You are on page 1of 7

BREASTFEEDING MEDICINE

Volume XX, Number XX, 2019


ª Mary Ann Liebert, Inc.
DOI: 10.1089/bfm.2019.0190

The Ketogenic Diet Including Breast Milk for Treatment


of Infants with Severe Childhood Epilepsy:
Feasibility, Safety, and Effectiveness

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
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

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.

Keywords: ketogenic diet, breast milk, infants, epilepsy, beta-hydroxybutyrate

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-

T he ketogenic diet (KD) is a high-fat, low-carbohydrate


diet1,2 used for the therapy of drug-resistant childhood
epilepsy.3 With increasing knowledge on the high efficiency of
hydrates is tolerated and breast feeding is usually fully re-
placed by a specialized high-fat ketogenic formula.10 In view
of the considerable physical11–17 and mental18 health ad-
the neonatal brain to metabolize ketone bodies4,5 and avail- vantages of mother’s milk, it nevertheless seems desirable to
ability of specialized ketogenic infant formulas, the KD is allow for incorporation of breastfeeding into the KD, the
increasingly used for the management of intractable epilepsy more in a group of patients particularly vulnerable to physical
already in the first year of life.6–9 and mental comorbidities.19,20
Exclusive breastfeeding is the optimal form of nutrition Until now, there are three case series on the inclusion of
during infancy, either exclusively during the first 6 months of breast milk into KD.21–23 At our center, both KD with and

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.
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

made ketogenic formula was available in Europe, infants


younger than 1 year of age were also included. The study Data collection
compared conventional KD without breastfeeding with a KD Data were retrieved from a database of pediatric patients
that permitted ingestion of breast milk. Eligible participants treated with KD. Patients were prospectively enrolled and
were infants <12 months of age fed with an exclusive or data entered from medical records and patient’s diaries
mixed liquid diet, but without parenteral nutrition. The pri- (collected at 1, 3, 6, and 12 months after KD start). The time
mary outcome was time to achieve clinically relevant ketosis. to clinically relevant ketosis was defined as time (hours) until
Important secondary outcomes were treatment responder rate ‡2 mmol/L blood beta-hydroxybutyrate27 was reached. The
and seizure freedom at 3 months and last follow-up visit and data with statistical analysis are reported in the text (see
the z-score of weight and height after 3 months. Moreover, Results section) and the time course of beta-hydroxybutyrate
continuation of breastfeeding, nutritional intake, growth, and blood levels (first 5 days and at 1 and at 3 months of therapy)
adverse effects were analyzed. was plotted and reported with the proportion of infants with
clinically relevant ketosis (‡2 mmol/L beta-hydroxybutyrate)
Ketogenic diet in Figure 1. The baseline characteristics were recorded as
shown in Table 1. Nutritional parameters and growth were
The KD was initiated without prior fasting or fluid re-
documented as shown in Table 3. The z-score differences
striction.24 Nursing mothers were invited to include their
from initiation of KD to the end of study were calculated and
breast milk into the KD. Before initiation of the diet, a
reported in the text (Results section). The effectiveness of
thorough neurologic and pediatric examination, video-
therapy is shown in Table 2. Treatment response was de-
electroencephalogram, and fasting blood samples were ob-
fined as a seizure reduction >50% compared to baseline
tained. After consent, the KD was calculated by a trained
(seizure count through 3 months before initiation of the
nutritionist using a computer-based algorithm (Supplemen-
KD), seizure freedom was defined 100% seizure reduction
tary Fig. S1). The KD was started at a fat/nonfat ratio of 1:1.24
compared to baseline, if maintained through to the last
A ketogenic formula (Ketocal; Nutricia Metabolics, Er-
follow-up visit. Adverse effects were recorded using an
langen, Germany; fat/nonfat ratio of 3:1 or 4:1) was therefore
adverse effects diary and recorded as shown in Table 4. Low
mixed with either conventional infant formula (fat/nonfat
fluid intake was defined as intake 30% below recommen-
ratio of 0.4:1) or expressed breast milk. For mature breast
dations,28 growth deficit as a z-score loss of body weight of >
milk, an average amount of fat, proteins, and carbohydrates
-0.8 and excessive weight gain as z-score increase of >1.6.
was used for calculation (100 mL containing 75 calories,
A sample of a prescription of a typical patient’s KD that
4.03 g of fat, 1.13 g of proteins, and 7 g of carbohydrates,
included breast milk is shown with the amounts of breast
equating to a fat/nonfat ratio of 0.4–0.6:1).25,26 To optimize
milk in Supplementary Table S2. For data entry into the
the fat content and to maximize the amount of breast milk,
database parental consent was obtained. Data collection and
mothers were encouraged to provide pumped hind milk. The
analysis were approved by the Ethics Committee of the
amounts of ketogenic formula were then increased stepwise
Medical University of Vienna (EK.-Nr. No. 1391/2013; EK-
to reach a fat:nonfat ratio of 3:1 (maximum)—depending on
Nr. 1591/2019).
beta-hydroxybutyrate levels (2–5 mmol/L). When beta-
hydroxybutyrate levels were lower or within this range,
Data analysis
fat/nonfat ratio was increased on a daily basis in both groups.
After reaching stable ketosis, the fat:nonfat ratio was lowered Statistic data description was used as appropriate (fre-
while maintaining ketosis to allow for a maximum amount of quency, median, interquartile range [IQR], range). For com-
ingested breast milk (or formula milk). In the breastfeeding parisons between groups, medians, odds ratios, confidence
group, transition from pumped mother’s milk to breastfeed- intervals, and Pearson’s chi-square, k-sample median test and
ing was encouraged. In this study, infants were breastfed after the median difference estimator (Hodge–Lehman) were used
bottle-feeding the calculated amount of ketogenic formula. as appropriate. For infants not receiving the KD at 3 months,
Plasma glucose, beta-hydroxybutyrate, and urine ketone levels the last follow-up visit on the KD was used for analysis. Data
BREAST MILK AND THE KETOGENIC DIET 3
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

