Laporan Penugasan Evidence Based Medicine

Blok Masalah Pada Anak 3.2 Tahun Ajaran 2020/2021

“The Incidence of Infantile Hypertrophic Pyloric Stenosis and its

Association with Folic Acid Supplementation during Pregnancy: A
Nested Case-Control Study”

Disusun oleh:
Berlyan Sekar Winahyu 18711034
Syifa Hanani Ramadhanti 18711052
Nadifa Azzahra Putri 18711179
Tutorial 1

PRODI PENDIDIKAN DOKTER

FAKULTAS KEDOKTERAN
UNIVERSITAS ISLAM INDONESIA
YOGYAKARTA
2020
RINGKASAN JURNAL
Infantile hypertrophic pyloric stenosis (IHPS) merupakan kelianan pada
bayi usia 2-8 minggu. Kasus ini juga merupakan kasus umum yang membutuhkan
operasi pada bayi usia satu bulan. Etiologi IHPS sebenarnya belum diketahui secara
pasti, namun banyak dikaitkan dengan faktor genetic dan lingkungan, seperti ibu
yang merokok, penggunaan antibiotik jenis makrolid pada bayi baru lahir minggu
atau pada ibu hamil, bayi lahir premature, primigravida, dan jenis kelamin laki-laki.
Penurunan insidensi IHPS dikaitkan dengan faktor lingkungan yang baik.
Penelitian ini bertujuan untuk melihat insidensi IHPS di Israel pada tahun 1999
hingga 2015, mengetahui penggunaan asam folat pada tahun tersebut, dan apakah
ada perubahan dengan mengonsumsi asam folat.
Penelitian ini dilakuakn di Maccabi Healthcare Services (MHS) karena
dianggap data yang diperoleh dapat mewakili penduduk Israel, penilaian
penggunaan suplemen asam folat selama periode 3 bulan sebelum kehamilan
hingga akhir kehamilan. Selama 1999 hingga 2015 insidensi IHPS dikelompokan
menjadi lima kelompok kontrol berdasarkan tanggal kelahiran, usia, dan daerah.
Variabel lain yang dipakai pada penelitian ini berupa usia ibu, tempat kelahiran,
status social ekonomi, penggunaan makrolid oleh ibu selama kehamilan dan pada
bayi dalam usia 3 bulan pertama, berat lahir, dan usia kehamilan. Pada penelitian
ini menggunakan analisis statistik dengan uji Fisher.
Penelitian ini mengambil subjek pasien dengan kasus IHPS dari tahun 1999
sampai 2015, didapatkan jumlah pasien dengan IHPS sebanyak 1899 kasus. Dari
hasil penelitian, didapatkan prevalensi terjadinya kasus IHPS dari tahun 1999
sampai 2015 menurun. Kejadian kasus IHPS pada tahun 1999 sebanyak 4,29:1000,
sedangkan pada tahun 2015 perbandingannya menjadi 2,03:1000. Faktor resiko
kasus IHPS diantaranya adalah kelahiran prematur, jenis kelamin laki-laki, dan
penggunaan makrolid oleh bayi. Faktor-faktor tersebut dibuktikan memiliki
hubungan dengan peningkatan kasus IHPS. Penelitian ini juga membuktikan
konsumsi asam folat oleh ibu selama hamil tidak mempengaruhi insidensi IHPS.
HAL BARU YANG DIPELAJARI
Hal baru yang diperoleh mahasiswa dari jurnal tersebut adalah pengetahuan
mengenai penyakit infantile hypertrophic pyloric stenosis (IHPS), jenis desain
penelitian dan metode analisis data. IHPS merupakan gangguan pada bayi biasanya
usia 2-8 minggu disebabkan oleh adanya stenosis pada pylorus dan merupakan
indikasi operasi paling umum pada bayi dalam bulan pertama kehidupannya.
Etiologi IHPS sampai saat ini masih belum diketahui namun faktor genetika dan
lingkungan turut berperan penting terhadap kejadian IHPS dalam beberapa dekade
terakhir. Faktor lingkungan yang turut berperan diantaranya ibu hamil yang
merokok, penggunaan botol pada bayi, perubahan posisi tidur bayi yang
berhubungan untuk pencegahan sudden infant death syndrome, kelahiran prematur
dan penggunaan makrolid saat hamil. Desain penelitian yang baru diketahui adalah
nested case-control study atau studi kasus control tersarang yang merupakan studi
kasus control yang mengunakan kasus dan kontrol dari populasi kohort yang telah
diikuti selama periode waktu tertentu. Hal yang baru diketahui lainnya adalah
metode analisis data menggunakan multivariable conditional logistic regression
yang merupakan tipe khusus dari analisis regresi logistik dimana pada desain ini
memungkinkan seseorang memperhitungkan stratifikasi dan pencocokan dimana
subjek kasus dengan beberapa syarat masing-masing dicocokkan dengan sejumlah
subjek control tanpa syarat.
TELAAH KRITIS

