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ISSN: 0972-24 0 8

Vol. 12 No. 4
JanMar 2012

Perinatology
Journal of Perinatal and Neonatal Care

Indexed in
EMBASE and CINAHL

Vol. 12 No. 4
JanMar 2012

Perinatology
Journal of Perinatal and Neonatal Care

Editor in chief

Dr Ranjan Kumar Pejaver


Bangalore
Managing Editor

Dr Jayashree B Keshav
Bangalore

Editorial Board

Dr Kamini A Rao, Bangalore


Dr BS Rama Murthy, Bangalore
Dr Pradeep M Rao, Bangalore

Dr I Manorama Thomas, Bangalore


Dr Arvind Shenoi, Bangalore
Dr Sulochana Gunasheela, Bangalore

National Advisory Committee

Dr DK Guha, Delhi
Prof. Anil Narang, Chandigarh
Dr Duru Shah, Mumbai
Dr Pratap Kumar, Manipal

Dr S Suresh, Chennai
Dr MKC Nair, Trivandrum
Dr SS Agarwal, Lucknow
Dr Evita Fernandes, Hyderabad

International Advisory Committee

Prof. Victor YH Yu, Australia


Dr Ibrahim Al Hifzi, Saudi Arabia
Dr RS Prasad, UK
Dr Ravi GP Krishnan, USA
Dr UK Wariyar, UK

Dr Rajam S Ramamurthy, USA


Dr Joachim Dudenhausen, Germany
Dr David A Clark, USA
Dr Koravangattu Sankaran, Canada

Indexed in
EMBASE and CINAHL

General
Information

Perinatology

Vol. 12 No. 4 JanMar 2012

Journal of Perinatal and Neonatal Care

The Journal
Perinatology (ISSN 0972-2408), one of the
few journals dedicated to the emerging
multidisciplinary field of perinatal medicine,
is published and distributed quarterly (in the
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Perinatology

Vol. 12 No. 4 JanMar 2012

Journal of Perinatal and Neonatal Care

Contents

Research Articles
Battling with Rising Prevalence of Gestational Diabetes MellitusAre Clinicians in
India on the Right Track?
Hema Divakar, Manyonda IT

Homozygosity Mapping of a Consanguineous South Indian Keratoconus Family


totheCytogenetic Region 14q11.2
Ramana AV, Shetty R, Kumaramanickvel G, Ramesh N

133

140

Review Article
Neonatal Continuous Positive Airway Pressure Ventilation
Sankaran K.

144

Fetal Medicine Update


Fetal and Neonatal Outcome of Congenital Cystic Adenomatoid Malformation
Diagnosed in the Second Trimester of Pregnancy
Shettikeri A, Radhakrishnan P

149

Picture Quiz

153

Self-assessment Quiz

155

Abstracts from Literature

157

Short Communications
Prenatal Diagnosis of Apert Syndrome in Second TrimesterA Case Report
Phadke SR, Mandal K, Ranganath P

Congenital Sternal Cleft with Pectus ExcavatumA Case Report


Somashekhar AR, Ranjana R

Congenital ChylothoraxAn Evidence-based Approach


Ramesh T, Vishwanath J, Pejaver RK

Presternal Bronchogenic Cyst: A Rare Site for a Rare Neonatal Tumor

159
163
165

Aftab Ahmed, Padmalatha Kadamba, Manjiri Somshekar, Pratima

169

Instructions to Authors

173

EMBLEM

Now
in a
new
look...

Perinatology

Vol. 12 No. 4 JanMar 2012

Journal of Perinatal and Neonatal Care

Editorial

Dear Friends,
I am glad to present to you the final issue of Volume 12 of Perinatology. By the
time the journal reaches you we will be well into 2012. Let me wish you, on
behalf of the editorial board and publishers, a very successful, peaceful, and
healthy 2012.
The journal, in its new format and style under the new publishers M/s The
Himalaya Drug Company, has successfully completed 1 year. The effort put
in by them for this journal deserves appreciation and applause. We plan to
restructure the editorial board and advisory committees to bring in academic
and experienced professionals who will take the journal to new heights. The
board members will be introduced in subsequent issues with short write-up on
each of them.
At the same time, as readers, your feedback and contributions in the form
of articles, and case reports are very crucial in our efforts to achieve high
standards. Let us all work toward achieving this goal.
Have a wonderful year ahead!

