Association of Maternal Diabetes With Neonatal Outcomes of Very Preterm and Very Low-Birth-Weight Infants: An International Cohort Study

Martina Persson; Prakesh S Shah; Franca Rusconi; Brian Reichman; Neena Modi; Satoshi Kusuda; Liisa Lehtonen; Stellan Håkansson; Junmin Yang; Tetsuya Isayama; Marc Beltempo; Shoo Lee; Mikael Norman

doi:10.1001/jamapediatrics.2018.1811

. 2018 Jul 2;172(9):867–875. doi: 10.1001/jamapediatrics.2018.1811

Association of Maternal Diabetes With Neonatal Outcomes of Very Preterm and Very Low-Birth-Weight Infants

An International Cohort Study

Martina Persson ^1,^2,^✉, Prakesh S Shah ^3,^4,⁵, Franca Rusconi ⁶, Brian Reichman ⁷, Neena Modi ⁸, Satoshi Kusuda ⁹, Liisa Lehtonen ¹⁰, Stellan Håkansson ¹¹, Junmin Yang ⁵, Tetsuya Isayama ⁹, Marc Beltempo ^5,¹², Shoo Lee ^3,^4,⁵, Mikael Norman ^13,¹⁴, for the International Network for Evaluating Outcomes of Neonates

¹Department of Medicine, Clinical Epidemiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

²Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

³Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada

⁴Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada

⁵Maternal-Infant Care Research Centre, Mount Sinai Hospital, Toronto, Ontario, Canada

⁶Unit of Epidemiology Meyer Children’s University Hospital and Regional Health Agency, Florence, Italy

⁷Israel Neonatal Network, Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer, Israel

⁸Neonatal Data Analysis Unit, Section of Neonatal Medicine, Department of Medicine, Imperial College London, Chelsea and Westminster campus, London, England

⁹Division of Neonatology, National Center for Child Health and Development, Tokyo, Japan

¹⁰Turku University Hospital and University of Turku, Finland

¹¹Department of Clinical Science/Pediatrics, Umeå University, Umeå, Sweden

¹²Department of Pediatrics, McGill University Health Centre, Montreal, Québec, Canada

¹³Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

¹⁴Department of Neonatal Medicine, Karolinska University Hospital, Stockholm, Sweden

Group Information: International Network for Evaluating Outcomes (iNeo) of Neonates investigators are listed at the end of this article.

Accepted for Publication: May 4, 2018.

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Corresponding Author: Martina Persson, MD, PhD, Clinical Epidemiology Unit (T2), Department of Medicine Solna, Karolinska Institutet, SE-171 76 Stockholm, Sweden (martina.persson@ki.se).

Published Online: July 2, 2018. doi:10.1001/jamapediatrics.2018.1811

Author Contributions: Dr Shah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Persson, Shah, Rusconi, Reichman, Lehtonen, Hakansson, Isayama, Beltempo, Lee, Norman.

Acquisition, analysis, or interpretation of data: Persson, Shah, Reichman, Kusuda, Lehtonen, Hakansson, Yang, Isayama, Lee, Norman.

Drafting of the manuscript: Persson, Kusuda, Norman.

Critical revision of the manuscript for important intellectual content: Persson, Shah, Rusconi, Reichman, Lehtonen, Hakansson, Yang, Isayama, Beltempo, Lee.

Statistical analysis: Shah, Yang, Lee, Norman.

Obtained funding: Shah.

Administrative, technical, or material support: Shah, Rusconi, Kusuda, Hakansson, Beltempo.

Supervision: Rusconi, Lee, Norman.

Conflict of Interest Disclosures: None reported.

Funding/Support: Funding for the International Network for Evaluating Outcomes of Neonates Investigators has been provided by a Canadian Institutes of Health Research Chair in Reproductive and Child Health Services and Policy Research grant (APR-126340) (Dr Shah). The Australian and New Zealand Neonatal Network is predominantly funded by membership contributions from participating centers. The Canadian Neonatal Network is funded by financial support from the Canadian Institutes of Health Research (grant FRN87518) and individual participating centers. The Finnish Medical Birth Register is governmentally funded and kept by the National Institute for Health and Welfare (THL). The Israel Neonatal Network very low-birth-weight infant database is partially funded by the Israel Center for Disease Control and the Ministry of Health. The Neonatal Research Network of Japan is partly funded by a Health Labour Sciences research grant from the Ministry of Health, Labour and Welfare of Japan. SEN1500 is supported by funds from the Spanish Neonatal Society. The Swedish Neonatal Quality Register is funded by the Swedish Government (Ministry of Health and Social Affairs) and the body of regional health care clinicians (County Councils). SwissNeoNet is partially funded by participating units in the form of membership fees. Tuscany Neonatal Network is funded by the Tuscany Region. The UK Neonatal Collaborative receives no core funding.

Role of the Funder/Sponsor: The funding organizations played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