Aetiology or harm critical appraisal guide

Validity Where do I look?

Are the objectives of the study clearly stated?
Ya, tujuan dari penelitian dipaparkan dengan jelas • Introduction,
seperti yang tertera pada judul jurnal. Dalam jurnal paragraf ke 5,
tersebut menuliskan sebagai berikut: Halaman 2

Were exposures and outcomes measured in the same

way in the patient groups? • Patients
Ya, adapun dalam penelitian ini data yang diambil dari and
tiap subjek adalah: methods
• Konsumsi asam folat paragraf 3
• Konsumsi makrolid pada ibu saat hamil dan pada dan 6,
bayi di tiga bulan pertama setelah lahir halaman 2
• Usia kehamilan • Result

• Jenis kelamin tabel 1,

• Status sosioekonomi halaman 3

• Berat badan lahir

• Usia ibu saat melahirkan
Were the patient groups clearly defined and
similar in prognosis other than exposure to the • Result tabel 1,
treatment or aetiological factor? halaman 3
Ya, karakteristik kelompok kontrol dan kasus hampir
mirip
 Was follow-up sufficiently complete and was it long
enough? • Result paragraf 1,
Penelitian ini mengambil data masa lampau sehingga halaman 3
follow-up dilakukan melaui data dari tahun 1999-2015

Did the study have a sufficiently large sample size?

Subjek yang digunakan sebanyak 7350 kelompok kontrol • Result
dan 1889 kelompok kasus IHPS tabel 1,
halaman 3

Was there statistical adjustment for important

differences between patient groups? • Statistical
Ya, untuk perbedaan kasus dan control diuji dengan uji analysis,
ANOVA atau Mann-Whitney. Odds ratio dan Confidence paragraf 2
Interval dihitung menggunakan conditional multivariable halaman 3
logistic regression. Model dilakukan penyesuaian
terhadap faktor confounder potensial dengan analisis
univariat dan pertimbangan klinik.
Is the temporal relationship plausible?
Ya, terdapat waktu yang cukup untuk meneliti apakah • Results, paragraf
peningkatan konsumsi suplemen asam folat berhubungan 1 halaman 3.
dengan penurunan kasus IHPS. Figure 1 halaman
2

Is there evidence of a dose-response?

Ya. Dosis asam folat yang dikonsumsi dibagi menjadi 3 • Results
dosis (tertile) dengan tertile 3 sebagai dosis terendah. Paragraf 3, baris
Terdapat perbedaan hasil yang tertera pada jurnal ke-7 halaman 3
tersebut: • Discussion
Paragraf
5,
halaman
4

Is the biological relationship plausible?

Tidak, dimana pada jurnal tersebut menjelaskan terdapat • Discussion
fase plateu dalam konsumsi asam folat yang menurunkan Paragraf 4-5,
plausibilitas terhadap peningkatan kejadian IHPS yang halaman 3-5
terus menerus. Adanya hubungan antara asupan asam
folat tertile 2 dengan kejadian IHPS pada bayi yang lahir
di usia 37-38 minggu oleh penulis dianggap sebagai
penemuan koinsidental.

Is there evidence of causation from a withdrawal-

rechallenge study? -

Tidak.

Clinical Importance Where do I look?