Dr Ranjan Kumar Pejaver


Editor in chief
Email: rpejaver@yahoo.com

Perinatology

Vol. 12 No. 4 JanMar 2012

Journal of Perinatal and Neonatal Care

Theme

International Womens Day (March 8)


International Womens Day, a global day marking the economic, political,
and social achievements of women, is celebrated on March 8th every year.
The origin of this day began as an acknowledgment of womens struggle to
make their workplaces better. It was their struggle that created the global
impetus for an International Womens Day.

Indian WomenFacts and Figures


According to the last census held, the percentage of female literacy in the
country is 65%. The sex ratiothe number of females per 1000 malesin the
0 to 6 age group has been consistently declining over the past few decades
and is found to be 927/1000. The average female life expectancy today in
India is 66 years.
As per the National Family Health Survey (NFHS), the number of pregnant
women who are anemic has jumped from about 49% to over 54%. Only 46%
of the births are assisted by trained health workers. And for every 100,000
live births, there are 228 maternal deaths. Only two-thirds of women who
receive any antenatal care (ANC), have the recommended 3+ ANC visits
during pregnancy. More than half of the deliveries are still noninstitutional.
According to the NFHS-3, the initiation of breastfeeding within 1 hour of birth
is reported in only 24.5% and exclusive breastfeeding up to the age of 6
months is only 46.3%.
Lasting solutions to the worlds most serious social, economic, and political
problems are unlikely to be solved until the basic rights and full potential of
women are achieved. The promotion and protection of womens rights are
vital in the global effort for peace and enduring progress. International
Womens Day is a day for global awareness and for international solidarity
among women.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Research
RESEARCH
Articles
ARTICLES

Battling with Rising Prevalence


of Gestational Diabetes
MellitusAre Clinicians in India
on the Right Track?
Hema Divakar*, Manyonda IT

Abstract
Background: Gestational diabetes mellitus (GDM) is associated
with increased perinatal morbidity with overt diabetes in infants
and mothers. In infants, GDM can append an intrauterine environmental risk factor to increased genetic risk for the development of obesity and/or diabetes.
Objective: To assess knowledge among obstetricians and gynecologists regarding management of GDM, after the diagnosis
has been made.
Materials and Methods: A 25-question online survey (www.
abcofobg.com) was developed to assess providers knowledge,
practices, and attitudes related to the management of GDM.
The final sample consisted of 584 respondents. The data were
analyzed using SPSS software (version 16.0).

*Correspondence
Dr Hema Divakar
Consultant in Obstetrics & Gynecology
Divakars Speciality Hospital,
Bangalore, India
Phone: +91 9900154448
Email: hema_divakar@yahoo.com

Results: Overall, 47.62% of doctors advised for self-monitoring at


home on a daily basis using a glucometer venous sample PLBS
on fortnightly visits and 41% resorted to PLBS estimation at 2-week
interval. Many doctors (64.29%) agreed that they would interfere
and deliver at 38 weeks and 35.71% of the doctors said that they
would wait for spontaneous labor. Overall, 85.71%, 84.52%, and
79.76% of doctors agreed that neonates of mothers with GDM
would have macrosomia, hypoglycemia, and respiratory distress
syndrome (RDS), respectively. Among neonates born to mothers
with GDM, 57.14% of doctors transferred 1 of 10 infants to neonatal intensive care unit (NICU) and 33.33% of doctors sent 5 of
10 infants to NICU. Of the 584 respondents, 70.24% were aware
of long-term complications of childhood obesity and adult onset
diabetes. Majority of doctors (92.86%) knew that type 2 diabetes
mellitus was the long-term complication in GDM mothers and
67.86% were aware of the possibility of GDM in next pregnancy.