International Network for Evaluating Outcomes of Neonates Investigators: Canadian Neonatal Network (CNN): Prakesh S Shah, MD, MSc (director, CNN and site investigator), Mount Sinai Hospital; Adele Harrison, MD, MBChB, Victoria General Hospital; Anne Synnes, MDCM, MHSC, and Joseph Ting, MD, B.C. Women’s Hospital and Health Centre; Zenon Cieslak, MD, Royal Columbian Hospital; Rebecca Sherlock, MD, Surrey Memorial Hospital; Wendy Yee, MD, Foothills Medical Centre; Khalid Aziz, MBBS, MA, MEd, and Jennifer Toye, MD, Royal Alexandra Hospital; Carlos Fajardo, MD, Alberta Children’s Hospital; Zarin Kalapesi, MD, Regina General Hospital; Koravangattu Sankaran, MD, MBBS, and Sibasis Daspal, MD, Royal University Hospital, Saskatoon; Mary Seshia, MBChB, Winnipeg Health Sciences Centre; Ruben Alvaro, MD, St. Boniface General Hospital; Amit Mukerji, MD, Hamilton Health Sciences Centre; Orlando Da Silva, MD, MSc, London Health Sciences Centre; Chuks Nwaesei, MD, Windsor Regional Hospital; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children; Michael Dunn, MD, Sunnybrook Health Sciences Centre; Brigitte Lemyre, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital; Kimberly Dow, MD, Kingston General Hospital; Ermelinda Pelausa, MD, Jewish General Hospital; Keith Barrington, MBChB, Hôpital Sainte-Justine; Christine Drolet, MD, and Bruno Piedboeuf, MD, Centre Hospitalier Universitaire de Québec; Martine Claveau, MSc, LLM, NNP, and Marc Beltempo, MD, McGill University Health Centre; Valerie Bertelle, MD, and Edith Masse, MD, Centre Hospitalier Universitaire de Sherbrooke; Roderick Canning, MD, Moncton Hospital; Hala Makary, MD, Dr. Everett Chalmers Hospital; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital; Akhil Deshpandey, MBBS, MRCPI, Janeway Children’s Health and Rehabilitation Centre; Jehier Afifi, MB BCh, MSc, IWK Health Centre; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital; and Shoo K Lee, MBBS, PhD (chairman, CNN), Mount Sinai Hospital. Finnish Medical Birth Register: Sture Andersson, MD, Helsinki University Hospital; Liisa Lehtonen, MD, Turku University Hospital; Outi Tammela, MD, Tampere University Hospital; Ulla Sankilampi, MD, Kuopio University Hospital; and Timo Saarela, MD, Oulu University Hospital. Israel Neonatal Network: Eli Heymann, MD, Assaf Harofeh Medical Center; Shmuel Zangen, MD, Barzilai Medical Center; Tatyana Smolkin, MD, Baruch Padeh Medical Center; Francis Mimouni, MD, Bikur Cholim Hospital; David Bader, MD, Bnai Zion Medical Center; Avi Rothschild, MD, Carmel Medical Center; Zipora Strauss, Chaim Sheba Medical Center; Clari Felszer, MD, Emek Medical Center; Hussam Omari, MD, French Saint Vincent de Paul Hospital; Smadar Even Tov-Friedman, MD, Hadassah University Hospital-Ein Karem; Benjamin Bar-Oz, MD, Hadassah University Hospital-Har Hazofim; Michael Feldman, MD, Hillel Yaffe Medical Center; Nizar Saad, MD, Holy Family (Italian) Hospital; Orna Flidel-Rimon, MD, Kaplan Medical Center; Meir Weisbrod, MD, Laniado Hospital; Daniel Lubin, MD, Mayanei Hayeshua Medical Center; Ita Litmanovitz, MD, Meir Medical Center; Amir Kugelman, MD, Rambam Medical Center; Eric Shinwell, MD, Rivka Ziv Medical Center; Gil Klinger, MD, Schneider Children’s Medical Center of Israel; Yousif Nijim, MD, Scottish (EMMS) Hospital; Alona Bin-Nun, MD, Shaare-Zedek Medical Center; Agneta Golan, MD, Soroka Medical Center; Dror Mandel, MD, Sourasky Medical Center; Vered Fleisher-Sheffer, MD,Western Galilee Medical Center; David Kohelet, MD, Wolfson Medical Center; and Lev Bakhrakh, MD, Yoseftal Hospital. Neonatal Research Network Japan: Satoshi Hattori, MD, Sapporo City Hospital; Masaru Shirai, MD, Asahikawa Kosei Hospital; Toru Ishioka, MD, Engaru Kosei Hospital; Toshihiko Mori, MD, NTT East Sappro Hospital; Takasuke Amizuka, MD, Aomori Prefecture Central Hospital; Toru Huchimukai, MD, Iwate Prefecture Ohfunato Hospital; Hiroshi Yoshida, MD, Tsuruoka City Shonai Hospital; Ayako Sasaki, MD, Yamagata University; Junichi Shimizu, MD, Tsuchiura Kyodo Hospital; Toshihiko Nakamura, MD, National Nishisaitama Central Hospital; Mami Maruyama, MD, Jichi Medical University Saitame Medical Center; Hiroshi Matsumoto, MD, Asahi Central Hospital; Shinichi Hosokawa, MD, National International Medical Center; Atsuko Taki, MD, Tokyo Medical and Dental University; Machiko Nakagawa, MD, Saint Luku Hospital; Kyone Ko, MD, Sanikukai Hospital; Azusa Uozumi, MD, Odawara City Hospital; Setsuko Nakata, MD, Iida City Hospital; Akira Shimazaki, MD, National Shinshu Ueda Medical Center; Tatsuya Yoda, MD, Saku General Hospital; Osamu Numata, MD, Nagaoka Red Cross Hospital; Hiroaki Imamura, MD, Koseiren Takaoka Hospital; Azusa Kobayashi, MD, Kanazawa Medical University; Shuko Tokuriki, MD, Fukui University; Yasushi Uchida, MD, National Nagara Medical Center; Takahiro Arai, MD, Takayama Red Cross Hospital; Mitsuhiro Ito, MD, Fujieda City Hospital; Kuniko Ieda, MD, Koritsu Tosei Hospital; Toshiyuki Ono, MD, Komaki City Hospital; Masashi Hayashi, MD, Okazaki City Hospital; Kanemasa Maki, MD, Yokkaichi City Hospital; MieToru Yamakawa, MD, Japan Baptist Hospital; Masahiko Kawai, MD, Kyoto University; Noriko Fujii, MD, Fukuchiyama City Hospital; Kozue Shiomi, MD, Kyoto City Hospital; Koji Nozaki, MD, Mitubishi Kyoto Hospital; Hiroshi Wada, MD, Yodogawa Christian Hospital; Taho Kim, MD, Osaka City Sumiyoshi Hospital; Yasuyuki Tokunaga, MD, Toyonaka City Hospital; Akihiro Takatera, MD, Chifune Hospital; Toshio Oshima, MD, Bell Land General Hospital; Hiroshi Sumida, MD, Rinku General Hospital; Yae Michinomae, MD, Yao City Hospital; Yoshio Kusumoto, MD, Osaka General Medical Center; Seiji Yoshimoto, MD, Kobe Children's Hospital; Takeshi Morisawa, MD, Kakogawa City Hospital; Tamaki Ohashi, MD, Hyogo Prefectural Awaji Hospital; Yukihiro Takahashi, MD, Nara Prefecture Medical University; Moriharu Sugimoto, MD, Tsuyama Central Hospital; Noriaki Ono, MD, Hiroshima University; Shinichiro Miyagawa, MD, National Kure Medical Center; Takahiko Saijo, MD, Tokushima University; Takashi Yamagami, MD, Tokushima City Hospital; Kosuke Koyano, MD, Kagawa University; Shoko Kobayashi, MD, Shikoku Medical Center for Children and Adults; Takeshi Kanda, MD, National Kyushu Medical Center; Yoshihiro Sakemi, MD, National Kokura Medical Center; Mikio Aoki, MD, National Nagasaki Medical Center; Koichi Iida, MD, Oita Prefectural Hospital; Mitsushi Goshi, MD, Nakatsu City Hospital; and Yuko Maruyama, MD, Imakyure General Hospital. Swedish Neonatal Quality Register: Jiri