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.

analysis was performed using the IBM Statistical Package Results


for Social Science (SPSS Statistics Version 25). The sig- Patient characteristics
nificance level was set at p £ 0.05. The hypothesis to be in-
vestigated was that the time to achieve clinically relevant A total of 201 children were screened and 83 patients
ketosis was similar in infants in whom breast milk was £1 year of age were identified. Four infants were excluded
continued during treatment with a KD compared with infants (KD started while receiving parenteral nutrition). The whole
treated with KD alone. final cohort consisted of 79 participants. The age when the

Table 1. Baseline Characteristics


Parameter Breast milk (n = 16) Formula only (n = 63) p
Female 6 (38) 26 (41) 1.0
Etiology known 12 (75) 43 (68) 0.76
Age at KD start (months) 5.3 [1.1–8.2] 6.7 [4.8–9] 0.82
Age at epilepsy onset (months) 2.2 [0.6–6] 3.1 [1.1–5.4] 0.91
Epilepsy onset before KD (days) 24 [15–79] 69 [33–139] 0.18
Drug-naive 2 (13) 8 (13) 1.0
Number of AEDs 2 [1–2.75] 2 [1–3] 0.65
z-score weight 0.5 [-0.3 to 0.9] - 0.5 [-1.2 to 0.3] 0.04
z-score height 0.8 [-0.6 to 1.7] 0.2 [-1.1 to 0.6] 0.15
Categorical data are presented as numbers with percentages in parentheses (tested using the chi-square test). Continuous data are
presented as the median and interquartile range in squared brackets (tested using the k-sample median test).
AEDs, antiepileptic drugs; KD, ketogenic diet.
4 DRESSLER ET AL.

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
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

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.

