Early Infant Diet and Islet Autoimmunity in the TEDDY Study

Ulla Uusitalo; Hye-Seung Lee; Carin Andrén Aronsson; Kendra Vehik; Jimin Yang; Sandra Hummel; Katherine Silvis; Åke Lernmark; Marian Rewers; William Hagopian; Jin-Xiong She; Olli Simell; Jorma Toppari; Anette-G. Ziegler; Beena Akolkar; Jeffrey Krischer; Suvi M. Virtanen; Jill M. Norris; the TEDDY Study Group

doi:10.2337/dc17-1983

Epidemiology/Health Services Research

Early Infant Diet and Islet Autoimmunity in the TEDDY Study

Ulla Uusitalo¹ ⇑,
Hye-Seung Lee¹,
Carin Andrén Aronsson²,
Kendra Vehik¹,
Jimin Yang¹,
Sandra Hummel³,
Katherine Silvis⁴,
Åke Lernmark²,
Marian Rewers⁵,
William Hagopian⁶,
Jin-Xiong She⁴,
Olli Simell⁷,
Jorma Toppari⁸,
Anette-G. Ziegler³,
Beena Akolkar⁹,
Jeffrey Krischer¹,
Suvi M. Virtanen¹⁰,¹¹,¹²,
Jill M. Norris¹³, and
the TEDDY Study Group*

Corresponding author: Ulla Uusitalo, ulla.uusitalo{at}epi.usf.edu.

¹Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL
²Department of Clinical Sciences, Lund University, Malmö, Sweden
³Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München and Forschergruppe Diabetes e.V., Munich, Germany
⁴Medical College of Georgia, Augusta University, Augusta, GA
⁵Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
⁶Pacific Northwest Diabetes Research Institute, Seattle, WA
⁷Department of Pediatrics, University of Turku, Turku, Finland
⁸Department of Physiology, Institute of Biomedicine, University of Turku; Department of Pediatrics, Turku University Hospital, Turku, Finland
⁹National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
¹⁰Nutrition Unit, National Institute for Health and Welfare, Helsinki, Finland
¹¹Faculty of Social Sciences and Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
¹²The Science Center of Pirkanmaa Hospital District, Tampere, Finland
¹³Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO

Diabetes Care 2018 Mar; 41(3): 522-530. https://doi.org/10.2337/dc17-1983

Article Figures & Tables

Tables

Table 1

Description of foods and food groups studied in relation to the risk of IA

Dietary Exposures
Breastfeeding and food exposures that were each studied separately	Selected foods: foods associated with IA in previous studies; they were studied as one combined variable	Any solid food: all solid foods that were studied as one combined variable
Exclusive breastfeeding
Any breastfeeding
Infant formula
Cow’s milk (any cow’s milk exposure)
All cereals	All cereals	All cereals
Gluten-containing cereals	Gluten-containing cereals	Gluten-containing cereals
Rice	Rice	Rice
Fruits and berries	Fruits and berries	Fruits and berries
Potatoes	Potatoes	Potatoes
Root vegetables	Root vegetables	Root vegetables
Meat (beef, pork, poultry, game)		Meat (beef, pork, poultry, game)
Fish and seafood		Fish and seafood
Egg	Egg	Egg
		Milk products (yogurt, sour cream, cheese, commercial baby foods containing yogurt, cottage cheese)
		Spinach
		Peas, green beans
		Cabbages (Chinese cabbage, red cabbage, cauliflower, broccoli, kale, cabbage turnip, collard, mustard green, turnip greens)
		Squash, pumpkin
		Tomato, tomato sauce
		Corn
		Other vegetable
		Sausage, hot dogs

Variables studied are shown in bold.