Kofron, MD, Södra Älvsborgs Sjukhus; Katarina Strand Brodd, MD, Mälarsjukhuset; Andreas Odlind, MD, Falu Lasarett; Lars Alberg, MD, Gällivare Sjukhus; Sofia Arwehed, MD, Gävle Sjukhus; Ola Hafström, MD, SU/Östra; Anna Kasemo, MD, Länssjukhuset; Karin Nederman, MD, Helsingborgs Lasarett; Lars Åhman, MD, Hudiksvalls Sjukhus; Fredrik Ingemarsson, MD, Länssjukhuset Ryhov; Henrik Petersson, MD, Länssjukhuset; Pernilla Thurn, MD, Blekingesjukhuset; Eva Albinsson, MD, Centralsjukhuset; Bo Selander, MD, Centralsjukhuset; Thomas Abrahamsson, MD, Universitetssjukhuset; Ingela Heimdahl, MD, Sunderby sjukhus; Kristbjorg Sveinsdottir, MD, Skånes Universitetssjukhus; Erik Wejryd, MD, Vrinnevisjukhuset; Anna Hedlund, MD, Skellefteå Lasarett; Maria Katarina Söderberg, MD, Kärnsjukhuset Skaraborg; Boubou Hallberg, MD, Karolinska Sjukhuset; Thomas Brune, MD, Södersjuhuset; Jens Bäckström, MD, Länssjukhuset; Johan Robinson, MD, Norra Älvsborgs Länssjukhus; Aijaz Farooqi, MD, Norrlands Universitetssjukhus; Erik Normann, MD, Akademiska Barnsjukhuset; Magnus Fredriksson, MD, Visby Lasarett; Anders Palm, MD, Västerviks Sjukhus; Urban Rosenqvist, MD, Centrallasarettet; Bengt Walde, MD, Centrallasarettet; Cecilia Hagman, MD, Lasarettet; Andreas Ohlin, MD, Universitetssjukhuset; Rein Florell, MD, Örnsköldsviks Sjukhus; and Agneta Smedsaas-Löfvenberg, MD, Östersunds Sjukhus. TIN Toscane Online Network: Carlo Dani, MD, Careggi University Hospital; Patrizio Fiorini, MD, Anna Meyer Children’s University Hospital; Paolo Ghirri, MD, University Hospital of Pisa; and Barbara Tomasini, MD, University Hospital of Siena. UK Neonatal Collaborative: Anita Mittal, MBChB, Bedford Hospital; Jonathan Kefas, MBChB, Lister Hospital; Anand Kamalanathan, MBChB, Arrowe Park Hospital; Jayachandran, MBChB, Leighton Hospital; Bill Yoxall, MBChB, Liverpool Women's Hospital; Tim McBride, MBChB, Ormskirk District General Hospital; Delyth Webb, MBChB, Warrington Hospital; Ross Garr, MBChB, Whiston Hospital; Ahmed Hassan, MBChB, Broomfield Hospital; Priyadarshan Ambadkar, MBChB, James Paget Hospital; Mark Dyke, MBChB, Norfolk & Norwich University Hospital; Katharine McDevitt, MBChB, Peterborough City Hospital; Glynis Rewitzky, MBChB, Queen Elizabeth Hospital; Angela D'Amore, MBChB, Rosie Maternity Hospital; Nagesh Panasa, MBChB, North Manchester General Hospital; Paul Settle, MBChB, Royal Bolton Hospital; Natasha Maddock, MBChB, Royal Oldham Hospital; Ngozi Edi-Osagie, MBChB, St Mary's Hospital; Christos Zipitis, MBChB, The Robert Albert Edward Infirmary; Carrie Heal, MBChB, Stepping Hill Hospital; Jacqeline Birch, MBChB, Tameside General Hospital; Abdul Hasib, MBChB, Darent Valley Hospital; Aung Soe, MBChB, Medway Maritime Hospital; Niraj Kumar, MBChB, Queen Elizabeth The Queen Mother Hospital; Hamudi Kisat, MBChB, Tunbridge Wells Hospital; Vimal Vasu, MBChB, William Harvey Hospital; Meera Lama, MBChB, Lancashire Women & Newborn Centre; Richa Gupta, MBChB, Royal Preston Hospital; Chris Rawlingson, MBChB, Victoria Hospital; Tim Wickham, MBChB, Barnet Hospital; Marice Theron, MBChB, The Royal Free Hospital; Giles Kendall, MBChB, University College Hospital; Aashish Gupta, MBChB, Basildon Hospital; Narendra Aladangady, MBChB, Homerton Hospital; Imdad Ali, MBChB, Newham General Hospital; Lesley Alsford, MBChB, North Middlesex University Hospital; Wilson Lopez, MBChB, Queen's Hospital; Vadivelam Murthy, MBChB, The Royal London Hospital; Caroline Sullivan, MBChB, Whipps Cross University Hospital; Mark Thomas, MBChB, Chelsea & Westminster Hospital; Tristan Bate, MBChB, Hillingdon Hospital; Sunit Godambe, MBChB, Queen Charlotte's Hospital; Sunit Godambe, MBChB, St Mary's Hospital; Timothy Watts, MBChB, Guy's & St Thomas’ Hospital; Jauro Kuna, MBChB, University Hospital Lewisham; John Chang, MBChB, Croydon University Hospital; Vinay Pai, MBChB, Kingston Hospital; Charlotte Huddy, MBChB, St George's Hospital; Salim Yasin, MBChB, St Helier Hospital; Richard Nicholl, MBChB, Northwick Park Hospital; Poornima Pandey, MBChB, Kettering General Hospital; Jonathan Cusack, MBChB, Leicester General Hospital; Venkatesh Kairamkonda, MBChB, Leicester Royal Infirmary; Dominic Muogbo, MBChB, Queen's Hospital; Liza Harry, MBChB, Alexandra Hospital; Phil Simmons, MBChB, Birmingham Heartlands Hospital; Julie Nycyk, MBChB, City Hospital, Birmingham; Phil Simmons, MBChB, Good Hope Hospital; Andrew Gallagher, MBChB, Worcestershire Royal Hospital; Tilly Pillay, MBChB, New Cross Hospital; Sanjeev Deshpande, MBChB, Royal Shrewsbury Hospital; Mahadevan, MBChB, Russells Hall Hospital; Alison Moore, MBChB, University Hospital of North Staffordshire; Simon Clark, MBChB, The Jessop Wing; Mehdi Garbash, MBChB, Darlington Memorial Hospital; Mithilesh Lal, MBChB, James Cook University Hospital; Majd Abu-Harb, MBChB, Sunderland Royal Hospital; Mehdi Garbash, MBChB, University Hospital Of North Durham; Alex Allwood, MBChB, Derriford Hospital; Michael Selter, MBChB, North Devon District Hospital; Paul Munyard, MBChB, Royal Cornwall Hospital; David Bartle, MBChB, Royal Devon & Exeter Hospital; Siba Paul, MBChB, Torbay Hospital; Graham Whincup, MBChB, Conquest Hospital; Abdus Mallik, MBChB, Frimley Park Hospital; Philip Amess, MBChB, Princess Royal Hospital; Charles Godden, MBChB, Royal Surrey County Hospital; Philip Amess, MBChB, Royal Sussex County Hospital; Peter Reynolds, MBChB, St Peter's Hospital; Indranil Misra, MBChB, Milton Keynes Foundation Trust Hospital; Peter De Halpert, MBChB, Royal Berkshire Hospital; Sanjay Salgia, MBChB, Stoke Mandeville Hospital; Rekha Sanghavi, MBChB, Wexham Park Hospital; Ruth Wigfield, MBChB, Basingstoke & North Hampshire Hospital; Abby Deketelaere, MBChB, Dorset County Hospital; Minesh Khashu, MBChB, Poole Hospital NHS Foundation Trust; Michael Hall, MBChB, Princess Anne Hospital; Charlotte Groves, MBChB, Queen Alexandra Hospital; Nick Brown, MBChB, Salisbury District Hospital; Nick Brennan, MBChB, St Richard's Hospital; Katia Vamvakiti, MBChB, Worthing Hospital; John McIntyre, MBChB, Royal Derby Hospital; Simon Pirie, MBChB, Gloucestershire Royal Hospital; Stephen Jones, MBChB, Royal United Hospital; Paul Mannix, MBChB, Southmead Hospital; Pamela Cairns, MBChB, St Michael's Hospital; Megan Eaton, MBChB, Yeovil District Hospital; Karin Schwarz, MBChB, Calderdale Royal Hospital; David Gibson, MBChB, Pinderfields General Hospital; Lawrence Miall, MBChB, Leeds Neonatal Service; David Gibson, MBChB, Pinderfields General Hospital; and Krishnamurthy, MBChB, Walsall Manor Hospital.