How strong is the association between exposure and
outcome (harm, disease)? • Results Paragraf
3, Halaman 3
Analisis menggunakan conditional logistic regression dengan Tabel 2
antara asupan asam folat dalam tertile dengan kejadian dan 3 halaman 4
IHPS tidak memiliki hubungan. Nilai p didapatkan 0.8
dan OR didapatkan 1. Penulis juga menghubungkan
antara asupan asam folat dengan kejadian IHPS
diklasifikasikan berdasarkan usia kehamilan saat
melahirkan dengan didapatkan hasil tidak memiliki
hubungan kecuali pada asupan asam folat (tertile 2)
dengan usia kehamilan saat melahirkan antara 37-38
minggu dengan p=0.046 dan OR=1,94. Namun setelah
dilakukan koreksi dengan metode Bonferroni,
didapatkan hasil yang tidak signifikan.

More information: Relative Risk, Absolute Risk

Reduction, and Number Need to Treat (harm).
How precise are the estimates of risk?
Penelitian menggunakan confidence interval 95% yang • Statistical analysis
menunjukan estimasi risiko paparan terhadap hasil sudah Halaman 3,
presisi. paragraf 3
• Results
Tabel 2 dan 3
halaman 4
Are the results discussed in relation to existing
knowledge and is the discussion biased? • Discussion
Pada pembahasan terdapat hasil dari penelitian dan hasil paragraph 1
penelitian dihubungkan dengan penelitian sebelumnya.

What level of evidence does this paper give?

• Methods
Pada penelitian ini level evidence berdasrkan Oxford
CEBM Levels of Evidence Hierarchy adalah 3a
Applicability Where do I look?
Were the study patients and their management similar
to those in my practice? • Methods
Methods
Ya, dalam penelitian ini paparan dan faktor resiko yang paragraph 3
disajikan dapat di aplikasikan dan digeneralisasi dengan dan 6
pasien yang ada di Indonesia.

Are the results useful in your patient?

• Results
Ya, pada penelitian menunjukkan hasil yang paragraph 3
signifikan pada penggunaan makrolid pada bayi
meningkatkan insidensi IHPS sedangkan pada
asupan asam folat saat kehamian tidak meunjukkan
hubungan dengan insidensi IHPS.
KESIMPULAN
Penelitian ini dapat disimpulkan
1. Validity: Baik
Data subjek yang digunakan merupakan data yang valid, poin
pengkategorian dari tiap kelompok kontrol dan kelompok kasus juga
sama.
2. Clinical Importance: tidak bermakna
Pada penelitian ini analisis pada data menghasilkan nilai p<0.05 maka
didapatkan hasil tidak bermakna secara statistik.
3. Applicability: bisa digunakan, pada penelitian ini dapat digunakan dan
dapat di generalisasi untuk pasien yang ada di Indonesia, sebab faktor
resiko yang disajikan terdapat pada pasien di Indonesia.
Lampiran jurnal
YJPSU-58690; No of Pages 6
Journal of Pediatric Surgery xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Journal of Pediatric Surgery

journal homepage: www.elsevier.com/locate/jpedsurg

The incidence of infantile hypertrophic pyloric stenosis and its

association with folic acid supplementation during pregnancy: A nested
case–control study☆
Yael S Rosenthal a, Gabriel Chodick a,b, Zachi Grossman b, Varda Shalev a,b, Gideon Koren a,b,⁎
a
Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
b
Maccabi Institute for Research and Innovation, Tel Aviv, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Background and Rationale: Several studies have suggested that the incidence of infantile hypertrophic pyloric ste-
Received 13 February 2018 nosis (IHPS) has decreased in recent decades. This decrement is controversial and not fully explained. Concur-
Received in revised form 8 April 2018 rently, there has been a major increase in folic acid consumption by pregnant women to prevent neural tube
Accepted 1 May 2018 defects. We aimed to describe IHPS incidence in Israel in recent years and to assess its potential association
Available online xxxx
with folic acid consumption.
Methods: Using the electronic medical database of a 2.1 million member health organization in Israel, we identi-
Key words:
Infantile hypertrophic pyloric stenosis
fied all cases (n = 1899) of IHPS occurring between 1999 and 2015. Cases were individually matched with up to 5
Folic acid controls (n = 7350) by birth date, sex, and region. Odds ratios and 95% confidence intervals by tertiles of cumu-
Prematurity lative dose of supplemented folic acid between three months prior to pregnancy and up to birth of index child
Breastfeeding were calculated using conditional logistic regression.
Macrolides Results: During the study period IHPS incidence declined from 4.3 in 1999 to 2.1 per 1000 live births in 2015
(p b 0.0001). No significant (p = 0.81) association was observed between folic acid intake during pregnancy
and risk of IHPS incidence. Preterm birth and infant's use of macrolides during first 3 postnatal months were sig-
nificantly (p b 0.01) associated with increased risk of IHPS.
Conclusions: Similar to other countries, IHPS incidence in Israel has decreased in recent years. The decrement can-
not be explained by increased use of folic acid.
Type of Study: Case Control Study.
Level of Evidence: Level III.
Summary: Using linkage to a large electronic patient database, this study investigated the association between
the decrease in infantile hypertrophic pyloric stenosis and maternal exposure to folic acid during pregnancy.
© 2018 Elsevier Inc. All rights reserved.

