Louveau I. Impact of intrauterine growth retardation and early protein intake on growth, adipose tissue, and the insulin-like growth factor system in piglets. Pediatr Res. 2009;65(1):45-50. doi:10.1203/PDR.0b013e318189b0b4
  9. Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C, Laopaiboon M, Medley N. Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. Cochrane Database Syst Rev. 2015;2015(2):CD007079. Published 2015 Feb 25. doi:10.1002/14651858.CD007079.pub3
  10. Argaw A, Toe LC, Hanley-Cook G, et al. Effect of prenatal micronutrient-fortified balanced energy-protein supplementation on maternal and newborn body composition: A sub-study from the MISAME-III randomized controlled efficacy trial in rural Burkina Faso. PLoS Med. 2023;20(7):e1004242. Published 2023 Jul 24. doi:10.1371/journal.pmed.1004242
  11. Tabrizi JS, Asghari A, Pourali F, Kousha H, Nikniaz L. Effects of Food Supplementation During Pregnancy on Maternal Weight Gain, Hemoglobin Levels and Pregnancy Outcomes in Iran. Matern Child Health J. 2019;23(2):258-264. doi:10.1007/s10995-018-2648-1
  12. Prameswari FS, Marliyati SA, Dewi M. A supplementary protein food for pregnant women with chronic energy deficiency to improve fetal growth. Jurnal Gizi Dan Pangan. 2020 Mar 28;15(1):1-0. doi.org/10.25182/jgp.2020.15.1.1-10
  13. Imdad A, Bhutta ZA. Effect of balanced protein energy supplementation during pregnancy on birth outcomes. BMC Public Health. 2011;11 Suppl 3(Suppl 3):S17. Published 2011 Apr 13. doi:10.1186/1471-2458-11-S3-S17
  14. Huybregts L, Roberfroid D, Lanou H, et al. Prenatal food supplementation fortified with multiple micronutrients increases birth length: a randomized controlled trial in rural Burkina Faso. Am J Clin Nutr. 2009;90(6):1593-1600. doi:10.3945/ajcn.2009.28253