Additional Contributions: We thank all investigators and data abstractors of the networks participating in the International Network for Evaluating Outcomes of Neonates Investigators consortium. We thank Sarah Hutchinson, PhD, Maternal-Infant Care Research Centre (MiCare), for providing editorial support for this articlet and other MiCare staff for organizational and statistical support. None of these individuals were compensated for their contributions.

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Corresponding author.

PMCID: PMC6143059 PMID: 29971428

Key Points

Question

Does maternal diabetes, a strong risk factor for very preterm birth, have an association with risks of in-hospital mortality or severe neonatal morbidity in very preterm infants?

Findings

In this international cohort study of singleton infants born very preterm, the risk of in-hospital mortality or severe neonatal morbidity for infants who were born to mothers with diabetes was not significantly different from the risk of infants who were born to mothers without diabetes.

Meaning

Maternal diabetes is not associated with an excess risk of in-hospital mortality or severe morbidity in infants born very preterm in high-income countries.

Abstract

Importance

Diabetes in pregnancy is associated with a 2-times to 3-times higher rate of very preterm birth than in women without diabetes. Very preterm infants are at high risk of death and severe morbidity. The association of maternal diabetes with these risks is unclear.

Objective

To determine the associations between maternal diabetes and in-hospital mortality, as well as neonatal morbidity in very preterm infants with a birth weight of less than 1500 g.

Design, Setting, Participants

This retrospective cohort study was conducted at 7 national networks in high-income countries that are part of the International Neonatal Network for Evaluating Outcomes in Neonates and used prospectively collected data on 76 360 very preterm, singleton infants without malformations born between January 1, 2007, and December 31, 2015, at 24 to 31 weeks’ gestation with birth weights of less than 1500 g, 3280 (4.3%) of whom were born to diabetic mothers.

Exposures

Any type of diabetes during pregnancy.

Main Outcomes and Measures

The primary outcome was in-hospital mortality. The secondary outcomes were severe neonatal morbidities, including intraventricular hemorrhages of grade 3 to 4, cystic periventricular leukomalacia, retinopathy of prematurity needing treatment and bronchopulmonary dysplasia, and other morbidities, including respiratory distress, treated patent ductus arteriosus, and necrotizing enterocolitis. Odds ratios (ORs) with 95% confidence intervals were estimated, adjusted for potential confounders, and stratified by gestational age (GA), sex, and network.

Results

The mean (SD) birth weight of offspring born to mothers with diabetes was significantly higher at 1081 (262) g than in offspring born to mothers without diabetes (mean [SD] birth weight, 1027 [270] g). Mothers with diabetes were older and had more hypertensive disorders, antenatal steroid treatments, and deliveries by cesarean delivery than mothers without diabetes. Infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. In-hospital mortality (6.6% vs 8.3%) and the composite of mortality and severe morbidity (31.6% vs 40.6%) were lower in infants of mothers with diabetes. However, in adjusted analyses, no significant differences in in-hospital mortality (adjusted OR, 1.16 (95% CI, 0.97-1.39) or the composite of mortality and severe morbidity (adjusted OR, 0.99 (95% CI, 0.88-1.10) were observed. With few exceptions, outcomes of infants born to mothers with and without diabetes were similar regardless of infant sex, GA, or country of birth.

Conclusions and Relevance

In high-resource settings, maternal diabetes is not associated with an increased risk of in-hospital mortality or severe morbidity in very preterm infants with a birth weight of fewer than 1500 g.

This cohort study explored the association between maternal diabetes and the risk of in-hospital mortality or severe neonatal morbidity for infants born very preterm across 7 national networks in high-income countries.

Introduction

Diabetes affects hundreds of millions of people. The incidence is compounded by obesity and is increasing in many parts of the world, including in women of reproductive age.^1,2 Diabetes and obesity are significant risk factors for spontaneous and indicated preterm delivery (<37 weeks’ gestation).^2,3,4 Despite advances in the care of women with pregestational diabetes (types 1 and 2), rates of preterm delivery remain 3- to 5-fold higher in women with diabetes than in the general obstetric population without diabetes.^5,6,7 Furthermore, the risk of preterm delivery is significantly increased in pregnancies with gestational diabetes.⁸

Worldwide, approximately 11% of births are preterm and the incidence is rising.⁹ Preterm birth is a major contributor to the global burden of disease.^10,11 Infants born with very low birth weights (<1500 g) or who are very preterm (<32 weeks’ gestation) constitute 1% to 2% of all births but account for up to half of all neonatal and infant deaths,¹² a significant proportion of childhood disability¹³ and high health care costs.¹² In offspring of women with diabetes, preterm birth is the most important contributor to neonatal morbidity.¹⁴

While the obstetric risks that are associated with diabetes in pregnancy are fairly well established, as is knowledge of the increased risks of malformations, fetal death, fetal macrosomia, and neonatal hypoglycemia, less is known about other neonatal outcomes.^5,6,7,15 In particular, it is unclear how maternal diabetes affects infants who are born very preterm. The few studies that address this question describe conflicting results. One article indicated a higher risk of respiratory distress syndrome (RDS) in preterm infants born to mothers with diabetes vs infants born to mothers without diabetes,¹⁶ while other studies did not detect a difference in the risk of RDS.¹⁷ Preterm infants born to mothers with diabetes have even been reported to have a lower risk of bronchopulmonary dysplasia than infants born to mothers without diabets.¹⁸ However, an increased risk of necrotizing enterocolitis (NEC), neonatal sepsis, and small head circumference at follow-up were recently reported for extremely preterm infants born to mothers with type 1 diabetes.^19,20

The overall research question was to fill the previously mentioned gap in knowledge and to provide solid estimates for neonatal outcomes in very preterm infants born to mothers with diabetes. Given the comparatively low prevalence of maternal diabetes and the low incidence of very preterm birth, large sample sizes are required to accurately estimate neonatal risks that are associated with maternal diabetes. The International Network for Evaluating Outcomes in Neonates (iNeo) is a collaboration between neonatal networks from high-income countries with the goal of improving outcomes for children born very preterm and with a very low birth weight.²¹ With detailed information on more than 100 000 infants, the iNeo database offers an opportunity to assess the associations of maternal diabetes with neonatal outcomes. We hypothesized that any maternal diabetes would increase the risk of in-hospital mortality and morbidity in very preterm infants with birth weights of fewer than 1500 g.

Methods

Setting

The study used data from national neonatal networks in 7 high-resource countries in 3 continents: Canada, Finland, Israel, Italy, Japan, Sweden, and the United Kingdom. The participating networks and the iNeo Coordinating Centre at the Maternal-Infant Research Centre, Mount Sinai Hospital in Toronto, Ontario, Canada, obtained data sharing agreements and research ethics approval for data collection and transfer. The rules and regulations of each country were followed and ethics approval was obtained by each individual country. All participants were informed about the collection of the data in the register with the purpose of quality assessment of care and research.

Data Sources

Prospectively collected individual-level data from the following neonatal networks were included: Canadian Neonatal Network,²² Finnish Medical Birth Register, Neonatal Research Network of Japan,²³ Israel Neonatal Network,²⁴ Tuscany Neonatal Network (TIN-Toscane online), the Swedish Neonatal Quality Register, and UK Neonatal Collaborative (UKNC).²⁵ Previous reports provide details of the proportion of neonates in this data set out of the total number of neonates born in each country.²⁵ Based on a consensus between all iNeo networks, data collection was standardized and included information on maternal age, maternal diabetes and hypertensive disorders in pregnancy, mode of delivery, neonatal characteristics, and outcomes. All variables were classified according to the tenth version of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).

Study Population

The study population included all singleton infants born alive in high-income countries who were very preterm (24-31 weeks’ gestation) and with a birth weight of less than 1500 g. The database did not hold information on stillbirths. Multiple pregnancies and major congenital malformations were excluded. The study period covered 9 years from January 1, 2007, to December 31, 2015.

Main Exposure

A diagnosis of any type of pregestational diabetes or gestational diabetes, recorded in tick boxes (pregestational or gestational diabetes were ticked if “yes”) or defined according to ICD 10 codes, was recorded as a dichotomous variable in the iNeo database. Differentiating between pregestational and gestational diabetes was not possible, and information on the duration of diabetes or the type of treatment (insulin or oral antidiabetic agents) was not available. The definitions and screening protocols for diabetes in pregnancy used in the participating countries are provided in eTable 1 in the Supplement.

