Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2016

Open Access 01-12-2016 | Study protocol

The Probiotics in Pregnancy Study (PiP Study): rationale and design of a double-blind randomised controlled trial to improve maternal health during pregnancy and prevent infant eczema and allergy

Authors: Christine Barthow, Kristin Wickens, Thorsten Stanley, Edwin A. Mitchell, Robyn Maude, Peter Abels, Gordon Purdie, Rinki Murphy, Peter Stone, Janice Kang, Fiona Hood, Judy Rowden, Phillipa Barnes, Penny Fitzharris, Jeffrey Craig, Rebecca F. Slykerman, Julian Crane

Published in: BMC Pregnancy and Childbirth | Issue 1/2016

Login to get access

Abstract

Background

Worldwide there is increasing interest in the manipulation of human gut microbiota by the use of probiotic supplements to modify or prevent a range of communicable and non-communicable diseases. Probiotic interventions administered during pregnancy and breastfeeding offer a unique opportunity to influence a range of important maternal and infant outcomes.
The aim of the Probiotics in Pregnancy Study (PiP Study) is to assess if supplementation by the probiotic Lactobacillus rhamnosus HN001 administered to women from early pregnancy and while breastfeeding can reduce the rates of infant eczema and atopic sensitisation at 1 year, and maternal gestational diabetes mellitus, bacterial vaginosis and Group B Streptococcal vaginal colonisation before birth, and depression and anxiety postpartum.

Methods/design

The PiP Study is a two-centre, randomised, double-blind placebo-controlled trial in Wellington and Auckland, New Zealand. Four hundred pregnant women expecting infants at high risk of allergic disease will be enrolled in the study at 14–16 weeks gestation and randomised to receive either Lactobacillus rhamnosus HN001 (6 × 109 colony-forming units per day (cfu/day)) or placebo until delivery and then continuing until 6 months post-partum, if breastfeeding.
Primary infant outcomes are the development and severity of eczema and atopic sensitisation in the first year of life. Secondary outcomes are diagnosis of maternal gestational diabetes mellitus, presence of bacterial vaginosis and vaginal carriage of Group B Streptococcus (at 35–37 weeks gestation). Other outcome measures include maternal weight gain, maternal postpartum depression and anxiety, infant birth weight, preterm birth, and rate of caesarean sections. A range of samples including maternal and infant faecal samples, maternal blood samples, cord blood and infant cord tissue samples, breast milk, infant skin swabs and infant buccal swabs will be collected for the investigation of the mechanisms of probiotic action.

Discussion

The study will investigate if mother-only supplementation with Lactobacillus rhamnosus HN001 in pregnancy and while breastfeeding can reduce rates of eczema and atopic sensitisation in infants by 1 year, and reduce maternal rates of gestational diabetes mellitus, bacterial vaginosis, vaginal carriage of Group B Streptococcus before birth and maternal depression and anxiety postpartum.

Trial registration

Australian New Zealand Clinical Trials Registration: ACTRN12612000196842.
Date Registered: 15/02/12.
Appendix
Available only for authorised users
Footnotes
1
In New Zealand, maternity care and delivery is managed through a system of lead maternity carers. These carers provide maternity care and support through the pregnancy, co-ordinate with other healthcare providers, organise scans and tests, manage the labour and provide care for the first six weeks of the baby’s life. Most lead maternity carers are midwives, though some doctors and obstetricians may also carry out the role.
 