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder diagnosed in
young infants, usually between 2 to 8 weeks of age [1,2]. It is among the
most common causes for surgery during the first month of life. Due to its
prominent clinical picture and severity of symptoms, IHPS is rarely missed.
The incidence of IHPS ranges from 0.5 to 5 cases per 1000 live births, with
large variability worldwide. The diagnosis is more common in the Western
world, among males (1:4–6) [1,2], first born children [3], preterm infants
[4], with formula feeding [5] and exposure to macrolide antibiotics [6,7].
Abbreviations: IHPS, infantile hypertrophic pyloric stenosis; SIDS, sudden infant death syn-
drome; MHS, Maccabi Health Services; FA, folic acid; OR, odds ratio; CI, confidence
interval.
☆ Potential Conflicts of Interest: The authors have no conflicts of interest relevant to this
article to disclose.
⁎ Corresponding author at: Kahn-Maccabi Institute of research and innovation, 4
Koifman St, Tel Aviv 6812509, Israel. Tel.: +972 587194777.
E-mail address: Koren_gid@mac.org.il. (G. Koren).
There is controversy regarding the trends in IHPS incidence world-
wide. Recent studies conducted in Scotland [8], Sweden [9], Germany
[10] Denmark [11], and the US [12,13] have suggested a decrease in
IHPS incidence. In contrast, a study conducted in seven different regions
in Europe found both significant increases and decreases in IHPS inci-
dence over time, with no uniform pattern [14]. Other, less recent studies
found an increase in IHPS incidence [15–19].
The etiology of IHPS is unknown but is thought to comprise of a com-
bination of genetic and environmental factors. A strong genetic contri-
bution has been found in a large study in Denmark [11] but in parallel
to the strong hereditary contribution, and because major genetic
changes are not expected to occur within two decades, the potentially
declining incidence rates of IHPS are commonly attributed to putative
changes in environmental determinants. Environmental factors sug-
gested include decreasing rates of maternal smoking [20], decreased ex-
posure to bottle feeding [5] and changes in infant's sleeping positions

https://doi.org/10.1016/j.jpedsurg.2018.05.005
0022-3468/© 2018 Elsevier Inc. All rights reserved.

Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005
2 Y.S. Rosenthal et al. / Journal of Pediatric Surgery xxx (2018) xxx–xxx
due to recommendations for the prevention of sudden infant death syn-
drome (SIDS) [21,22]. The association between SIDS and IHPS has been
ultimately ruled out [22]. Maternal smoking [20] and formula feeding
[5] have been associated with elevated risk for IHPS, but changes of
these factors over several decades have not been explored. Other deter-
minants associated with higher risk for IHPS include preterm delivery
[3,4], early use of macrolide antibiotics by the infant [6,7] and maternal
macrolide use during pregnancy [6]. However, these two factors were
not shown to have decreased in the last few decades.
All the above have led us to explore the potential role of gestational
use of folic acid, as a major environmental factor that has increased over
the past two decades, concurring with the changes in incidence of IHPS
reported in many countries worldwide. In the past two decades, folic
acid has become widely used by pregnant women to prevent neural
tube defects [23].
The objectives of the present study were threefold: (a) to determine
the yearly trends in IHPS incidence in Israel between 1999 and 2015;
(b) To record the trend in folic acid use during these years; (c) To assess
whether changes in IHPS incidence are associated with the increase in
folic acid consumption.
1. Patients and methods
1.1. Settings
Maccabi Healthcare Services (MHS) is the second largest health
maintenance organization in Israel, insuring over 2 million members.
According to the Israeli National Health Insurance act, MHS is forbidden
to reject any civilian who wishes to be insured. Consequently, MHS in-
sures every section and its data are representative of the Israeli popula-
tion. Since the early 1990’s MHS has established electronic patient
records, where all medical data are collected, including medication pre-
scriptions and purchases.
1.2. Study population and design
1.2.1. Incidence of IHPS
IHPS cases were identified in MHS database according to the Interna-
tional Classification of Diseases version 9 with clinical modification (ICD-
Fig. 1. Yearly incidence rates of IHPS (in blue) and of folic acid purchases (green). a = 17.523, b = −0.444 (95% C.I. = −0.575 to −0.313).
Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005
9-CM) codes from community physicians or hospital discharge charts.
Incidence rates of IHPS per 1000 live births during the period between
years 1999 and 2015, were calculated by dividing the number of cases
in each year by the total number of live births in MHS during the respec-
tive year.
1.2.2. Assessment of folic acid consumption during pregnancy
We assessed prenatal exposure to folic acid (FA) by calculating
mother's personal number and dose of FA supplementation purchased
throughout the time period starting 3 months prior to gestation and
until birth. The total cumulative dose (in μg) of purchased FA was calcu-
lated and divided to tertiles. Although a woman could purchase folic
acid and multivitamins containing folic acid over the counter, she
would have to pay out of pocket substantially higher price than receiv-
ing it through MHS.
1.2.3. Nested case control analysis
We identified every newborn diagnosed with IHPS and registered in
MHS between the years 1999 and 2015 (inclusive), and matched them
with up to five controls by exact birth date, sex, and region.
1.2.4. Quantification of exposure to folic acid during pregnancy
For all study participants (IHPS and controls) we calculated in MHS
database all individual purchases of folic acid supplementation, includ-
ing dose and number of packs starting 12 months before birth date.
1.2.5. Other study variables
Demographic variables included maternal age and region of birth.
Socioeconomic status (SES) was categorized to quartiles based on the
poverty index of the member's enumeration area, as defined by
Israel's 2008 national census. The poverty index is based on several pa-
rameters including household income, educational level, crowding,
physical conditions, and car ownership [13].
Macrolide use by the mother during pregnancy, infant use of
macrolides in the first 3 postnatal months, birth weight, and gestational
age were also collected.
 Y.S. Rosenthal et al. / Journal of Pediatric Surgery xxx (2018) xxx–xxx 3

Fig. 2. Odds ratio of IHPS as a function of gestational age.