Outcomes

The main outcome was in-hospital infant mortality. Secondary outcomes included a composite of mortality and severe neonatal morbidity. In addition, severe and major morbidities were analyzed as separate outcomes. Severe neonatal morbidity was defined as 1 or more of the following diagnoses: intraventricular hemorrhage (IVH) grade of 3 to 4,²⁶ cystic periventricular leukomalacia (cPVL),²⁷ treated severe retinopathy of prematurity (ROP),²⁸ and bronchopulmonary dysplasia (BPD, defined as oxygen requirement, with or without mechanical respiratory support, at 36 weeks of postmenstrual age or at time of transfer to level 2 units).²⁹ Additional morbidities studied were RDS, severe brain injury (IVH grade 3-4 or cPVL), pharmacologically or surgically treated patent ductus arteriosus, and NEC.³⁰ Necrotizing enterocolitis was analyzed in a subgroup of the cohort because data from the UKNC were not available for stage 2 or 3 NEC.

Covariates

Covariates and potential confounders included advanced (≥35 years) maternal age at delivery, hypertensive disorder of pregnancy (chronic hypertension, gestational hypertension, preeclampsia, eclampsia, or HELLP syndrome), any treatment with antenatal corticosteroids, mode of delivery, delivery outside of a tertiary center (outborn; for all networks but UKNC), gestational age (GA) at delivery, sex, birth weight z score, and neonatal network.

Statistical Analysis

Maternal and infant characteristics and outcomes were compared between neonates born to mothers with and without diabetes. Frequency (percentage) or means with standard deviations were reported. Differences were assessed with Pearson χ² and the t test for categorical variables and continuous variables, respectively. Univariate and multivariable logistic analyses were applied for primary and secondary outcomes. Odds ratios (ORs) with 95% confidence intervals were estimated. In the adjusted analyses, covariates were included as confounders based on the literature or statistical significance. Maternal age was introduced as a dichotomous variable (ie, age ≥35 years, yes or no) and GA was analyzed by week and birth weight as z scores. Two regression models were used: model 1 included the following possible confounders: a maternal age of 35 years or older, maternal hypertensive disorder in pregnancy, GA, sex, birth weight z score, and network. Model 2 included the variables in model 1 as well as antenatal treatment with corticosteroids, mode of delivery, and outborn status. Stratified analyses by GA, sex, and network were also performed.

Finally, propensity score (PS) matching was used, stratified by networks. The PS represented a single-index variable summarizing the maternal and perinatal covariates known or hypothesized to be either related to the exposure (maternal diabetes) or the neonatal outcomes. Matching the PS among infants born to mothers with diabetes to that of infants born to mothers without diabetes was performed using the SAS macro “match.sas” (SAS Institute) and was based on a caliper width of 0.2 times the standard deviation of the logit-transformed PS. Within each matched sample (n = 2914 pairs), covariates were tested for balance using paired t tests for continuous variables, and the McNemar tests for categorical covariates. The association between maternal diabetes and neonatal outcomes in each matched sample was examined using logistic regression analyses as described previously, using generalized estimating equations with an unstructured correlation. All analyses were conducted using SAS, version 9.4 (SAS Institute) with a 2-sided significance level of P = .05. The statistic package R (R Foundation) was applied to generate the plot.

Results

Between January 1, 2007, and December 31, 2015, there were 78 126 singleton eligible infants, 76 360 (95.7%) of whom had information on maternal diabetes; 3280 (4.3%) infants were born to mothers with diabetes. Compared with mothers without diabetes, women with diabetes were older, had more hypertensive complications, were administered antenatal corticosteroids more often, and had cesarean deliveries more frequently (Table 1). Infants of mothers with diabetes had a higher GA and higher birth weight but lower mean birth weight z score than infants of mothers without diabetes. The rate of small for GA was similar between infants with mothers with and without diabetes; infants born to mothers without diabetes were born outside a tertiary unit more often than infants of mothers with diabetes (Table 1).

Table 1. Characteristics of Very Preterm Infants With a Very Low Birth Weight and Their Mothers.

Characteristic	No. (%)		P Value
Characteristic	Infants of Mothers With Diabetes (n = 3280)	Infants of Mothers Without Diabetes (n = 73 080)	P Value
Maternal Characteristics
Maternal age ≥35 y	1107 (36.7)	15 616 (22.5)	<.01
Hypertensive disorders of pregnancy^a	1106 (34.1)	15 214 (20.9)	<.01
Antenatal corticosteroids	2674 (83.5)	54 307 (76.6)	<.01
Cesarean delivery	2365 (72.4)	46 359 (65.3)	<.01
Neonatal Characteristics
Apgar score <7 at 5 min^b	710 (27.1)	12 723 (28.1)	.28
Gestational age, No. (%)
28-31 wk	2145 (65.4)	40 662 (55.6)	<.01
<28 wk	1135 (34.6)	32 418 (44.4)	<.01
Males	1707 (52.1)	38 434 (52.6)	.53
Birth weight, mean (SD)
Grams	1081 (262)	1027 (270)	<.01
z Score	−0.31 (0.91)	−0.28 (0.93)	.04
Small for gestational age	498 (15.2)	10 759 (14.7)	.47
Outborn,^b^,^c No./total No. (%)	196/2634 (7.4)	4239/46 106 (9.2)	<.01

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^{^a}

Hypertension in pregnancy includes gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome.

^{^b}

UK Neonatal Collaborative info unavailable.

^{^c}

No. is number in the group and total No. is the total number in the category.

Infants of mothers with diabetes had lower crude risks of in-hospital mortality and the composite of in-hospital mortality or severe neonatal morbidity (IVH grade 3-4, cPVL, treated ROP, or BPD) than infants of mothers without diabetes (Table 2). Similarly, infants of mothers with diabetes had lower rates of IVH grade of 3 to 4, treated ROP, treated patent ductus arteriosus, and BPD than infants of mothers without diabetes. In contrast, the crude risks of RDS and NEC were higher in infants of mothers with diabetes than in infants of mothers without diabetes. After adjusting for confounders (model 1), infants of mothers with diabetes had a lower risk of IVH. This difference disappeared after further adjustment for antenatal steroid treatment, mode of delivery, and outborn status (eTable 2 in the Supplement). In the final step using PS matched analyses, the risk estimates for adverse neonatal outcomes remained similar between the 2 groups (Table 2, Figure).

Table 2. In-Hospital Mortality and Morbidity of Very Preterm Infants of Mothers With Diabetes.

Characteristic	No. (%)		OR (95% CI)
Characteristic	Infants of Mothers With Diabetes (n = 3280)	Infants of Mothers Without Diabetes (n = 73 080)	Crude	Model 1 Adjusted^a	Model 2 Adjusted^b	Model 3 PS-Matched^c
In-hospital mortality	215 (6.6)	6043 (8.3)	0.78 (0.68-0.90)	1.06 (0.90-1.24)	1.16 (0.97-1.39)	1.08 (0.88-1.32)
In-hospital mortality or severe neonatal morbidity^d	984 (31.6)	28 803 (40.6)	0.67 (0.62-0.73)	0.94 (0.86-1.03)	0.99 (0.88-1.10)	0.94 (0.85-1.04)
RDS	2165 (67.0)	45 237 (62.4)	1.22 (1.13-1.32)	1.04 (0.96-1.13)	1.01 (0.91-1.11)	1.05 (0.95-1.17)
IVH grade 3-4 or cPVL	218 (6.9)	6187 (8.7)	0.78 (0.68-0.90)	0.84 (0.72-0.98)	0.91 (0.77-1.08)	0.91 (0.75-1.12)
Treated PDA	766 (23.4)	18 536 (25.4)	0.90 (0.83-0.97)	1.00 (0.91-1.10)	0.98 (0.89-1.09)	1.01 (0.91-1.13)
Severe ROP (treated)	157 (4.8)	5259 (7.2)	0.82 (0.70-0.96)	0.93 (0.77-1.11)	0.85 (0.69-1.03)	1.01 (0.81-1.26)
BPD	611 (20.3)	18 544 (27.9)	0.66 (0.60-0.72)	0.96 (0.87-1.07)	1.01 (0.89-1.14)	0.94 (0.83-1.06)
NEC^e	137 (5.2)	1940 (4.2)	1.25 (1.04-1.49)	1.18 (0.97-1.43)	1.18 (0.97-1.44)	1.10 (0.84-1.43)

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Abbreviations: BPD, bronchopulmonary dysplasia; cPVL, cystic periventricular leukomalacia; IVH, intraventricular hemorrhage; N, total number in category; n, number in group; NEC, necrotizing enterocolitis; OR, odds ratio; PDA, patent ductus arteriosus; PS, propensity score; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity.