Literature
1.
Cénit MC, Matzaraki V, Tigchelaar EF, Zhernakova A. Rapidly expanding knowledge on the role of the gut microbiome in health and disease. Biochim Biophys Acta. 2014;1842:1981–92.CrossRefPubMed
2.
Prescott SL. Early-life environmental determinants of allergic diseases and the wider pandemic of inflammatory noncommunicable diseases. J Allergy Clin Immunol. 2013;131:23–30.CrossRefPubMed
3.
Wallace TC, Guarner F, Madsen K, Cabana MD, Gibson G, Hentges E, et al. Human gut microbiota and its relationship to health and disease. Nutr Rev. 2011;69:392–403.CrossRefPubMed
4.
Pawankar R, Canonica RW, Holgate ST, Lockey RL, Blaiss M, editors. World Allergy Organisation (WAO) White Book on Allergy: update 2013. Milwaukee: World Allergy Organization; 2013.
5.
Silvers KM, Frampton CM, Wickens K, Epton MJ, Pattemore PK, Ingham T, et al. Breastfeeding protects against adverse respiratory outcomes at 15 months of age. Matern Child Nutr. 2009;5:243–50.CrossRefPubMed
6.
Pelucchi C, Chatenoud L, Turati F, Galeone C, Moja L, Bach J-F, et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: A meta-analysis. Epidemiology. 2012;23:402–14.CrossRefPubMed
7.
Osborn DA, Sinn JKH. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst. Rev. 2007; Art. No.: CD006475. DOI: 10.​1002/​14651858.​CD006475.
8.
Panduru M, Panduru NM, Sălăvăstru CM, Tiplica G-S. Probiotics and primary prevention of atopic dermatitis: a meta-analysis of randomized controlled studies. J Eur Acad Dermatol Venereol. 2015;29:232–42.CrossRefPubMed
9.
Wickens K, Black PN, Stanley TV, Mitchell E, Fitzharris P, Tannock GW, et al. A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2008;122:788–94.CrossRefPubMed
10.
Wickens K, Black P, Stanley TV, Mitchell E, Barthow C, Fitzharris P, et al. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years. Clin Exp Allergy. 2012;42:1071–9.CrossRefPubMed
11.
Wickens K, Stanley TV, Mitchell EA, Barthow C, Fitzharris P, Purdie G, et al. Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: Does it also reduce atopic sensitization? Clin Exp Allergy. 2013;43:1048–57.CrossRefPubMed
12.
Huurre A, Laitinen K, Rautava S, Korkeamäki M, Isolauri E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebo-controlled study. Clin Exp Allergy. 2008;38:1342–8.CrossRefPubMed
13.
Hertz-Picciotto I, Park H-Y, Dostal M, Kocan A, Trnovec T, Sram R. Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development. Basic Clin Pharmacol Toxicol. 2008;102:146–54.CrossRefPubMed
14.
Breckler LA, Hale J, Jung W, Westcott L, Dunstan JA, Thornton CA, et al. Modulation of in vivo and in vitro cytokine production over the course of pregnancy in allergic and non-allergic mothers. Pediatr Allergy Immunol. 2010;21:14–21.CrossRefPubMed
15.
Pyrhonen K, Laara E, Hiltunen L, Kaila M, Nayha S. Season of the first trimester in pregnancy predicts senstization to food allergens in childhood: a population-based cohort study from Finland. J Epidemiol Community Heal. 2010; doi:10.​1136/​jech.​2009.​105411.
16.
Abrahamsson T, Jakobsson T, Bottcher M, Fredrikson M, Jenmalm MC, Bjorksten B, et al. Probiotics in prevention of IgE-associated eczema: A double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007;119:1174–80.CrossRefPubMed
17.
Niers L, Martin R, Rijkers G, Sengers F, Timmerman H, van Uden N, et al. The effects of selected probiotic strains on the development of eczema (the PandA study). Allergy. 2009;64:1349–58.CrossRefPubMed
18.
Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: A randomized controlled trial. J Allergy Clin Immunol. 2007;119:184–91.CrossRefPubMed
19.
Flohr C, Johansson S, Wahlgren C-F, Williams H. How atopic is atopic dermatitis? J Allergy Clin Immunol. 2004;114:150–8.CrossRefPubMed
20.
Dotterud CK, Storro O, Johnsen R, Oien T, Storrø O, Johnsen R, et al. Probiotics in pregnant women to prevent allergic disease: a randomized, double-blind trial. Br J Dermatol. 2010;163:616–23.CrossRefPubMed