Table 2

Characteristics associated with any IA

	Study population,	Any IA (N = 703)			IAA (N = 272)			GADA (N = 299)
	N	N (%)	HR (95% CI)	P value	N (%)	HR (95% CI)	P value	N (%)	HR (95% CI)	P value
Country
Finland	1,654	180 (25.6)	1.40 (1.15, 1.71)	<0.001	89 (32.7)	2.28 (1.67, 3.11)	<0.001	110 (36.8)	1.00 (0.72, 1.39)	0.999
Germany	510	54 (7.7)	1.30 (0.96, 1.76)	0.092	20 (7.4)	1.36 (0.82, 2.25)	0.234	60 (20.1)	0.82 (0.47, 1.42)	0.471
Sweden	2,283	240 (34.1)	1.30 (1.08, 1.56)	0.005	83 (30.5)	1.38 (1.02, 1.89)	0.039	15 (5.0)	1.25 (0.96, 1.62)	0.103
U.S.	3,116	229 (32.6)	1		80 (29.4)	1		114 (38.1)	1
High-risk HLA genotype (DR3/4)
Yes	2,956	344 (48.9)	1.61 (1.38, 1.88)	<0.001	128 (47.1)	1.54 (1.21, 1.96)	<0.001	150 (50.2)	1.65 (1.31, 2.07)	<0.001
No	4,607	359 (51.1)	1		144 (52.9)	1		149 (49.8)	1
FDR with T1D
Yes	857	136 (19.4)	1.99 (1.64, 2.43)	<0.001	58 (21.3)	2.32 (1.71, 3.15)	<0.001	52 (17.4)	1.85 (1.36, 2.53)	<0.001
No	6,706	567 (80.6)	1		214 (78.7)	1		247 (82.6)	1
Sex of the child
Female	3,698	322 (45.8)	0.87 (0.75, 1.00)	0.056	152 (44.1)	0.81 (0.64, 1.03)	0.079	144 (48.2)	0.95 (0.76, 1.19)	0.661
Male	3,865	381 (54.2)	1		120 (55.9)	1		155 (51.8)	1
Probiotics, age at first exposure
<28 days	538	41 (5.8)	0.70 (0.50, 0.97)	0.022	15 (5.5)	0.53 (0.31, 0.91)	0.021	15 (5.0)	0.72 (0.42, 1.24)	0.237
≥28 days	7,025	662 (94.2)	1		257 (94.5)	1		284 (95.0)	1

Table 3

Association of timing of dietary exposures with the risk of IA (any IA, IAA, or GADA)