^{^a}

Model 1 adjusted for maternal age of 35 years or older, maternal hypertensive disease in pregnancy, gestational age, sex, birth weight z score, and network.

^{^b}

Model 2 adjusted for the same covariates as in model 1 and antenatal corticosteroids, mode of delivery, and outborn.

^{^c}

Model 3: PS-matched ORs, stratified by network.

^{^d}

Severe neonatal morbidity defined as IVH grade 3-4, cPVL, treated ROP, or BPD.

^{^e}

UK info unavailable.

Figure. — Severe neonatal morbidity was indicated by an intraventricular hemorrhage (IVH) grade of 3 to 4, cystic periventricular leukomalacia (cPVL), and severe retinopathy of prematurity (ROP) that needed treatment or bronchopulmonary dysplasia (BPD). Propensity score–matched odds ratios were stratified by network. The infants were very preterm infants (<32 weeks of gestation) and were considered very low birth weight (<1500 g). NEC indicates necrotizing enterocolitis; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome.

A stratified analysis by GA week was conducted to identify GA-related risks of maternal diabetes. Infants of mothers with diabetes had a significantly higher risk of mortality at 26 weeks’ gestation and mortality or severe morbidity at 31 weeks’ gestation than infants of mothers without diabetes, while no difference in risk was found in other GA strata (test for an interaction between maternal diabetes and GA on in-hospital mortality: GA [SE], −0.02 [0.03]; P = .58) (Table 3). The rate of in-hospital mortality or severe neonatal morbidity in very preterm infants of mothers with diabetes varied from 23% to 39% across the 7 networks, but the adjusted odds of adverse outcomes in infants of mothers with diabetes did not differ significantly from that in infants of mothers without diabetes (test for interaction between maternal diabetes and network on in-hospital mortality: Canadian Neonatal Network [SE], −0.05 [0.30]; Israel Neonatal Network [SE], −0.18 [0.33]; Neonatal Research Network of Japan [SE], 0.14 [0.31]; Swedish Neonatal Quality Register [SE], 0.34 [0.42]; Finnish Medical Birth Register [SE], 0.22 [0.35]; P = .30) (Table 4).

Table 3. Mortality and Composite Outcome of Infants Born to Mothers With or Without Diabetes by Gestational Age.

Gestational Age, wk	No. (%)		OR (95% CI)
Gestational Age, wk	Infants of Mothers With Diabetes	Infants of Mothers Without Diabetes	Crude	Adjusted^a
In-hospital mortality
24	42/162 (25.9)	1760/6171 (28.5)	0.88 (0.61-1.25)	1.10 (0.70-1.71)
25	35/209 (16.8)	1294/7347 (17.6)	0.94 (0.65-1.36)	1.07 (0.69-1.68)
26	47/336 (14.0)	984/8817 (11.2)	1.29 (0.94-1.77)	1.65 (1.13-2.40)
27	31/428 (7.2)	799/10 083 (7.9)	0.91 (0.63-1.32)	0.87 (0.54-1.40)
28	29/528 (5.5)	556/11 684 (4.8)	1.16 (0.79-1.71)	1.52 (0.92-2.50)
29	14/614 (2.3)	353/11 605 (3.0)	0.74 (0.43-1.28)	1.05 (0.55-1.98)
30	9/578 (1.6)	190/10 072 (1.9)	0.82 (0.42-1.61)	0.51 (0.16-1.66)
31	8/425 (1.9)	107/7301 (1.5)	1.29 (0.62-2.66)	1.92 (0.79-4.67)
Composite outcome, in-hospital mortality or severe neonatal morbidity^b
24	130/159 (81.8)	5103/6090 (83.8)	0.87 (0.58-1.30)	1.13 (0.68-1.88)
25	141/203 (69.5)	5235/7165 (73.1)	0.84 (0.62-1.14)	0.85 (0.61-1.19)
26	185/325 (56.9)	5170/8575 (60.3)	0.87 (0.70-1.09)	1.08 (0.83-1.41)
27	171/413 (41.4)	4550/9815 (46.4)	0.82 (0.67-1.00)	1.03 (0.80-1.33)
28	149/503 (29.6)	3905/11 364 (34.4)	0.80 (0.66-0.98)	0.99 (0.77-1.26)
29	107/581 (18.4)	2670/11 208 (23.8)	0.72 (0.58-0.89)	0.89 (0.68-1.18)
30	61/541 (11.3)	1434/9704 (14.8)	0.73 (0.56-0.96)	0.75 (0.51-1.09)
31	40/394 (10.2)	736/7024 (10.5)	0.97 (0.69-1.35)	1.59 (1.05-2.42)

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Abbreviation: OR, odds ratio.

^{^a}

Adjusted for the following: a maternal age of 35 years or older, maternal hypertensive disease in pregnancy, antenatal corticosteroids, mode of delivery, gestational age, sex, outborn-birth weight z score, and network.

^{^b}

Severe neonatal morbidity defined as intraventricular hemorrhage grade 3-4, cystic periventricular leukomalacia, retinopathy of prematurity stage ≥3, or bronchopulmonary dysplasia.

Table 4. Composite Outcome of Very Preterm Infants Born to Mothers With Diabetes by Neonatal Network.

Neonatal Network	No./Total No. (%)		OR (95% CI)
Neonatal Network	Infants of Mothers With Diabetes	Infants of Mothers Without Diabetes	Crude	Adjusted^b
CNN	316/1130 (28.0)	4203/11 305 (37.2)	0.66 (0.57-0.75)	0.96 (0.80-1.14)
FinMBR	66/190 (34.7)	493/1385 (35.6)	0.96 (0.70-1.32)	1.17 (0.79-1.74)
INN	70/295 (23.7)	1855/5452 (34.0)	0.60 (0.46-0.79)	0.82 (0.60-1.14)
NRNJ	269/697 (38.6)	8245/21 512 (38.3)	1.01 (0.87-1.18)	1.07 (0.89-1.29)
SNQ	21/65 (32.3)	1247/3525 (35.4)	0.87 (0.52-1.47)	1.31 (0.72-2.38)
TuscanNN	23/101 (22.8)	240/831 (28.9)	0.73 (0.45-1.18)	0.94 (0.52-1.71)
UKNC	219/641 (34.2)	12 520/26 935 (46.5)	0.60 (0.51-0.70)	0.85 (0.70-1.04)
All networks	984/3280 (31.6)	28 803/73 080 (40.6)	0.67 (0.62-0.73)	0.99 (0.88-1.10)

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Abbreviations: BPD, bronchopulmonary dysplasia; CNN, Canadian Neonatal Network; FinMBR, Finnish Medical Birth Registry; INN, Israel Neonatal Network; NRNJ, Neonatal Research Network of Japan; OR, odds ratio; SNQ, Swedish Neonatal Quality Register; TuscanNN, Tuscany Neonatal Network (Italy); UKNC, UK Neonatal Collaborative.

^{^a}

In-hospital mortality or severe neonatal morbidity defined as intraventricular hemorrhage grade 3-4, cystic periventricular leukomalacia, -retinopathy of prematurity stage ≥3, or BPD.

