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Dieta Cetogenica Incluyendo Leche Materna
Dieta Cetogenica Incluyendo Leche Materna
Anastasia Dressler,1 Chiara Häfele,1 Vito Giordano,1 Franz Benninger,2 Petra Trimmel-Schwahofer,1
Gudrun Gröppel,1 Sharon Samueli,1 Martha Feucht,1 Christoph Male,1 and Andreas Repa1
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Abstract
Objective: The ketogenic diet (KD) is a high-fat and restricted carbohydrate diet for treating severe childhood
epilepsy. In infants, breast milk is usually fully replaced by a ketogenic formula. At our center, mothers are
encouraged to include breastfeeding into the KD if still breastfeeding. This retrospective study describes
achievement and maintenance of ketosis with or without inclusion of breast milk.
Methods: Data were retrieved from a prospective longitudinal database of children treated with KD for
epilepsy analyzing infants <1 year of age. The time to achieve clinically relevant ketosis (‡2 mmol/L beta-
hydroxybutyrate) was compared with and without inclusion of breast milk into standard KD. Ketosis, nutritional
intakes, effectiveness, adverse effects, and successful continuation of breastfeeding were evaluated.
Results: A total of 79 infants were eligible for analysis. In 20% (16), breast milk was included. Infants with
breast milk included into the KD achieved relevant ketosis in 47 hours (interquartile range [IQR] 24–95)
compared with 41 hours (IQR 22–70; p = 0.779) in infants with standard KD. Beta-hydroxybutyrate at day 2
was 3.1 mmol/L (IQR 0.5–4.9) and 3.8 mmol/L (IQR 2.2–4.9). Infants with breast milk included received higher
amounts of carbohydrates at baseline and calories at 3 months. Seizure freedom and adverse effects showed no
relevant differences. No infections occurred in infants receiving breast milk. In two infants, KD was initiated
with breast-feds after bottle-feeding KD formula. In 31%, breastfeeding was continued after the KD, and in
25%, inclusion of breast milk and breastfeeding was maintained until complete weaning. Before discharge from
hospital, the amount of breast milk included was median 90 mL/day (IQR 53–203) equivalent to median 9%
(IQR 6–15).
Conclusions: Appropriate ketosis was achieved in most infants and maintained within 48 hours. Incorporation
of breast milk into KD is feasible, safe, and effective.
Introduction life or as central part of a mixed diet later on. To induce and
maintain ketosis in KD, only a restricted amount of carbo-
Departments of 1Pediatrics and Adolescent Medicine and 2Child and Adolescent Neuropsychiatry, Medical University Vienna,
Vienna, Austria.
1
2 DRESSLER ET AL.
without inclusion of mother’s milk are well established. were measured three times a day while KD was established. At
Studies that directly compared the effectiveness of a KD with home, urine ketone levels, seizures, nutrition, and adverse
and without breast milk are still lacking. The objective of our effects were documented in a patient’s diary. At each outpa-
study was to retrospectively analyze the feasibility, effec- tient visit, a thorough pediatric, neurological, and nutritional
tiveness, and safety of a KD regimen that includes breast milk analysis was performed. Nutritional parameters (fluids, total
compared to standard KD without breastfeeding in infants calories, protein, lipid, and carbohydrate intake) and growth
younger than 1 year of age. parameters (weight, height, and cranial circumference) were
assessed. At outpatient visits, blood analyses included fasting
Methods plasma glucose and beta-hydroxybutyrates according to a
standardized protocol.3,9,27 Outpatient visits were performed
Study design after 1 month and after 3, 6, and 12 months after KD start. For
This study is a retrospective database analysis of infants infants not receiving the KD at 3 months, last follow-up on the
with childhood epilepsy that were treated with a KD at our KD was taken for analysis.
clinic (Department of Pediatrics, Medical University of The clinical data of infants with inclusion of breast milk
Vienna, Austria; September 1999 to December 2018). The into their KD are displayed in Supplementary Table S1.
KD program at the study center was started in 1999 in tod- A detailed individual prescription of a KD that includes
dlers and older children. From 2006 onward, when a ready- breast milk is given in Supplementary Table S2.
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FIG. 1. Ketone levels and relevant ketosis (mmol/L). The time course of ketosis is shown as the trajectories of the serum
beta-hydroxybutyrate levels (day 1 to 5 and at 1 and 3 months; median and standard deviation) and the percentage of infants
achieving a clinically relevant ketosis (>2 mmol/L beta-hydroxybutyrate) ( p = 0.008 at day 3). *p < 0.01, tested using the
chi-square test.
Table 2. Effectiveness
Breast milk Formula only
Parameter (n = 16) (n = 63) Odds ratio and 95% CI p
Treatment response (at 3 months) 10 (67)a 44 (70) 0.9 (0.3–2.9) 1.00
Treatment response (at final follow-up visit) 10 (67)a 44 (72)b 0.8 (0.2–2.4) 0.75
Seizure freedom (at 3 months) 9 (40)a 20 (27) 3.2 (1–10.3) 0.07
Seizure freedom (at final follow-up visit) 8 (53)a 22 (36)b 2 (0.7–6.3) 0.25
Categorical data are presented as numbers with percentages in parentheses (tested using the chi-square test), and the odds ratio between
groups with 95% CIs in parentheses.
a
Data of one patient missing.
b
Data of two patients missing.