21.
Rautava S, Kalliomaki M, Isolauri E. Probiotics during pregnancy and breastfeeding might confer immunological protection against atopic disease in the infant. J Allergy Clin Immunol. 2002;109:119–21.CrossRefPubMed
22.
Prescott SL, Wickens K, Westcott L, Jung W, Currie H, Black PN, et al. Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon-ƴ and breast milk transforming growth factor-β and immunoglobin A detection. Clin Exp Allergy. 2008;38:1606–14.CrossRefPubMed
23.
Bottcher M, Abrahamsson T, Fredriksson M, Jakobsson T, Bjorksten B. Low breast milk TGF-B2 is induced by Lactobacillus reuteri supplmentation and associates with reduced risk of sensitization during infancy. Pediatr Allergy Immunol. 2008;19:497–504.CrossRefPubMed
24.
Barrett HL, Dekker Nitert M, Conwell LS, Callaway LK. Probiotics for preventing gestational diabetes. Cochrane Database Syst Rev. 2014; Art. No.: CD009951. DOI: 10.​1002/​14651858.​CD009951.
25.
International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676–82.CrossRefPubMedCentral
26.
Poston L, Harthoorn LF, Van Der Beek EM. Obesity in pregnancy: Implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res. 2011;69:175–80.CrossRefPubMed
27.
Vohr BR, Boney CM. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Neonatal Med. 2008;21:149–57.
28.
Chandler-Laney PC, Bush NC, Granger WM, Rouse DJ, Mancuso MS, Gower BA. Overweight status and intrauterine exposure to gestational diabetes are associated with children’s metabolic health. Pediatr Obes. 2011;7:44–52.CrossRef
29.
Nitert MD, Barrett HL, Foxcroft K, Tremellen A, Wilkinson S, Lingwood B, et al. SPRING: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women. BMC Pregnancy Childbirth. 2013;13:50.CrossRefPubMedPubMedCentral
30.
Laitinen K, Poussa T, Isolauri E, the Nutrition Allergy Muscosal Immunology & Intestinal Microbiota Group. Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: a randomised controlled trial. Br J Nutr. 2009;101:1679–87.PubMed
31.
Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br J Nutr. 2010;103:1792–9.CrossRefPubMed
32.
Ilmonen J, Isolauri E, Poussa T, Laitinen K. Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo-controlled trial. Clin Nutr. 2011;30:156–64.CrossRefPubMed
33.
Luoto R, Kalliomäki M, Laitinen K, Isolauri E. The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int J Obes. 2010;34:1531–7.CrossRef
34.
Lindsay KL, Kennelly M, Culliton M, Smith T, Maguire OC, Shanahan F, et al. Probiotics in obese pregnancy do not reduce maternal fasting glucose: A double-blind, placebo-controlled, randomized trial (Probiotics in Pregnancy Study). Am J Clin Nutr. 2014;99:1432–9.CrossRefPubMed
35.
Hanson L, Vandevusse L, Duster M, Warrack S, Safdar N. Feasibility of oral prenatal probiotics against maternal Group B Streptococcus vaginal and rectal colonization. J Obstet Gynecol Neonatal Nurs. 2014;43:294–304.CrossRefPubMed
36.
Stojanović N, Plećaš D, Plešinac S. Normal vaginal flora, disorders and application of probiotics in pregnancy. Arch Gynecol Obstet. 2012;286:325–32.CrossRefPubMed
37.
Mastromarino P, Vitali B, Mosca L. Bacterial vaginosis: a review on clinical trials with probiotics. New Microbiol. 2013;36:229–38.PubMed
38.
Moghaddam NM. Recto-vaginal colonization with Group B Streptococcus in pregnant women referred to a hospital in Iran and its effect on Lactobacillus normal flora. J Biol Sci. 2010;10:166–9.CrossRef
39.
Yudin MH, Money DM. Screening and management of bacterial vaginosis in pregnancy. J Obstet Gynaecol Can. 2008;30:702–8.CrossRefPubMed
40.
41.
Carey J, Klebanoff M, Hauth J, Hillier S, Thom E, Ernest J, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med. 2000;342:534–40.CrossRefPubMed
42.