^{^b}

Adjusted for a maternal age of 35 years or older, maternal hypertensive disease in pregnancy, antenatal corticosteroids, mode of delivery, gestational age, sex, outborn, and birth weight z score.

An analysis of adverse outcomes in girls and boys of mothers with diabetes did not reveal any significant difference between the sexes (test for interaction between maternal diabetes and infant sex on in-hospital mortality [SE]: −0.18 [0.11]; P = .10) (eTable 2 in the Supplement). Girls of mothers with diabetes had a significantly higher risk of in-hospital mortality (adjusted OR, 1.37; 95% CI, 1.06, 1.77) than girls of mothers without diabetes (eTable 3 in the Supplement).

Discussion

This study has 3 clinically important findings: (1) very preterm infants born to mothers with diabetes are not at a higher risk of in-hospital mortality or morbidity than the population without diabetes, (2) the odds for adverse neonatal outcomes in very preterm infants born to mothers with diabetes did not vary between countries despite different screening and diagnostic protocols for gestational diabetes, and (3) the results are consistent for most GAs, both sexes, and all national populations assessed.

Strength and Limitations

To our knowledge, this study is the largest with adequate power to detect clinically important associations of maternal diabetes with neonatal outcomes of very preterm infants. The number of infants was sufficient to assess outcomes by week of GA and for boys and girls independently. Data on diabetes exposure and outcomes were collected according a standardized protocol, limiting information bias. With data on very preterm births from 7 countries on 4 different continents, we believe that our results have high external validity because of the various diabetes protocols used and populations.

Our study also has limitations. The most important is that although individual databases, such as that from the UKNC and the Swedish Neonatal Quality Register, contain details on all admissions to neonatal care, the iNeo database, like some international databases, such as the Vermont Oxford Network, only includes information on infants with birth weights of 1500 g or less. Maternal diabetes may lead to either restricted or enhanced fetal growth. By including only infants with a birth weight of less than 1500 g we have excluded a significant portion of very preterm infants with birth weights above the mean, particularly those born at 29 to 31 weeks’ gestation. However, the risk of neonatal mortality and morbidity in infants of mothers with diabetes born at 28 to 31 weeks’ gestation was not significantly different than that of infants born before 28 weeks (including large-for-GA infants), suggesting that this limitation may not have introduced a significant selection bias.

Our study was restricted to live births and we did not have information on abortions or fetal deaths before 24 weeks of gestation. The risks of fetal death due to factors like major malformations and placental insufficiency are higher in pregnancies with maternal diabetes. Thus, it is possible that the offspring included in the study reflect a selection of healthier pregnancies, which may have led to an underestimation of the risks associated with maternal diabetes and preterm birth.

Moreover, the data did not enable us to differentiate the type of maternal diabetes (ie, type 1, type 2, or gestational diabetes), and we had no information on the level of glycemic control before or during pregnancy or on diabetes-related complications (except for hypertensive disorders in pregnancy). Despite accounting for many important confounders, we cannot exclude residual confounding by unmeasured or unknown confounders. Neonatal outcomes differed slightly between networks, which may reflect differences in definitions, screening programs, and obstetric interventions. However, the lack of difference in the risk of infants of mothers with or without diabetes was consistent through all networks.

Comparison With Other Studies

Overall, we did not identify increased odds of mortality or severe morbidity in infants born very preterm to mothers with diabetes when compared with infants of mothers without diabetes. This is largely in keeping with data from previous studies,^17,19,20,31 even though some studies report an increased adjusted risk of NEC in infants of mothers with diabetes.^19,20 We also identified higher crude risks of NEC and RDS in infants of mothers with diabetes than infants of mothers without diabetes, but after adjusting for potential confounders there were no significant differences. Notably, women with diabetes had significantly more risk factors than women without diabetes. On the other hand, antenatal treatment with corticosteroids, cesarean delivery, and delivery at a tertiary unit were more common in pregnancies with diabetes. This is likely a reflection of a more intense monitoring of these high-risk pregnancies. Similar to our study, Grandi et al²⁰ reported that women with diabetes delivering very preterm were more likely to have received antenatal care compared with controls without diabetes, and a study from Israel reported a higher proportion of antenatal corticosteroid treatment in pregnancies with maternal diabetes than nondiabetic pregnancies.¹⁷

Importantly, in our study infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. Our results align with several other studies,^17,20 while others found opposite results¹⁹ or no significant difference in GA (or birth weight) between infants of mothers with or without diabetes.³¹ In our study, the higher mean GA at delivery of infants of mothers with diabetes is likely to have attenuated the crude neonatal risks associated with diabetes. Indeed, GA has been demonstrated to be the most important predictor of morbidity in infants of mothers with diabetes¹⁴ as well as mothers without diabetes.

The outlook for women with diabetes and their infants has improved significantly over the last decade following the use of a more active diabetes management strategy before and during pregnancy.^5,8,32,33 However, the rates of both spontaneous and indicated preterm birth increased several-fold over the same period.³ Risk factors for preterm birth in pregnancies with diabetes include a history of preterm birth, unsatisfactory metabolic control, a premature rupture of membranes that is associated with urogenital infections, diabetes-related complications (such as chronic hypertension), preeclampsia, and, in particular, overt nephropathy.^{3,34,35,36,37} Even incipient nephropathy (ie, microalbuminuria) was demonstrated to increase the risk of preterm birth in pregnancies with maternal diabetes.³⁸ However, maternal hyperglycemia in diabetes, assessed as elevated hemoglobin A_1c levels throughout pregnancy, is an independent risk factor for adverse pregnancy outcomes also in women without signs of microvascular or macrovascular diabetes-related complications.³⁴ We could not address this concern in this study as we did not have information on either the level of glycemic control or on the type of diabetes.

The 2-hour glucose cutoff for diagnosis of gestational diabetes after oral glucose tolerance test varied between countries, spanning from 140 mg/dL (to convert to micromoles per liter, multiply by 0.0555) (United Kingdom) to 180 mg/dL (Sweden). These differences most likely contributed to some of the network variation in prevalence of maternal diabetes among very preterm births, spanning from 1.8% in Sweden to 12% in Finland. Sweden has, next to Finland, the highest incidence of type 1 diabetes in the world.³⁹ Even so, only about 0.4% of pregnancies in Sweden are complicated by type 1 diabetes⁵ and gestational diabetes is much more common than pregestational diabetes. Therefore, in this study, the higher prevalence of diabetes in pregnant Finnish women than pregnant Swedish women is likely a reflection of different screening protocols and diagnostic criteria for gestational diabetes in the 2 countries (eTable 1 in the Supplement). However, despite the varying prevalence of the different types of diabetes, all networks reported similar odds for adverse neonatal outcomes for very preterm infants of mothers with diabetes compared with mothers without diabetes. Thus, very preterm birth is a strong risk factor for neonatal mortality and morbidity, irrespective of maternal diabetes.

Our study found similar risks of mortality and morbidity in boys and girls born to mothers with diabetes. This is in accordance with previous findings in pregnancies with diabetes,⁴⁰ but in contrast to reports from the general obstetric population, in which boys face an excess risk of mortality and morbidity.⁴¹

Conclusions

Diabetes in pregnancy is a significant risk factor for very preterm birth. However, in high-resource settings, diabetes in pregnancy is not associated with an increased risk of in-hospital neonatal mortality or severe morbidity in infants born before 32 weeks and with a birth weight of less than 1500 g.