CI, confidence interval.
KD was started was 6.2 months (median; IQR: 4.4–8.4 After KD was implemented, infants who received breast milk
months; range: 14.6 days–12.0 months) with a majority of in their KD consumed significantly more energy (difference
infants (63/79; 80%) already receiving exclusively formula between medians of 7 kcal, p = 0.044). Individual data of
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and less infants being breastfed (16/79; 20%; exclusively: 10/ infants who received a KD with breast milk are displayed in
79; 12.7%; partially: 6/79; 7.6%). Upon invitation to include Supplementary Table S1. The main type of epilepsy was
breast milk into their infants KD, all mothers decided to do West Syndrome (14/16) of varying etiology. On the first day
so. Infants on formula received standard KD by default. More of the KD, infants who also received breast milk received
infants were male (47/79; 69%). The etiology of epilepsy was 144 mL of mothers’ milk (median; IQR 90–307 mL/day,
unknown in every third infant (31/79; 30%). The KD was the min. 34 mL–max. 600 mL), which was 30% (median; IQR 6–
first antiepileptic therapy in a small minority of infants (10/ 50%) of liquid meals (fat/nonfat ratio: 1.83:1; median; IQR
79; 13%): most infants (69/79; 87%) received antiepileptic 1.5–2.5). On day 3, the amount of breast milk included was
drugs (AED) before KD initiation. In this study, the amount 90 mL (median; IQR 53–203 mL/day, min 24 mL–max.
of concomitant AEDs at initiation of KD was two (median; 260 mL), which was 9% (IQR 6–15%, range 3–38%) of
range: IQR: 1–2, range: 0–4). The amount of previously used liquid meals. The fat/nonfat ratio of liquid meals was median
AEDs until the KD was started was two (median; IQR 1–3, 2.48:1 (IQR 2.01–2.6). The median duration of including
range: 0–12). The median duration of KD was 10.7 months breast milk was 127 days (IQR: 17–166 days; range: 7–482
(IQR 5.7–20.5 months; range: 0.4–74). Baseline character- days). An example of a ketogenic prescription is given in
istics of participants by group are shown in Table 1. The z- Supplementary Table S1.
scores of body weight at baseline were significantly higher in Growth (z-score difference for weight and height from
infants who received breast milk. Other parameters did not baseline to last follow-up) was not significantly different
differ significantly. The median duration of KD was 10.1 between the two groups: difference z-score of weight: 0.08
months (IQR: 7.0–25.8 months). versus 0.25 (median, 95% CI: -0.28 to 0.76; p = 0.82), dif-
ference z-score of height: -0.22 versus 0.48 (median, 95%
Ketosis and treatment effectiveness CI: -0.41 to 1.22; p = 0.43).
The time to achieve clinically relevant ketosis did not differ Feasibility
significantly between groups ( p = 0.78). Ketosis was reached in
infants with breast milk after 47 hours (median; IQR: 24–95 Eight out of 16 (50%) mothers who started to include
hours), in infants without breast milk after 41 hours (median; breast milk into the KD continued to provide breast milk for
IQR: 22–70 hours). The proportion of infants with a beta- more than 3 months. Five mothers (31%) provided breast
hydroxybutyrate level >2 mmol/L (defined as clinically rele- milk less than a month (stopped after 7, 8, 10, and 10 and 19
vant) was significantly lower in infants with inclusion of breast days). Five mothers (31%) managed to nurse their infants on
milk on the third day of the KD only (Fig. 1). Two infants in the the KD, with three mothers who switched to breastfeeding
group without breast milk failed to achieve clinically rele- after pumping milk at the start of KD and two mothers who
vant ketosis (beta-hydroxybutyrate levels: 0.2–0.9 and 0.2– nursed from the first day of the KD. Four mothers (25%)
1.8 mmol/L) and three infants achieved clinically relevant provided breast milk until weaning without switching to in-
ketosis as late as after 8, 9, and 15 days, because of medications fant formula.
containing small amounts of carbohydrates, which was detected
and resolved. The time-course of beta-hydroxybutyrate levels Adverse effects
was not significantly different between both groups (Fig. 1). The There was no significant difference in total adverse effects
KD was equally effective in both groups. About two thirds of (Table 4). Constipation and low fluid intake was as the most
infants showed seizure reduction by more than half, and in about frequent adverse effect in both groups. Intermittent high tri-
a third of infants, seizures ceased completely (Table 2). glycerides at 3 months were observed in up to 30% of infants.
Z-score weight 0.6 [-1.3 to 0.9] -0.1 (-1.3 to 0.9) -0.3 (-1.2 to 0.6)
Z-score height 0.4 [-0.3 to 1.3] 0.2 (-1.4 to 1.1) -0.3 (-1.4 to 0.5)
Continuous data are presented as medians with interquartile range in squared brackets (tested using the k-sample median test) and median
estimator between groups (Hodges–Lehman) with 95% CIs in parentheses.
a
p < 0.05.
b
p < 0.01.
