Choline Intake During Pregnancy and Child Cognition at Age 7 Years

Caroline E. Boeke; Matthew W. Gillman; Michael D. Hughes; Sheryl L. Rifas-Shiman; Eduardo Villamor; Emily Oken

Am J Epidemiol. 2013;177(12):1338-1347.

Abstract and Introduction

Abstract

Animal models indicate that exposure to choline in utero improves visual memory through cholinergic transmission and/or epigenetic mechanisms. Among 895 mothers in Project Viva (eastern Massachusetts, 1999–2002 to 2008–2011), we estimated the associations between intakes of choline, vitamin B₁₂, betaine, and folate during the first and second trimesters of pregnancy and offspring visual memory (measured by the Wide Range Assessment of Memory and Learning, Second Edition (WRAML2), Design and Picture Memory subtests) and intelligence (measured using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2)) at age 7 years. Mean second-trimester intakes were 328 (standard deviation (SD), 63) mg/day for choline, 10.5 (SD, 5.1) µg/day for vitamin B₁₂, 240 (SD, 104) mg/day for betaine, and 1,268 (SD, 381) µg/day for folate. Mean age 7 test scores were 17.2 (SD, 4.4) points on the WRAML 2 Design and Picture Memory subtests, 114.3 (SD, 13.9) points on the verbal KBIT-2, and 107.8 (SD, 16.5) points on the nonverbal KBIT-2. In a model adjusting for maternal characteristics, the other nutrients, and child's age and sex, the top quartile of second-trimester choline intake was associated with a child WRAML2 score 1.4 points higher (95% confidence interval: 0.5, 2.4) than the bottom quartile (P-trend = 0.003). Results for first-trimester intake were in the same direction but weaker. Intake of the other nutrients was not associated with the cognitive tests administered. Higher gestational choline intake was associated with modestly better child visual memory at age 7 years.

Introduction

Methyl donor nutrients like choline, vitamin B₁₂, betaine, and folate may affect brain development through involvement in methylation processes,^[1] and choline may be particularly important because of its role in cholinergic transmission.^[2] Animal studies demonstrate that higher choline exposure in utero improves memory.^[3] Offspring of rat dams given choline supplementation during mid- to late gestation displayed better visuospatial memory than those of unsupplemented dams.^[4–6] In rodents, choline supplementation in utero changed gene-specific methylation and protein expression, increased cell proliferation, and decreased apoptosis in the fetal hippocampus, the region of the brain associated with memory.^[7–9]

Few studies in humans have examined the association of maternal gestational choline intake with child cognition. Among US mother-child pairs, serum choline concentrations in maternal and umbilical cord blood were not associated with child intelligence quotient (IQ) at age 5 years (e.g., 0.61 IQ points per unit difference in cord serum choline level (P = 0.36)).^[10] In Project Viva, gestational choline intake was not associated with score on the Peabody Picture Vocabulary Test, Third Edition (PPVT-III), a test of receptive language (per 450-mg/day increase in second-trimester choline intake, adjusted difference = 0.8, 95% confidence interval (CI): −7.4, 9.0), or the Wide Range Assessment of Visual Motor Abilities (WRAVMA) (adjusted difference = −0.4, 95% CI: −7.6, 6.8) at age 3 years.^[11] However, the IQ, PPVT-III, and WRAVMA tests do not specifically measure visuospatial memory, which is the cognitive domain that is consistently affected by choline intake in animal models. In the Framingham Offspring Cohort, choline intake during adulthood was associated with better performance on visual and verbal memory tests.^[12]

In contrast to choline, more studies have examined maternal intakes of folate and vitamin B₁₂ in relation to child cognition in humans. In the Pune^[13] and Mysore Parthenon^[14] studies in India, higher maternal plasma B₁₂ and folate levels at approximately 28–30 weeks of pregnancy were associated with improved offspring cognition, including attention and short-term memory at ages 9–10 years. In a cohort study in Mexico, maternal dietary vitamin B₁₂ deficiency was associated with a reduced neurodevelopmental index in offspring within the first year of life.^[15] However, these previous studies did not carefully assess total diet to control for confounding and examined only a few methyl donor nutrients.

We sought to examine maternal first- and second-trimester dietary intake of methyl donor nutrients during pregnancy in relation to child visual memory in a generally well-nourished US population. We hypothesized that high maternal intake of choline and other methyl donor nutrients would be associated with higher memory test scores in children at age 7 years.