Nutritional intake and growth Discussion


Infants who were breastfed at baseline received a lower The KD is a well-established diet for severe early-onset
fat:nonfat ratio and significantly more carbohydrates (Table 3). epilepsy syndromes.3,9 The present article reports for the first
BREAST MILK AND THE KETOGENIC DIET 5

Table 3. Nutritional Parameters


Estimator median difference
Parameter Breast milk (n = 16) Formula only (n = 63) and 95% CI
At start
Ratio (fat:nonfat) 2.5 [2.1–2.5] 2.8 [2.5–3.0]a 0.4 (0–0.5)a
Fluids per kg per day (mL) 126 [118–152] 123 [99–144] -7.2 (-28 to 8.7)
Calories per kg per day (kcal) 98 [88–115] 92 [84–107] -6.5 (-18 to 3.4)
Proteins per kg per day (g) 2 [1.9–2.5] 2 [1.6–2.3] -0.1 (-0.4 to 0.1)
Lipids per kg per day (g) 9.3 [8.1–11] 8.8 [7.8–10] -0.6 (-1.6 to 0.5)
Carbohydrates per kg per day (g) 1.9 [1.5–2.2]b 1.1 [1–1.8]b -0.6 (-0.9 to -0.2)b
After 3 months
Ratio (fat/nonfat) 2.5 [2.0–2.9] 2.9 [2.0–3.0] 0.1 (0–0.5)
Fluids per kg per day (mL) 113 [97–135] 98 [82–115] -16 (-33 to 0.7)
Calories per kg per day (kcal) 91 [80–106]a 84 [74–93]a -8.8 (-19 to 0.1)a
Proteins per kg per day (g) 1.8 [1.6–2.4] 1.7 [1.6–2.0] -0.2 (-0.4 to 0.07)
Lipids per kg per day (g) 8.3 [7.4–9.4] 7.7 (6.8–8.8) -0.6 (-1.5 to 0.3)
Carbohydrates per kg per day (g) 1.5 [1.2–2.5] 1.2 (0.9–1.9) -0.3 (-0.8 to 0.03)
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

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
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