Anukam K, Osazuwa E, Ahonkhai I, Ngwu M, Osemene G, Bruce AW, et al. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized controlled trial. Microbes Infect. 2006;8:1450–4.CrossRefPubMed
43.
MacPhee R, Hummelen R, Bisanz J, Miller W, Reid G. Probiotic strategies for the treatment and prevention of bacterial vaginosis. Expert Opin Pharmacother. 2010;11:2985–95.CrossRefPubMed
44.
Rodriguez-Granger J, Alvargonzalez JC, Berardi A, Berner R, Kunze M, Hufnagel M, et al. Prevention of group B streptococcal neonatal disease revisited. the DEVANI European project. Eur J Clin Microbiol Infect Dis. 2012;31:2097–104.CrossRefPubMed
45.
Javanmanesh F, Eshraghi N. Prevalence of positive recto-vaginal culture for Group B streptococcus in pregnant women at 35–37 weeks of gestation. Med J Islam Repub Iran. 2013;27:7–11.PubMedPubMedCentral
46.
Grimwood K, Stone PR, Gosling IA, Green R, Darlow BA, Lennon DR, et al. Late antenatal carriage of Group B Streptococcus by New Zealand women. Aust NZ J Obstet Gynaecol. 2002;42:182–6.CrossRef
47.
Goldenberg RL, Thompson C. The infectious origins of stillbirth. Am J Obstet Gynecol. 2003;189:861–73.CrossRefPubMed
48.
49.
Campbell N, Eddy A, Darlow B, Stone P, Grimwood K. The prevention of early-onset neonatal group B streptococcus infection: technical report fron the New Zeland GBS Consensus Working Party. NZ Med J. 2004;117:1–19.
50.
Acikgoz ZC, Gamberzade S, Gocer S, Ceylan P. Inhibitor effect of vaginal lactobacilli on group B streptococcus. Mikrobiyol Bul. 2005;39:17–23.PubMed
51.
Zárate G, Nader-Macias ME. Influence of probiotic vaginal lactobacilli on in vitro adhesion of urogenital pathogens to vaginal epithelial cells. Lett Appl Microbiol. 2006;43:174–80.CrossRefPubMed
52.
Plascencia L, García HS, Lacroix M, Rosa B, Uscanga A. Effect of culture medium on bacteriocin production by Lactobacillus rhamnosus HN001 and Lactobacillus reuteri ATCC 53608. J Microbiol Biotechnol Food Sci. 2013;2:2462–8.
53.
Borre YE, O’Keeffe GW, Clarke G, Stanton C, Dinan TG, Cryan JF. Microbiota and neurodevelopmental windows: Implications for brain disorders. Trends Mol Med. 2014;20:509–18.CrossRefPubMed
54.
Foster JA, McVey Neufeld K-A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12.CrossRefPubMed
55.
Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–12.CrossRefPubMed
56.
Marques TM, Cryan JF, Shanahan F, Fitzgerald GF, Ross RP, Dinan TG, et al. Gut microbiota modulation and implications for host health: Dietary strategies to influence the gut-brain axis. Innov Food Sci Emerg Technol. 2014;22:239–47.CrossRef
57.
Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci. 2011;108:16050–5.CrossRefPubMedPubMedCentral
58.
Messaoudi M, Violle N, Bisson JF, Desor D, Javelot H, Rougeot C. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2:256–61.CrossRefPubMed
59.
Benton D, Williams C, Brown A. Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr. 2007;61:355–61.CrossRefPubMed
60.
Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat D, et al. Consumption of fermented milk product with probiotic moduates brain activity. Gastroenterology. 2013;144(7):1394–401.CrossRefPubMed
61.
O’hara MW, Swain AM. Rates and risk of postpartum depression—a meta-analysis. Int Rev Psychiatry. 1996;8:37–54.CrossRef
62.
Dennis CL, Doswell T. Psychosocial and psychological interventions for preventing postpartum depression. Cochrane database Syst. Rev. 2013; Art.No.: CD001134. DOI: 10.​1002/​14651858.​CD001134.
63.
Dias CC, Figueiredo B. Breastfeeding and depression: A systematic review of the literature. J Affect Disord. 2015;171:142–54.CrossRefPubMed
64.
Vliegen N, Casalin S, Luyten P. The course of postpartum depression: a review of longitudinal studies. Harv Rev Psychiatry. 2014;22:1–22.CrossRefPubMed
65.
Themeau TM, Grambsch PM. Modeling survival data: extending the Cox Model. New York: Springer; 2000.
66.
European Task Force on Atopic Dermatitis. Severity Scoring of Atopic Dermatitis: The SCORAD Index. Dermatology. 1993;186:23–31.CrossRef