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Next Section

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Selected Characteristics of 813 Mother-Child Pairs in Project Viva According to Quartile of Second-Trimester Choline Intake, Eastern Massachusetts, 1999–2002 to 2008–2011 ^a
	Overall	Quartile of Second-Trimester Choline Intake
	Overall	Quartile 1	Quartile 2	Quartile 3	Quartile 4
Mother
Age, years	32.9 (4.6)	32.1 (4.9)	32.6 (4.3)	33.3 (4.4)	33.6 (4.7)
Prepregnancy BMI^b	24.4 (4.9)	24.7 (5.2)	24.5 (5.1)	24.3 (4.5)	23.9 (4.8)
Gestational weight gain, pounds^c	34.3 (11.4)	34.6 (10.6)	32.9 (11.9)	34.5 (11.2)	35.0 (11.8)
Physical activity during pregnancy, hours/week	6.7 (6.3)	7.0 (7.5)	6.8 (5.9)	6.5 (5.4)	6.7 (6.1)
Second-trimester energy intake, calories/day	2,149 (606)	2,007 (558)	2181 (626)	2178 (573)	2229 (643)
Energy-adjusted daily dietary intake during second trimester
Choline, mg	328 (63)	253 (29)	308 (11)	344 (11)	406 (49)
Vitamin B₁₂, µg	10.5 (5.1)	8.8 (2.8)	9.8 (3.3)	10.7 (3.3)	12.7 (8.1)
Betaine, mg	240 (104)	224 (101)	244 (105)	233 (89)	258 (118)
Folate, µg	1,268 (381)	1,197 (418)	1261 (382)	1308 (338)	1306 (376)
Second-trimester fish intake, servings/day	0.2 (0.2)	0.2 (0.2)	0.2 (0.2)	0.2 (0.2)	0.3 (0.3)
KBIT-2 composite score	108.8 (14.8)	107.2 (14.4)	110.2 (13.7)	110.3 (14.4)	107.4 (16.4)
Child
Birth-weight-for-gestational-age z score	0.2 (1.0)	0.1 (0.9)	0.3 (1.0)	0.3 (1.0)	0.3 (1.0)
Age at 7-year visit, years	7.8 (0.8)	7.9 (0.7)	7.8 (0.8)	7.9 (0.9)	7.8 (0.8)
WRAML2 score	17.2 (4.4)	16.6 (4.6)	17.2 (4.6)	17.2 (4.4)	17.8 (3.9)
KBIT-2 verbal score	114.3 (13.9)	112.9 (14.5)	114.5 (13.3)	115.2 (14.1)	114.5 (13.8)
KBIT-2 nonverbal score	107.8 (16.5)	106.3 (16.3)	108.0 (16.3)	108.0 (17.2)	109.1 (16.3)
BMI z score at age 7 years	0.3 (1.0)	0.4 (0.9)	0.2 (1.0)	0.2 (1.0)	0.3 (1.0)

Abbreviations: BMI, body mass index; KBIT-2, Kaufman Brief Intelligence Test, Second Edition; WRAML2, Wide Range Assessment of Memory and Learning, Second Edition (Design and Picture Memory subtests).
^aAll data shown are mean values with standard deviations in parentheses. Median choline intakes (and ranges) were as follows: overall, 326 mg/day (range, 141–806); quartile 1, 260 mg/day (range, 141–288); quartile 2, 309 mg/day (range, 288–326); quartile 3, 344 mg/day (range, 326–364); quartile 4, 392 mg/day (range, 364–806).
^bWeight (kg)/height (m)².
^c1 pound = 0.45 kg.