Dietary exposure	IA	Duration of breastfeeding or age at introduction of food (months)						HR (95% CI)^*	P value^*
		Among those who developed autoantibodies			Among those who did not develop autoantibodies
		N	Not breastfed or food was not introduced by the end of follow-up (%)	Mean (SD)	N	Not breastfed or food was not introduced by the end of follow-up (%)	Mean (SD)
Exclusive breastfeeding	Any IA	703	0	1.3 (1.9)	6,860	0	1.2 (1.8)	1.00 (0.96, 1.04)	0.980
	IAA	272		1.4 (1.9)	7,291		1.2 (1.8)	1.01 (0.95, 1.07)	0.763
	GADA	299		1.3 (1.9)	7,264		1.2 (1.8)	1.01 (0.95, 1.07)	0.810
Any breastfeeding	Any IA	694	1.3	8.4 (7.3)	6,617	3.5	7.4 (6.4)	1.01 (1.00, 1.02)	0.118
	IAA	270		8.5 (6.7)	7,041		7.5 (6.5)	1.01 (0.99, 1.03)	0.205
	GADA	294		8.6 (8.2)	7,017		7.4 (6.5)	1.01 (1.00, 1.03)	0.123
Any infant formula	Any IA	598	14.9	1.2 (2.5)	6,006	12.4	1.2 (2.3)	0.99 (0.96, 1.02)	0.522
	IAA	235		1.4 (2.7)	6,369		1.2 (2.3)	1.02 (0.96, 1.05)	0.574
	GADA	257		1.3 (2.5)	6,347		1.2 (2.3)	1.01 (0.96, 1.06)	0.696
Cow’s milk	Any IA	701	0.3	2.1 (3.1)	6,824	0.5	1.8 (2.8)	1.01 (0.98, 1.04)	0.474
	IAA	270		2.2 (3.2)	7,255		1.8 (2.8)	1.02 (0.98, 1.07)	0.301
	GADA	299		2.0 (3.0)	7,226		1.9 (2.8)	1.01 (0.97, 1.05)	0.613
Any solid food	Any IA	701	0.3	3.6 (1.4)	6,839	0.3	3.5 (1.4)	1.03 (0.97, 1.09)	0.384
	IAA	272		3.5 (1.4)	7,268		3.5 (1.4)	0.99 (0.90, 1.08)	0.757
	GADA	297		3.7 (1.3)	7,243		3.5 (1.4)	1.07 (0.97, 1.17)	0.159
Selected foods	Any IA	701	0.3	3.7 (1.3)	6,838	0.3	3.6 (1.4)	1.03 (0.97, 1.09)	0.368
	IAA	272		3.6 (1.3)	7,267		3.6 (1.4)	1.01 (0.91, 1.11)	0.873
	GADA	297		3.7 (1.3)	7,242		3.6 (1.4)	1.00 (1.00, 1.01)	0.118
Cereals, any	Any IA	699	0.6	4.4 (1.4)	6,810	0.7	4.2 (1.4)	1.03 (0.97, 1.10)	0.330
	IAA	271		4.4 (1.4)	7,238		4.2 (1.4)	1.01 (0.91, 1.14)	0.789
	GADA	296		4.3 (1.3)	7,213		4.2 (1.4)	1.03 (0.94, 1.14)	0.525
Gluten-containing cereals	Any IA	699	0.6	5.8 (2.1)	6,708	2.2	5.7 (2.0)	1.05 (1.01, 1.10)	0.023
	IAA	271		5.9 (2.1)	7,136		5.7 (2.0)	1.08 (1.00, 1.16)	0.038
	GADA	296		5.8 (2.0)	7,111		5.7 (2.0)	1.06 (0.99, 1.13)	0.121
Rice	Any IA	699	0.6	5.0 (1.9)	6,755	1.5	4.8 (1.8)	1.02 (0.97, 1.07)	0.445
	IAA	271		5.1 (2.0)	7,183		4.8 (1.8)	1.01 (0.93, 1.10)	0.779
	GADA	296		4.8 (1.7)	7,158		4.8 (1.8)	1.00 (0.93, 1.08)	0.936
Root vegetables	Any IA	701	0.3	4.3 (1.2)	6,806	0.8	4.3 (1.3)	1.03 (0.96, 1.10)	0.464
	IAA	272		4.2 (1.2)	7,235		4.3 (1.3)	1.00 (0.90, 1.12)	0.942
	GADA	297		4.4 (1.3)	7,210		4.3 (1.3)	1.05 (0.95, 1.16)	0.352
Potatoes	Any IA	699	0.6	5.2 (2.2)	6,698	2.4	5.3 (2.4)	1.05 (1.00, 1.10)	0.051
	IAA	271		5.1 (2.1)	7,126		5.3 (2.4)	1.05 (0.97, 1.14)	0.200
	GADA	296		5.4 (2.4)	7,101		5.3 (2.3)	1.06 (0.99, 1.13)	0.116
Fruits or berries	Any IA	700	0.4	4.3 (1.4)	6,806	0.8	4.2 (1.5)	1.04 (0.98, 1.10)	0.167
	IAA	272		4.3 (1.5)	7,234		4.2 (1.5)	1.04 (0.95, 1.14)	0.372
	GADA	296		4.4 (1.4)	7,210		4.2 (1.5)	1.05 (0.96, 1.14)	0.315
Meat	Any IA	692	1.6	6.0 (1.8)	6,676	2.7	6.1 (2.0)	1.02 (0.97, 1.08)	0.457
	IAA	269		6.0 (1.7)	7,099		6.1 (2.0)	1.03 (0.94, 1.12)	0.564
	GADA	292		6.1 (2.0)	7,076		6.1 (2.0)	1.04 (0.96, 1.12)	0.364
Egg	Any IA	684	2.7	8.9 (2.5)	6,458	5.9	8.7 (2.5)	1.02 (0.99, 1.05)	0.288
	IAA	266		8.9 (2.7)	6,876		8.7 (2.5)	1.00 (0.95, 1.06)	0.878
	GADA	290		8.9 (2.4)	6,852		8.7 (2.5)	1.04 (0.99, 1.09)	0.140
Fish or other seafood	Any IA	662	5.8	8.6 (3.6)	6,210	9.5	8.6 (3.6)	1.01 (0.98, 1.04)	0.537
	IAA	256		8.5 (3.8)	6,616		8.6 (3.6)	0.99 (0.94, 1.05)	0.810
	GADA	280		8.7 (3.6)	6,592		8.6 (3.6)	1.03 (0.98, 1.08)	0.258

↵*HR and corresponding P value were obtained from the Cox regression model adjusted for country, HLA genotype, FDR status, sex of the child, and probiotic use <28 days. HRs reflect the change in the risk with 1-month longer breastfeeding or 1-month delay in food introduction.