CI, confidence interval.
time the feasibility, effectiveness, and safety of a KD that intake after 3 months of therapy was observed in infants with
includes breast milk compared to the conventional exclu- KD where breast milk was included.
sively formula-based approach in infants. Clinically relevant Effectiveness of the KD at 3 months was high in both
ketosis was typically achieved within the first 48 hours of groups: infants with breast milk showed response in 67% and
therapy and maintained throughout the KD. A higher caloric seizure freedom in 40%; infants without breast milk showed
response in 70% and seizure freedom in 27%. The most
Table 4. Adverse Effects frequent adverse effects were low fluid intake and constipa-
tion in both groups. However, during the first 3 months no
Breast milk Formula infections occurred in infants receiving breast milk compared
Parameter (n = 16) only (n = 63)
to infants without breast milk included. The microbiome in
Any adverse effect 13 (81) 50 (79) mother’s breast milk and areolar skin shapes the infant’s gut
Tirednessa 1 (6) 5 (8) in early life, underscoring the importance of breastfeeding in
Beta-hydroxybutyrate 1 (6) 14 (22) the maturation the infants gut microbiome, which has im-
high (>5 mmol/L)b plications on infections and immunity.29,30
Hypoglycemia (<45 mg/dL)a 0 (0) 3 (5) In addition, the higher carbohydrate intake and lower
Glucose low (45–59 mg/dL)a 1 (6) 7 (11) fat/nonfat ratio was reflected by a lower percentage of hypo-
Low fluid intakeb 6 (38) 23 (37) glycemia and high lipids in infants with breast milk included.
Vomitingb 3 (19) 4 (6)
Also, a higher percentage of KD refusal and constipation seen
Intravenous liquids for 3 (19) 5 (8)
low fluid intakea in this group might reflect a flavor preference for breast milk
Refusal of KDb 2 (13) 3 (5) due to the mixed feeding of KD formula and breast milk and a
Solid food refusalb 1 (6) 17 (27) greater nutritional change.
Triglycerides high 2 (13) 20 (32) In two infants, KD was initiated with feedings at the breast
(>150 mg/dL)b after bottle-feeding the KD formula, and in five infants,
High cholesterol 0 (0) 3 (5) breastfeeding was successfully continued after the KD was
(>200 mg/dL)b stopped.
Constipationb 8 (50) 19 (30) Breastfeeding is the normative standard for infant nutrition,
Diarrheab 0 (0) 4 (6) providing healthy growth and development, recommended
Cholecystolithiasisb 1 (6) 1 (2)
exclusively during the first 6 months and advised to be
Infectionsb 0 (0) 9 (14)
Carnitine deficiencyb 0 (0) 2 (3) continued up to 1 year of age or beyond while gradually
Kidney stonesb 0 (0) 1 (2) introducing solid foods.31 Breast feeding as well as in-
Weight gainb 0 (0) 2 (3) cluding pumped breast milk does not only provide macro-
Growth deficitb 2 (13) 7 (11) and micronutrients but also promotes intestinal, immune,
and cognitive development.32 In infants with inborn errors
Data are presented as numbers with percentages in parentheses of metabolism such as phenylketonuria33,34 breast milk on
(tested using the chi square test).
a
During the first week of the KD. demand is frequently included after having given a small
b
During the first 3 months of the KD. amount of specialized formula when close clinical and
KD, ketogenic diet. metabolic monitoring is guaranteed.35
6 DRESSLER ET AL.
The prescription of the KD allows only very restricted show that continuing nursing while implementing the KD is
amounts of carbohydrates, so that the inclusion of breast milk complicated for both team and mothers and only achieved in
is difficult, let alone the continuation of breastfeeding. In the a minority. Effectiveness and safety are not different. How-
previously reported case series,21–23 feeding at the breast ever, infections do not occur when breast milk is included.
while on KD was described in 3 cases,21 and expressed breast Based on our results, we suggest to aim at continuation of
milk was used in the other 14.22,23 Also in our cohort, two breastfeeding at start of the KD by bottle-feeding the keto-
infants were exclusively breastfed: the allowed amount of genic formula and to feed the remaining amount of tolerable
breast milk was fed at the breast after the calculated amount carbohydrates at the breast—as recommended also for inborn
of ketogenic formula to guarantee the calculated fat/nonfat errors of metabolism such as phenylketonuria.33–35
ratio. However, most mothers in our cohort preferred to ex- Future research should focus on the question how to further
press breast milk. Regardless of the beneficial properties of optimize the composition of human breast milk, for example,
pumping human milk, infants fed with pumped milk have by using hind milk to allow for even higher amounts of breast
been recently described to show a different and less diverse milk and booster the fat/nonfat ratio. Moreover, long-term
microbiome than breastfed infants,36 so that breastfeeding beneficial effects of breast milk with respect to growth,
while on the KD should be encouraged. cognitive development, and effects on the gut microbiome
As described in the study by Cole et al.,21 fat/nonfat ratios are to be explored in future studies.
were lower also in our patients who received breast milk,
which was also confirmed by a higher amount of calories per Disclosure Statement
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