Table 2. Selected Characteristics (Number and Percentage) of 813 Mother-Child Pairs in Project Viva According to Quartile of Second-Trimester Choline Intake, Eastern Massachusetts, 1999–2002 to 2008–2011
	Overall		Quartile of Second-Trimester Choline Intake
	Overall		Quartile 1		Quartile 2		Quartile 3		Quartile 4
	No.	%	No.	%	No.	%	No.	%	No.	%
Mother
Race/ethnicity
Asian	48	5.9	6	3.0	11	5.4	8	3.9	23	11.3
Black	86	10.6	23	11.3	21	10.3	17	8.3	25	12.3
Hispanic	31	3.8	3	1.5	8	3.9	10	4.9	10	4.9
White	619	76.1	162	79.8	158	77.8	165	80.9	134	66.0
>1 race/other	29	3.6	9	4.4	5	2.5	4	2.0	11	5.4
Education
Completed high school or less	197	24.2	60	29.6	41	20.2	44	21.6	52	25.6
Completed college	294	36.2	75	37.0	77	37.9	75	36.8	67	33.0
Completed graduate degree	322	39.6	68	33.5	85	41.9	85	41.7	84	41.4
Multipara	420	51.7	95	46.8	109	53.7	105	51.5	111	54.7
Smoking status
Never smoker	574	70.6	143	70.4	143	70.4	139	68.1	149	73.4
Smoked during early pregnancy	64	7.9	19	9.4	12	5.9	17	8.3	16	7.9
Former smoker	175	21.5	41	20.2	48	23.7	48	23.5	38	18.7
Child
Male sex	402	49.5	98	48.3	96	47.3	106	52.0	102	50.3
Household
Income >$70,000/year	538	69.4	122	63.9	140	70.0	150	76.5	126	67.0
Biological father
Completed high school or less	235	28.9	70	34.5	57	28.1	52	25.5	56	27.6
Completed college	307	37.8	65	32.0	85	41.9	83	40.7	74	36.5
Completed graduate degree	271	33.3	68	33.5	61	30.1	69	33.8	73	36.0

Table 3. Association Between Maternal Choline Intake During the First and Second Trimesters of Pregnancy and Child WRAML2 Score at Age 7 Years, Project Viva ( n = 890 Mother-Child Pairs), Eastern Massachusetts, 1999–2002 to 2008–2011 ^a
Trimester and Model^b	Quartile of Material Choline Intake							P for Trend
	Quartile 1 (Referent)	Quartile 2		Quartile 3		Quartile 4
	Quartile 1 (Referent)	β	95% CI	β	95% CI	β	95% CI
First trimester (n = 861)	266 (162–293)^c	312 (294–332)		349 (332–375)		404 (375–668)
1	0	0.4	−0.4, 1.2	1.0	0.1, 1.8	0.7	−0.1, 1.5	0.06
2	0	0.3	−0.5, 1.1	0.8	−0.1, 1.6	0.6	−0.3, 1.4	0.12
3	0	0.2	−0.6, 1.1	0.7	−0.1, 1.6	0.6	−0.2, 1.5	0.09
4	0	0.3	−0.6, 1.1	0.8	0.0, 1.7	0.7	−0.2, 1.5	0.08
Second trimester (n = 808)	260 (141–288)	309 (288–326)		344 (326–364)		392 (364–806)
1	0	0.5	−0.3, 1.4	0.6	−0.3, 1.4	1.2	0.3, 2.0	0.01
2	0	0.5	−0.3, 1.4	0.6	−0.2, 1.5	1.2	0.3, 2.1	0.01
3	0	0.5	−0.4, 1.3	0.5	−0.3, 1.4	1.2	0.3, 2.1	0.01
4	0	0.6	−0.3, 1.4	0.7	−0.2, 1.5	1.4	0.5, 2.4	0.003

Abbreviations: CI, confidence interval; HOME, Home Observation for Measurement of the Environment; KBIT-2, Kaufman Brief Intelligence Test, Second Edition; WRAML2, Wide Range Assessment of Memory and Learning, Second Edition (Design and Picture Memory subtests).
^aThe β coefficient represents the mean difference in WRAML2 score from the lowest quartile (referent).
^bModel 1, unadjusted; model 2, adjusted for intakes of vitamin B12, betaine, and folate; model 3, additionally adjusted for maternal KBIT-2 score; model 4, additionally adjusted for maternal age, race/ethnicity, education, parity, smoking, and fish and energy intake during pregnancy; paternal education; HOME score; and child's sex and age at the 7-year visit.
^cMedian maternal choline intake (range), in mg/day.