Table 4

Categorized duration of breastfeeding and timing of introduction of complementary foods and risk of IA (any IA or GADA)

IA	Dietary exposure^*	Timing in months^*	Number of children who developed any IA or GADA, N (%)	Number of children who did not develop any IA or GADA, N (%)	Unadjusted HR (95% CI)	P value	Adjusted^† HR (95% CI)	P value
Any IA	Gluten-containing cereals	<4	28 (6)	445 (94)	0.68 (0.47, 0.99)	0.047	0.67 (0.54, 0.98)	0.037
		4–9	637 (10)	6,048 (90)	1		1
		>9	31 (14)	185 (86)	1.57 (1.07, 2.31)	0.022	1.44 (0.97, 2.16)	0.074
	Any breastfeeding	≤7	334 (9)	3,575 (91)	0.93 (0.80, 1.08)	0.326	0.94 (0.81, 1.09)	0.426
	Any breastfeeding	>7	360 (11)	3,042 (89)	1		1
	Cow’s milk	≤5	584 (10)	5,922(91)	0.83 (0.68, 1.00)	0.055	0.85 (0.69, 1.04)	0.115
	Cow’s milk	>5	117 (11)	902 (89)	1		1
	Cereals	≤4	483 (9)	4,765 (91)	0.99 (0.85, 1.17)	0.945	1.09 (0.92, 1.30)	0.309
	Cereals	>4	216 (10)	2,045 (90)	1		1
	Rice	≤7	618 (9)	6,196 (91)	0.79 (0.63, 0.99)	0.046	0.87 (0.69, 1.10)	0.233
	Rice	>7	75 (13)	502 (87)	1		1
	Fruit and berries	≤4	460 (9)	4,552 (91)	0.99 (0.85, 1.15)	0.868	1.00 (0.85, 1.18)	0.999
	Fruit and berries	>4	240 (10)	2,254 (90)	1		1
	Potato	≤7	578 (10)	5,345 (90)	1.19 (0.98, 1.45)	0.077	0.98 (0.77, 1.25)	0.898
	Potato	>7	121 (8)	1,353 (92)	1		1
	Meat	≤8	615 (10)	5,762 (90)	1.27 (1.01, 1.59)	0.040	1.13 (0.88, 1.45)	0.344
	Meat	>8	77 (8)	914 (92)	1		1
	Egg	≤9	282 (9)	3,002 (91)	0.86 (0.74, 0.99)	0.045	0.84 (0.72, 0.99)	0.035
	Egg	>9	402 (10)	3,456 (90)	1		1
GADA	Any breastfeeding	≤6	120 (3)	3,476 (97)	1.20 (0.95, 1.52)	0.126	1.17 (0.92, 1.49)	0.196
GADA	Any breastfeeding	>6	174 (5)	3,541 (95)	1		1
	Rice	≤6	264 (4)	6,435 (96)	1.25 (0.87, 1.78)	0.224	1.10 (0.76, 1.58)	0.623
	Rice	>6	28 (4)	664 (96)	1		1
	Fish and seafood	≤9	188 (4)	4,538 (96)	0.88 (0.70, 1.12)	0.290	1.11 (0.81, 1.53)	0.507
	Fish and seafood	>9	92 (4)	2,054 (96)	1		1

↵*Dietary exposure: timing of breastfeeding or food; categorization of timing of gluten-containing cereals’ introductions was based on martingale residuals whereas dichotomizations of timing of other dietary exposures in relation to the risk of any IA or GADA were based on change-point methods using log-rank test (28); only statistically significant (P < 0.05) cut points are shown. No statistically significant cut point of timing of a dietary exposure for IAA was detected.
↵†The Cox regression model was adjusted for country, HLA genotype, FDR status, sex of the child, and probiotic use <28 days.