67.
Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001–2004 National Health and Nutrition Examination Survey data. Obstet Gynecol. 2007;109:114–20.CrossRefPubMed
68.
Waldie KE, Peterson ER, D’Souza S, Underwood L, Pryor JE, Carr PA, et al. Depression symptoms during pregnancy: Evidence from Growing Up in New Zealand. J Affect Disord. 2015;186:66–73.CrossRefPubMed
69.
Williams HC, Burney PGJ, Hay RJ, Archer CB, Shipley MJ, Hunter JJA, et al. The UK Working Party’s Diagnostic Criteria for Atopic Dermatitis. Br J Dermatol. 1994;131:383–96.CrossRefPubMed
70.
Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. 1991;29:297–301.PubMedPubMedCentral
71.
Cox JL, Holden JM, Sagovsky R. Detection of post natal depression: development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987;150:782–6.CrossRefPubMed
72.
Marteau TM, Bekker H. The development of a six-item short-form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI). Br J Clin Psychol. 1992;31(Pt 3):301–6.CrossRefPubMed
73.
WHO Expert Committee. Physical Status: the use and interpretation of anthropometry. Technical Report Series No. 854. Geneva: World Health Organisation; 1995.
74.
Ramírez-Santana C, Pérez-Cano FJ, Audí C, Castell M, Moretones MG, López-Sabater MC, et al. Effects of cooling and freezing storage on the stability of bioactive factors in human colostrum. J Dairy Sci. 2012;95:2319–25.CrossRefPubMed
75.
76.
Dekker JW, Wickens K, Black PN, Stanley T, Mitchell EA, Fitzharris P, et al. Safety aspects of probiotic bacterial strains Lactobacillus rhamnosus HN001 and Bifidobacterium animalis subsp. lactis HN019 in human infants aged 0–2 years. Intern Dairy J. 2009;19:149–54.CrossRef
77.
Dugoua J-J, Machado M, Zhu X, Chen X, Koren G, Einarson TR. Probiotic safety in pregnancy: A systematic review and meta-analysis of randomized controlled trials of Lactobacillus, Bifidbacterium, and Saccharomyces spp. J Obstet Gynaecol Can. 2009;31:542–52.CrossRefPubMed
78.
Kaplas N, Isolauri E, Lampi A-M, Ojala T, Laitinen K. Dietary counseling and probiotic supplementation during pregnancy modify placental phospholipid fatty acids. Lipids. 2007;42:865–70.CrossRefPubMed
79.
Campbell DE. Probiotics and primary prevention of atopic disease: are we closer to a firm evidence base for clinical use? Clin Exp Allergy. 2013;43:978–80.CrossRefPubMed
80.
Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8:1–13.CrossRef
Metadata
Title
The Probiotics in Pregnancy Study (PiP Study): rationale and design of a double-blind randomised controlled trial to improve maternal health during pregnancy and prevent infant eczema and allergy
Authors
Christine Barthow
Kristin Wickens
Thorsten Stanley
Edwin A. Mitchell
Robyn Maude
Peter Abels
Gordon Purdie
Rinki Murphy
Peter Stone
Janice Kang
Fiona Hood
Judy Rowden
Phillipa Barnes
Penny Fitzharris
Jeffrey Craig
Rebecca F. Slykerman
Julian Crane
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2016
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-016-0923-y

Other articles of this Issue 1/2016

BMC Pregnancy and Childbirth 1/2016 Go to the issue

Research article

The availability of emergency obstetric care in the context of the JSY cash transfer programme in Madhya Pradesh, India

Research article

Breech delivery at a University Hospital in Tanzania

Research article

Determinants of breastfeeding initiation and cessation among employed mothers: a prospective cohort study

Research article

Determinants of institutional birth among women in rural Nepal: a mixed-methods cross-sectional study

Research article

Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review

Research article

High prevalence of herpes simplex virus (HSV)- type 2 co-infection among HIV-positive women in Ukraine, but no increased HIV mother-to-child transmission risk