133

Research Articles
RESEARCH
Divakar
H, et al. ARTICLES
Rising prevalence of gestational diabetes mellitus
Conclusions: This study raises the challenge of translating the evidence from well-resourced research studies into initiatives that
are affordable and feasible, whether in richer or poorer parts
of the world. Also, results of the study reveal the urgent need to
improve quality of diabetes treatment and care that is accessible and community-based with multi-disciplinary teams and
patient-centered approach.
Key words: GDM management, neonatal management, Ob-gyn
specialist, perinatal morbidity, overt diabetes

Background
Diabetes mellitus, a known chronic illness, has become
a major health problem worldwide. According to the
World Health Organization, diabetes has emerged as an
epidemic affecting 246 million people across the world.
Among those affected, almost 80% of onus exists in
developing countries.1
Although there is no evidence that perinatal mortality
is increased in pregnancies with treated gestational
diabetes (GDM), some studies have shown perinatal
mortality to be increased in untreated GDM.24 Gestational diabetes is associated with increased perinatal
morbidity with overt diabetes (macrosomia, neonatal
hypoglycemia, hyperbilirubinemia, respiratory distress
syndrome) in infants and mothers.5 In infants, GDM
can append an intrauterine environmental risk factor
to increased genetic risk for the development of obesity
and/or diabetes.68 Insulin therapy for GDM is associated with less adiposity in offsprings.9 Asian origin and
especially ethnic Indians are at a higher risk of developing GDM and subsequent type 2 diabetes mellitus
(T2DM).1012 Timely screening of all pregnant women
for glucose intolerance would help to achieve euglycemia and adequate nutrition supply would prevent the
vicious cycle of transmitting glucose intolerance from
one generation to the other.13
This study was conducted to assess knowledge among
obstetricians and gynecologists regarding management
of GDM, after the diagnosis was made.

Materials and Methods

A 25-question online survey (www.abcofobg.com) was


developed to assess providers knowledge, practices, and

134 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

attitudes related to the management of GDM. The final


sample consisted of 584 respondents. The questionnaire included 25 questions altogether related to patient
education, glycemic control follow-up frequency, fetal
surveillance, timing of delivery, mode of delivery,
neonatal management, and maternal follow-up. All
data were entered into an electronic database without
personal identifiers, to maintain confidentiality. The
data were analyzed using SPSS software (version 16.0).

Results
A total of 584 respondents participated in the survey.
Table 1 shows the variables related to management of
GDM.

a) Glucose monitoringmethod
and frequency in GDM patients
who were on insulin
Overall, 47.62% of doctors advised for self-monitoring
at home on a daily basis using a glucometer venous
sample PLBS on fortnightly visits and 41% resorted to
PLBS estimation at 2-week interval without daily estimates.

b) Time and mode of delivery in


well-controlled patients
Many doctors (64.29%) said to interfere and deliver
at 38 weeks and 35.71% of the doctors chose to wait
for spontaneous labor. The doctors who chose interfere and deliver preferred 37 weeks (60.27%) and
36 weeks (26.1%) of gestational age for delivery; the
preferred mode of delivery was either elective lower

Research Articles
RESEARCH
ARTICLES
Divakar H, et al. Rising prevalence of gestational
diabetes
mellitus
Table 1. Awareness on Management of GDM and Before Delivery
Awareness on Management of GDM and before Delivery
All my patients on insulin are followed up by
Home self-monitoring by glucometer
PLBS at regular intervals
Other
When my patients are well controlled, I prefer to
Interfere and deliver
Wait for spontaneous labor
You chose Interfere and Deliver above. At what number of weeks would you do this?
<32
32
33
34
35
36
37
38
39
40
You choose to wait for spontaneous labor above. Until what number of weeks would you wait?
<32
32
33
34
35
36
37
38
39
40
You chose Interfere and Deliver above. What is the preferred mode of delivery?
Elective LSCS
Induction and trial of labor if no obstetric contraindication
When my patients are poorly controlled, I prefer to wait until the following number of weeks
before intervention
Elective LSCS
Induction of labor, if inducible
Morbidity of mother in GDM is more because of
Increased incidence of C-section
Increased incidence of infection
Other
Increased incidence of C-section and infection
Increased incidence of C-section and other
Increased incidence of infection and other
All