day at 3 months. A gradual introduction and a modified


fat/nonfat ratio of 2:1 up to 2.5:1 allowed us to keep a high A.D. has received travel reimbursement and speaker
amount of breast milk integrated in the KD while maintaining honoraria from SHS, Nutricia, and Vitaflo; P.T. has received
ketosis. travel reimbursement from SHS, Nutricia, and Vitaflo. M.F.
Finally, including breast milk during KD in infants with received travel reimbursement from SHS, Nutricia. None was
epilepsy allows for achieving stable ketosis and maybe to related to this article. The other authors have no conflicts of
maintain some the health benefits of breast milk as well as interest to disclose.
mother–infant bonding.
Our data show the feasibility of including expressed breast Funding Information
milk into the KD and to maintain breast-feeding—even until No funding was received for this article.
weaning in 25% of patients. Treatment response (i.e., re-
duction in seizure frequency, as well as seizure freedom) is in Supplementary Material
accordance with infants on standard KD.6,7,9,37,38 The higher
percentage of seizure freedom in infants with breast milk Supplementary Figure S1
included, although not significant, might reflect the docu- Supplementary Table S1
mented epidemiological association of breastfeeding with a Supplementary Table S2
decreased risk of epilepsy.39 On the contrary, infants with a
KD that included breast milk were slightly younger and re- References
ceived less AEDs than infants without breast milk, which also 1. Kossoff EH, McGrogan JR. Worldwide use of the keto-
favors a better response to therapy.6 This potential additional genic diet. Epilepsia 2005;46:280–289.
benefit of breast milk on the effectiveness of the KD still 2. Freeman JM, Kossoff EH, Hartman AL. The ketogenic
remains to be studied, in particular with regard to develop- diet: One decade later. Pediatrics 2007;119:535–543.
mental and cognitive long-term outcome. 3. Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal
clinical management of children receiving dietary therapies
Strength and limitations for epilepsy: Updated recommendations of the International
Ketogenic Diet Study Group. Epilepsia Open 2018;3:175–
This is the first study that directly compared a KD with 192.
breast milk included to the standard KD that is exclusively 4. Cremer JE, Braun LD, Oldendorf WH. Changes during
based on formula. In addition, we analyzed the largest group development in transport processes of the blood-brain
of infants (n = 16) and described in detail how to achieve barrier. Biochim Biophys Acta 1976;448:633–637.
ketosis and maintain feeding at the breast, however, in a 5. Hawkins RA, Willianson DH, Krebs HA. Ketone-body
cohort of 79 infants, this is a relatively small sample for utilization by adult and suckling rat brain in vivo. Biochem
subgroup analysis. The fact that ketosis can be achieved in J 1971;122:13–18.
most patients within the first 48 hours is promising: Data are, 6. Dressler A, Trimmel-Schwahofer P, Reithofer E, et al. The
however, still very limited, especially on mothers actually ketogenic diet in infants—Advantages of early use. Epi-
nursing their children while on the KD. Since the team has lepsy Res 2015;116:53–58.
gained experience in including breast milk to the standard 7. Hong AM, Turner Z, Hamdy RF, et al. Infantile spasms
KD during the study period, protocols changed insofar as in treated with the ketogenic diet: Prospective single-center
the last year’s nursing while on the KD was accepted by experience in 104 consecutive infants. Epilepsia 2010;51:
mothers earlier, that is, already from the first day of the KD. 1403–1407.
8. Prezioso G, Carlone G, Zaccara G, et al. Efficacy of ke-
Summary and Conclusions togenic diet for infantile spasms: A systematic review. Acta
Neurol Scand 2018;137:4–11.
Our results show that ketosis and hence seizure control is 9. Dressler A, Benninger F, Trimmel-Schwahofer P, et al.
feasible with inclusion of breast milk into the KD. We also Efficacy and tolerability of the ketogenic diet versus high-
BREAST MILK AND THE KETOGENIC DIET 7

dose ACTH for infantile spasms: A single center parallel- 27. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal
cohort randomized controlled trial. Epilepsia 2019;60:441– clinical management of children receiving the ketogenic
451. diet: Recommendations of the International Ketogenic Diet
10. Rubenstein JE. Use of the ketogenic diet in neonates and Study Group. Epilepsia 2009;50:304–317.
infants. Epilepsia 2008;49 Suppl 8:30–32. 28. van der Louw E, van den Hurk D, Neal E, et al. Ketogenic
11. Kramer MS, Kakuma R. Optimal duration of exclusive diet guidelines for infants with refractory epilepsy. Eur J
breastfeeding. Cochrane Database Syst Rev 2012: Paediatr Neurol 2016;20:798–809.
CD003517. 29. Pannaraj PS, Li F, Cerini C, et al. Association between
12. Ip S, Chung M, Raman G, et al. Breastfeeding and maternal breast milk bacterial communities and establishment and
and infant health outcomes in developed countries. Evid development of the infant gut microbiome. JAMA Pediatr
Rep Technol Assess 2007:1–186. 2017;171:647–654.
13. OECD/EU. Health at a Glance: Europe 2016–State of 30. Hermansson H, Kumar H, Collado MC, et al. Breast milk
Health in the EU Cycle. Paris: OECD Publishing, 2016. microbiota is shaped by mode of delivery and intrapartum
14. Gouveri E, Papanas N, Hatzitolios AI, et al. Breastfeeding antibiotic exposure. Front Nutr 2019;6:4.
and diabetes. Curr Diabetes Rev 2011;7:135–142. 31. Section on B. Breastfeeding and the use of human milk.
15. Paul IM, Bartok CJ, Downs DS, et al. Opportunities for the Pediatrics 2012;129:e827–e841.
primary prevention of obesity during infancy. Adv Pediatr 32. Neville MC, Anderson SM, McManaman JL, et al. Lacta-
2009;56:107–133. tion and neonatal nutrition: Defining and refining the crit-
Downloaded by Boston University package from www.liebertpub.com at 12/02/19. For personal use only.