1.3. Statistical analysis Concurrently and predominantly between 1999 and 2003, folic acid
purchases have risen dramatically (Fig. 1). Association between IHPS
Differences between cases and controls were tested using Fisher's and Odds ratio for IHPS increased as gestational age at birth decreased
analysis of variance (ANOVA) or the non-parametric Mann–Whitney (Fig. 3).
test as appropriate for continuous variables (e.g. age, birth weight). Conditional logistic regression revealed no association between folic
Odds ratios (OR) and 95% confidence intervals (CI) for IHPS by acid intake (in tertiles) and IHPS incidence (p = 0.81) (Table 2). In mul-
tertiles of exposure dose to FA were calculated using conditional multi- tivariable analysis, preterm birth and macrolide use by infant in the first
variable logistic regression. The model was adjusted for potential con- 3 months (mostly in the first 3 weeks) were significantly associated
founders based on univariate analysis and clinical judgment. In with higher OR for IHPS (OR = 2.4 and 1.9 respectively). Maternal use
addition, we also calculated ORs for IHPS by tertiles of FA dosage, strat- of macrolides throughout the pregnancy was positively associated
ified by gestational week at birth. with IHPS but did not reach statistical significance (p = 0.1). When
Statistical analyses were performed using IBM Corp. Released 2012. stratifying for gestational age and dose of folic acid intake in tertiles
IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp. (Table 3), there was no association between IHPS incidence and folic
The statistical power was based on assumptions regarding exposure acid supplementation, except for the 1st tertile of folic acid supplemen-
to FA, multiple correlation coefficient of 0.5, and an expected OR of 0.7 at tation (low supplementation) at 37–38 weeks gestation, where the risk
5% significance had a power of 85%. for IHPS was found to be in higher (OR = 1.94, p = 0.046). After correc-
tion for multiple comparisons by the Bonferroni method, this difference
2. Results also did not reach statistical significance. Our data also show an ongoing
decline in macrolide use in babies throughout the relevant years (Fig. 4).
2.1. Incidence of IHPS
3. Discussion
A total of 1899 IHPS cases (67.9% males) were identified between
1999 and 2015 and were individually matched with up to 5 controls Our results show a consistent monotonic decline in IHPS incidence
(n = 7350) (Table 1). IHPS incidence rates exhibited a marked decline in Israel between 1999 and 2015 and a significant negative correlation
from 4.29 per 1000 live births in 1999 to 2.03 per 1000 live births in between IHPS incidence and year of diagnosis. This trend is similar the
2015(p b 0.0001). The trend of decreased IHPS incidence over the one seen in other countries in recent years [8–12], and contributes to
years was significant (R2 = 0.7, p b 0.01) (Fig. 1). (See Fig. 2.) the uncertainty regarding the putative causes for this decline. No asso-
ciation was found between FA intake and IHPS incidence.
Table 1 Two previous studies that addressed IHPS in Israel and were pub-
Characteristics of study groups. lished in 1955 [24] and 1980 [25] found incidence rates of 5 per 1000
controls IHPS cases P value
live births, similar to the rate found in the first years of our cohort.
This may suggest a relatively steady rate that has begun declining in re-
n % n %
cent decades, and points towards a recent environmental change. Con-
Sex male 4991 67.9% 1291 68.0% .948 versely, data regarding IHPS trends from other studies between 1970 to
female 2359 32.1% 608 32.0%
2015 show an increase in IHPS incidence until the 1990’s followed by a
SES⁎ (mean) 12 4 11 4 b0.001
Gestational age (mean) 39.5 1.6 39.2 2.0 b0.001 decline from there on out (Fig. 3) which might suggest a temporary en-
Birth weight (gr.) (mean) 3248.7 586.2 3214.8 572.0 .165 vironmental change that caused this change in trends.
Maternal age at birth (mean) 31.19 5.09 29.99 5.20 b0.001 The decrease in incidence found in our cohort concurred with a
SES, Socioeconomic status. marked increase in gestational folic acid consumption. However, unlike
⁎ Socioeconomic status ranges between 1 (lowest) to 20 (highest). the steady decrease in IHPS throughout the period, the increase in folic

Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005
4 Y.S. Rosenthal et al. / Journal of Pediatric Surgery xxx (2018) xxx–xxx

Fig. 3. Incidence rates of IHPS in different countries from 1970 and on, showing a general trend of increase till the mid 1990s, and trending down subsequently.

acid consumption plateaued around 2004, which decreases the plausi-
bility that folic acid plays a role in the decline in IHPS incidence. Indeed,
the conditional logistic regression confirms a lack of association be-
tween folic acid consumption and IHPS.
When stratifying for gestational age, there was no association be-
tween FA intake and IHPS, except for the first consumption tertile
(low intake) of babies born at 37–38 weeks. However, this trend was
nullified upon correction for multiple comparisons. Moreover, if babies
born in early gestational age were more susceptible to IHPS when
Table 3
Odds ratio for IHPS by tertile of folic acid intake (in MG), stratified by gestational age.

Gestational age groups p OR 95.0% CI for Exp(B)

Lower Upper
Table 2
Odds ratio for IHPS: a multivariable conditional logistic regression. b= 36.0 or b 2000 g FA tertile 3 .906
FA tertile 2 .657 .667 .111 3.990
p OR 95.0% CI OR FA tertile 1 1.000 1.000 .141 7.099
Lower Upper 37.0–38.037-38 weeks FA tertile 3 .129
FA tertile 2 .046⁎ 1.943 1.011 3.733
Folic acid intake (mg) ref. (tertile 3) .809 1 (ref.) FA tertile 1 .306 1.416 .727 2.756
Folic acid intake tertile 1 .528 .9510 .8130 1.112 39 weeks FA tertile 3 .601
Folic acid intake tertile 2 .659 .9660 .8300 1.125 FA tertile 2 .381 .886 .675 1.162
Gestational age at birth ref. 40+ weeks)) FA tertile 1 .392 .896 .695 1.153
b36 weeks or b2000 g b0.001 2.442 1.860 3.205 40 weeks or above FA tertile 3 .275
37–38 weeks .133 1.159 .9560 1.406 FA tertile 2 .763 1.070 .691 1.657
39 weeks .170 1.113 .9550 1.298 FA tertile 1 .136 1.400 .900 2.179
Maternal macrolide use during pregnancy .107 1.361 .9360 1.978
⁎ this difference becomes statistically insignificant after correction for multiple
Child macrolide use during first 3 months .002 1.960 1.267 3.030
comparisons.

Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005
 Y.S. Rosenthal et al. / Journal of Pediatric Surgery xxx (2018) xxx–xxx
Fig. 4. Percentages of infants receiving macrolides over the years.
using low amounts of supplementary folic acid, we would expect this ef-
fect to be seen in earlier gestational weeks as well. In light of that, we be-
lieve that this is likely a coincidental finding.
Few other studies have examined the correlation between folic acid
consumption and IHPS. In a meta-analysis conducted in order to explore
birth defects after grain fortification with folic acid [26], a statistically
significant positive association was found (OR = 1.49, 95%CI
1.18–1.89). If correct, that study could have a major impact on the use
of folic acid in pregnancy, and the practice of pediatric surgery as related
to pyloric stenosis. Conversely, a study [27] that examined the preva-
lence of birth defects after grain fortification in the US found a minor,
though statistically significant, decrease in IHPS risk after fortification
(OR = 0.95 CI 0.9–0.99]. However, both studies were based on ecologi-
cal data and did not address this subject directly. Two other studies that
have also addressed pyloric stenosis indirectly found no statistically sig-
nificant association [28,29] It is worth noting that Israel does not fortify
grains with folic acid.
Our study has several strengths worth noting; large numbers of IHPS
contributing to the study's power, unselected patient population, sys-
tematically collected data from consecutive years, comprehensive data
from electronic records of folic acid purchases and accurate diagnostic
records due to the database system and to the prominent clinical man-
ifestation of IHPS. Our study was also able to demonstrate known risk
factors for IHPS, such as male sex [2], history of macrolides use [6,7], ma-
ternal use of macrolids during pregnancy [30] and prematurity. Noting
this, along with the fact that the survival rate of preterm babies is con-
tinuously rising [31], we would expect the incidence of IHPS to increase
rather than decrease.
Several potential weaknesses should beacknowledged. It is impor-
tant to note that although the HMO provided a much lower price for
FA, folic acid can be purchased over the counter without being docu-
mented. This may render our data regarding FA purchases incomplete.
However, there is no reason to believe that FA purchases through the
HMO differed between cases and controls. In light of that, incomplete
data on folic acid purchases should not cause a differential bias and un-
likely to confound the results.
The decline seen in macrolide use by infants (Fig. 4) can potentially
somewhat contribute to the drop in incidence seen in recent years [32].
However, only a small minority of children were treated with
macrolides, thus other causes should be explored. Feeding method has
been previously studied as a potential factor contributing to the chang-
ing trends in IHPS. As suggested in a recent study [33], bottle feeding at
discharge from hospital was independently associated with higher risk
for IHPS (OR = 2.1). To address this potential cause, we investigated a
subset of 598 women from MHS follow-up clinics, finding that virtually
all (99.9%) women breastfed after birth. Our data imply that feeding
Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005
5
method is most likely not the a major factor accountable for the dra-
matic change seen in IHPS incidence in our cohort.
4. Conclusions
In conclusion, incidence rates of IHPS have declined between 1999
and 2015. Overall, there is no evidence for an association between the
apparent increase in folic acid intake and the decreasing incidence of
IHPS. Although many factors have been associated with IHPS, none
seems to exclusively explain the major decline in IHPS, and thus the un-
certainty regarding this trend remains to be explored by future studies
that should address all potential causes simultaneously.
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Please cite this article as: Rosenthal YS, et al, The incidence of infantile hypertrophic pyloric stenosis and its association with folic acid supplemen-
tation during pregnancy: A n..., J Pediatr Surg (2018), https://doi.org/10.1016/j.jpedsurg.2018.05.005