Table 4. Association Between Maternal Methyl Donor Intake During the First and Second Trimesters of Pregnancy and Child Cognitive Outcomes at Age 7 Years (Final Model ^a), Project Viva ( n = 895 Mother-Child Pairs), Eastern Massachusetts, 1999–2002 to 2008–2011 ^b
Methyl Donor and Cognitive Test	Quartile of Maternal Methyl Donor Intake							P for Trend
	Quartile 1 (Referent)	Quartile 2		Quartile 3		Quartile 4
	Quartile 1 (Referent)	β	95% CI	β	95% CI	β	95% CI
First Trimester
Choline
WRAML2	0.00	0.3	−0.6, 1.1	0.8	0.0, 1.7	0.7	−0.2, 1.5	0.08
KBIT-2 verbal	0.00	1.4	−0.9, 3.7	1.4	−1.0, 3.7	1.3	−1.1, 3.7	0.32
KBIT-2 nonverbal	0.00	0.3	−2.8, 3.4	−0.6	−3.7, 2.5	1.0	−2.2, 4.2	0.63
Vitamin B₁₂
WRAML2	0.00	0.1	−0.8, 1.0	−0.1	−1.1, 0.8	0.0	−1.0, 1.0	0.94
KBIT-2 verbal	0.00	3.0	0.5, 5.5	0.9	−1.7, 3.5	0.4	−2.3, 3.1	0.59
KBIT-2 nonverbal	0.00	0.0	−3.3, 3.4	2.3	−1.2, 5.8	1.1	−2.5, 4.7	0.47
Betaine
WRAML2	0.00	0.5	−0.4, 1.3	0.2	−0.7, 1.0	0.8	−0.1, 1.7	0.14
KBIT-2 verbal	0.00	−2.0	−4.3, 0.3	−1.4	−3.8, 1.0	−0.8	−3.2, 1.6	0.84
KBIT-2 nonverbal	0.00	0.6	−2.5, 3.7	−0.1	−3.2, 3.1	2.6	−0.6, 5.9	0.11
Folate
WRAML2	0.00	0.0	−0.9, 0.8	0.4	−0.5, 1.4	0.5	−0.4, 1.4	0.21
KBIT-2 verbal	0.00	0.7	−1.7, 3.0	1.2	−1.3, 3.7	−0.2	−2.7, 2.3)	0.93
KBIT-2 nonverbal	0.00	−1.7	−4.9, 1.4	−1.2	−4.5, 2.1	−0.6	−3.9, 2.7	0.85
Second Trimester
Choline
WRAML2	0.00	0.6	−0.3, 1.4	0.7	−0.2, 1.5	1.4	0.5, 2.4	0.003
KBIT-2 verbal	0.00	0.4	−2.0, 2.9	1.1	−1.3, 3.6	0.9	−1.7, 3.5	0.43
KBIT-2 nonverbal	0.00	1.6	−1.6, 4.8	1.3	−1.8, 4.5	3.5	0.1, 6.9	0.06
Vitamin B₁₂
WRAML2	0.00	0.3	−0.6, 1.3	−0.2	−1.2, 0.8	0.2	−0.8, 1.3	0.86
KBIT-2 verbal	0.00	−1.3	−3.9, 1.4	−1.5	−4.3, 1.2	−1.2	−4.1, 1.7	0.51
KBIT-2 nonverbal	0.00	1.1	−2.3, 4.5	1.0	−2.6, 4.6	−0.1	−3.8, 3.7	0.81
Betaine
WRAML2	0.00	0.4	−0.5, 1.3	−0.1	−1.0, 0.8	0.5	−0.5, 1.4	0.46
KBIT-2 verbal	0.00	0.1	−2.4, 2.6	1.0	−1.5, 3.5	1.2	−1.4, 3.8	0.29
KBIT-2 nonverbal	0.00	−0.9	−4.1, 2.4	−0.7	−4.0, 2.6	1.1	−2.3, 4.5	0.37
Folate
WRAML2	0.00	−0.5	−1.4, 0.4	−0.6	−1.5, 0.3	−0.7	−1.6, 0.3	0.11
KBIT-2 verbal	0.00	2.5	0.0, 4.9	0.1	−2.4, 2.5	−0.4	−3.0, 2.1	0.95
KBIT-2 nonverbal	0.00	−0.6	−3.9, 2.6	−2.8	−6.1, 0.4	−1.4	−4.7, 2.0	0.22

Abbreviations: CI, confidence interval; HOME, Home Observation for Measurement of the Environment; KBIT-2, Kaufman Brief Intelligence Test, Second Edition; WRAML2, Wide Range Assessment of Memory and Learning, Second Edition (Design and Picture Memory subtests).
^aResults were adjusted for maternal age, race/ethnicity, education, parity, smoking, intakes of choline, vitamin B₁₂, betaine, and folate, fish, and energy during pregnancy, and KBIT-2 score; paternal education; HOME score; and child's sex and age at the 7-year visit.
^bThe β coefficient represents the mean difference in score from the lowest quartile (referent).