Supplement.

eTable 1. Screening protocols, diagnostic criteria and registry data for diabetes in pregnancy by participant network or country

eTable 2. Adverse neonatal outcomes of very preterm boys compared to girls of diabetic mothers

eTable 3. Adverse neonatal outcomes in very preterm infants of diabetic mothers versus non-diabetic mothers, stratified by sex

Click here for additional data file.^{(116KB, pdf)}

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24.Bader D, Kugelman A, Boyko V, et al. ; Israel Neonatal Network . Risk factors and estimation tool for death among extremely premature infants: a national study. Pediatrics. 2010;125(4):696-703. doi: 10.1542/peds.2009-1607 [DOI] [PubMed] [Google Scholar]
25.Kelly LE, Shah PS, Håkansson S, et al. . Perinatal health services organization for preterm births: a multinational comparison. J Perinatol. 2017;37(7):762-768. doi: 10.1038/jp.2017.45 [DOI] [PubMed] [Google Scholar]
26.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]
27.de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res. 1992;49(1):1-6. doi: 10.1016/S0166-4328(05)80189-5 [DOI] [PubMed] [Google Scholar]
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29.Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82(4):527-532. [PubMed] [Google Scholar]
30.Bell MJ, Ternberg JL, Feigin RD, et al. . Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7. doi: 10.1097/00000658-197801000-00001 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Rehan VKMD, Moddemann D, Casiro OG. Outcome of very-low-birth-weight (< 1,500 grams) infants born to mothers with diabetes. Clin Pediatr (Phila). 2002;41(7):481-491. doi: 10.1177/000992280204100705 [DOI] [PubMed] [Google Scholar]
32.Cnattingius S, Berne C, Nordström ML. Pregnancy outcome and infant mortality in diabetic patients in Sweden. Diabet Med. 1994;11(7):696-700. doi: 10.1111/j.1464-5491.1994.tb00335.x [DOI] [PubMed] [Google Scholar]
33.Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol. 1993;10(4):330-333. doi: 10.1055/s-2007-994754 [DOI] [PubMed] [Google Scholar]
34.Lauszus FF, Fuglsang J, Flyvbjerg A, Klebe JG. Preterm delivery in normoalbuminuric, diabetic women without preeclampsia: the role of metabolic control. Eur J Obstet Gynecol Reprod Biol. 2006;124(2):144-149. doi: 10.1016/j.ejogrb.2005.05.015 [DOI] [PubMed] [Google Scholar]
35.Kitzmiller JL, Combs CA. Diabetic nephropathy and pregnancy. Obstet Gynecol Clin North Am. 1996;23(1):173-203. doi: 10.1016/S0889-8545(05)70251-5 [DOI] [PubMed] [Google Scholar]
36.Jensen DM, Damm P, Ovesen P, et al. . Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes: results from a nationwide Danish study. Diabetes Care. 2010;33(1):90-94. doi: 10.2337/dc09-1219 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Mimouni F, Miodovnik M, Siddiqi TA, Berk MA, Wittekind C, Tsang RC. High spontaneous premature labor rate in insulin-dependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. Obstet Gynecol. 1988;72(2):175-180. [PubMed] [Google Scholar]
38.Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Mølvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care. 2001;24(10):1739-1744. doi: 10.2337/diacare.24.10.1739 [DOI] [PubMed] [Google Scholar]
39.Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G; EURODIAB Study Group . Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027-2033. doi: 10.1016/S0140-6736(09)60568-7 [DOI] [PubMed] [Google Scholar]
40.Persson M, Fadl H. Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational and gestational diabetes—a population-based study. Diabet Med. 2014;31(9):1047-1054. doi: 10.1111/dme.12479 [DOI] [PubMed] [Google Scholar]
41.Kraemer S. The fragile male. BMJ. 2000;321(7276):1609-1612. doi: 10.1136/bmj.321.7276.1609 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement.

eTable 1. Screening protocols, diagnostic criteria and registry data for diabetes in pregnancy by participant network or country

eTable 2. Adverse neonatal outcomes of very preterm boys compared to girls of diabetic mothers

eTable 3. Adverse neonatal outcomes in very preterm infants of diabetic mothers versus non-diabetic mothers, stratified by sex

Click here for additional data file.^{(116KB, pdf)}

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[poi180044r26] 26.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]

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[poi180044r31] 31.Rehan VKMD, Moddemann D, Casiro OG. Outcome of very-low-birth-weight (< 1,500 grams) infants born to mothers with diabetes. Clin Pediatr (Phila). 2002;41(7):481-491. doi: 10.1177/000992280204100705 [DOI] [PubMed] [Google Scholar]

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[poi180044r33] 33.Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol. 1993;10(4):330-333. doi: 10.1055/s-2007-994754 [DOI] [PubMed] [Google Scholar]

[poi180044r34] 34.Lauszus FF, Fuglsang J, Flyvbjerg A, Klebe JG. Preterm delivery in normoalbuminuric, diabetic women without preeclampsia: the role of metabolic control. Eur J Obstet Gynecol Reprod Biol. 2006;124(2):144-149. doi: 10.1016/j.ejogrb.2005.05.015 [DOI] [PubMed] [Google Scholar]

[poi180044r35] 35.Kitzmiller JL, Combs CA. Diabetic nephropathy and pregnancy. Obstet Gynecol Clin North Am. 1996;23(1):173-203. doi: 10.1016/S0889-8545(05)70251-5 [DOI] [PubMed] [Google Scholar]

[poi180044r36] 36.Jensen DM, Damm P, Ovesen P, et al. . Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes: results from a nationwide Danish study. Diabetes Care. 2010;33(1):90-94. doi: 10.2337/dc09-1219 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi180044r37] 37.Mimouni F, Miodovnik M, Siddiqi TA, Berk MA, Wittekind C, Tsang RC. High spontaneous premature labor rate in insulin-dependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. Obstet Gynecol. 1988;72(2):175-180. [PubMed] [Google Scholar]

[poi180044r38] 38.Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Mølvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care. 2001;24(10):1739-1744. doi: 10.2337/diacare.24.10.1739 [DOI] [PubMed] [Google Scholar]

[poi180044r39] 39.Patterson CC, Dahlquist GG, Gyürüs E, Green A, Soltész G; EURODIAB Study Group . Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027-2033. doi: 10.1016/S0140-6736(09)60568-7 [DOI] [PubMed] [Google Scholar]

[poi180044r40] 40.Persson M, Fadl H. Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational and gestational diabetes—a population-based study. Diabet Med. 2014;31(9):1047-1054. doi: 10.1111/dme.12479 [DOI] [PubMed] [Google Scholar]

[poi180044r41] 41.Kraemer S. The fragile male. BMJ. 2000;321(7276):1609-1612. doi: 10.1136/bmj.321.7276.1609 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Association of Maternal Diabetes With Neonatal Outcomes of Very Preterm and Very Low-Birth-Weight Infants

Martina Persson, MD, PhD

Prakesh S Shah, MD

Franca Rusconi, MD

Brian Reichman, MbChB

Neena Modi, MD

Satoshi Kusuda

Liisa Lehtonen

Stellan Håkansson, MD

Junmin Yang, MSc

Tetsuya Isayama, MD, PhD

Marc Beltempo, MD

Shoo Lee, FRCPC

Mikael Norman, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, Participants

Exposures

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Setting

Data Sources

Study Population

Main Exposure

Outcomes

Covariates

Statistical Analysis

Results

Table 1. Characteristics of Very Preterm Infants With a Very Low Birth Weight and Their Mothers.

Table 2. In-Hospital Mortality and Morbidity of Very Preterm Infants of Mothers With Diabetes.

Figure. Association of Maternal Diabetes and Adverse Neonatal Outcomes After Very Preterm Birth.

Table 3. Mortality and Composite Outcome of Infants Born to Mothers With or Without Diabetes by Gestational Age.

Table 4. Composite Outcome of Very Preterm Infants Born to Mothers With Diabetes by Neonatal Network.

Discussion

Strength and Limitations

Comparison With Other Studies

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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