16. Zhou Y, Chen J, Li Q, et al. Association between breast- ical questions. J Mammary Gland Biol Neoplasia 2012;17:
feeding and breast cancer risk: Evidence from a meta- 167–188.
analysis. Breastfeed Med 2015;10:175–182. 33. Banta-Wright SA, Kodadek SM, Houck GM, et al. Com-
17. Sung HK, Ma SH, Choi JY, et al. The effect of breast- mitment to breastfeeding in the context of phenylketonuria.
feeding duration and parity on the risk of epithelial ovarian J Obstet Gynecol Neonatal Nurs 2015;44:726–736.
cancer: A systematic review and meta-analysis. J Prev Med 34. Banta-Wright SA, Kodadek SM, Steiner RD, et al. Chal-
Public Health 2016;49:349–366. lenges to breastfeeding infants with phenylketonuria.
18. Girard LC, Farkas C. Breastfeeding and behavioural J Pediatr Nurs 2015;30:219–226.
problems: Propensity score matching with a national cohort 35. Pichler K, Michel M, Zlamy M, et al. Breast milk feeding
of infants in Chile. BMJ Open 2019;9:e025058. in infants with inherited metabolic disorders other than
19. Nickels KC, Wirrell EC. Cognitive and social outcomes of phenylketonuria—A 10-year single-center experience.
epileptic encephalopathies. Semin Pediatr Neurol 2017;24: J Perinat Med 2017;45:375–382.
264–275. 36. Moossavi S, Sepehri S, Robertson B, et al. Composition
20. Weatherburn CJ, Heath CA, Mercer SW, et al. Physical and and variation of the human milk microbiota are influenced
mental health comorbidities of epilepsy: Population-based by maternal and early-life factors. Cell Host Microbe 2019;
cross-sectional analysis of 1.5 million people in Scotland. 25:324–335.e4.
Seizure 2017;45:125–131. 37. Kossoff EH, Hedderick EF, Turner Z, et al. A case-control
21. Cole NW, Pfeifer HH, Thiele EA. Initiating and main- evaluation of the ketogenic diet versus ACTH for new-
taining the ketogenic diet in breastfed infants. ICAN 2010; onset infantile spasms. Epilepsia 2008;49:1504–1509.
2:177–180. 38. Pires ME, Ilea A, Bourel E, et al. Ketogenic diet for in-
22. Fenton C, Randall R, Groveman SA, et al. Use of expressed fantile spasms refractory to first-line treatments: An open
breast milk with the ketogenic diet. ICAN 2015;7:342–346. prospective study. Epilepsy Res 2013;105:189–194.
23. Le Pichon JB, Thompson L, Gustafson M, et al. Initiating 39. Sun Y, Vestergaard M, Christensen J, et al. Breastfeeding
the ketogenic diet in infants with treatment refractory epi- and risk of epilepsy in childhood: A birth cohort study.
lepsy while maintaining a breast milk diet. Seizure 2019;69: J Pediatr 2011;158:924–929.
41–43.
24. Dressler A, Stocklin B, Reithofer E, et al. Long-term out- Address correspondence to:
come and tolerability of the ketogenic diet in drug-resistant Anastasia Dressler, MD
childhood epilepsy—The Austrian experience. Seizure Department of Pediatrics and Adolescent Medicine
2010;19:404–408. Medical University Vienna
25. Ballard O, Morrow AL. Human milk composition: Nu- Waehringer Guertel 18–20
trients and bioactive factors. Pediatr Clin North Am 2013; A-1090 Wien
60:49–74. Austria
26. Jenness R. The composition of human milk. Semin Peri-
natol 1979;3:225–239. E-mail: anastasia.dressler@meduniwien.ac.at

You might also like