N=584

278
243
63

375
209

14
0
14
0
0
152
354
14
35
0

0
0
0
0
42
28
167
28
320
0

138
446

47.62
41.67
10.71

64.29
35.71

2.4
0
2.4
0
0
26.1
60.7
2.4
6
0

0
0
0
0
7.21
4.8
28.6
4.8
54.8
0

23.7
76.3

292
292

279
230
91
112
35
35
35

50
50

47.7
39.4
15.5
19.1
5.95
5.95
5.95

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 135

Research Articles
RESEARCH
Divakar
H, et al. ARTICLES
Rising prevalence of gestational diabetes mellitus
segment caesarean section (LSCS) (50%) or by induction of labor (50%). Most of the doctors agreed that the
morbidity of the mother in GDM was due to increased
incidence of C-section (47.7%) and increased incidence
of infection (39.4%).

c) Awareness on neonatal
management
Table 2 shows the variables related to neonatal management.

Neonatal problems
Overall, 85.71%, 84.52%, and 79.76% of doctors
agreed that neonates of mothers with GDM would have
macrosomia, hypoglycemia, and RDS, respectively.

Figure 1. Doctors advice during postpartum followup.

Expected weight at birth


In doctors practice, the average weight of neonates
born to mothers with GDM was 3.5 kg (30.95%), 3 kg
(21.43%), and 4 kg (19.05%).

Transfer to NICU
Among the neonates born to mothers with GDM,
57.14% of doctors transferred 1 of 10 infants to NICU
and 33.33% of doctors sent 5 of 10 infants to NICU.
Of the 584 respondents, 70.24% were aware of longterm complications of childhood obesity and adult
onset diabetes.

d) Maternal follow-up
Many doctors (92.68%) advised for 6 weeks of postpartum follow-up and 94.05% of doctors advised for
sugar testing on that visit. Most of the doctors (55.95%)
performed a random blood sugar and only a few
(17.86%) requested for 75 g glucose challenge test in the
postpartum period. Only 70% of doctors spoke to the
follow-up patients about lifestyle change and diet advice
and the need for annual checkup (Figure 1). Majority of
the doctors (92.86%) knew that T2DM was the longterm complication in GDM mothers and 67.86% were
aware of the possibility of GDM in next pregnancy.

e) Multispeciality team
As shown in Figure 2, to an Ob-gyn specialist, facilities
available as a multispeciality team were ultrasonologist

136 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Figure 2. Services (team approach) available at


gynec clinics.

(95.24%), neonatalogist (80.95%), dietician (63.1%),


and endocrinologist (60.71%).

Discussion
This study aimed to assess knowledge of doctors about
management of GDM and follow-up after delivery and
awareness about long-term complications.

a) Management of the GDM


patients who were on insulin
In general, insulin preparations and dosage schedules
should be tailored to the abnormalities present in the
glycemic profile and patient acceptability. Care should
be taken to minimize the risk of hypoglycemia, especially nocturnal episodes. It is therefore ideal to monitor

Research Articles
RESEARCH
ARTICLES
Divakar H, et al. Rising prevalence of gestational
diabetes
mellitus
Table 2. Awareness About Neonatal and Postpartum Management
Awareness after the Delivery
N=584
Neonates out of GDM have higher incidence

of
Macrosomia
501
Hypoglycemia
494
Hyperglycemia
49
RDS
466
FGR
111
IVH
111
NEC
153
Anemia
28
Hyperbilirubinemia
320
35
Other
In your practice, the average weight of

neonates born out of GDM mother is


125
3
0
3.1
42
3.2
7
3.3
7
3.4
181
3.5
0
3.6
14
3.7
42
3.8
7
3.9
111
4
28
>4.0
In your practice, neonates born to GDM

mothers transfer to NICU


334
1 out of 10 babies
195
5 out of 10 babies
56
10 out of 10 babies

I advice postpartum follow-up at


542
6 weeks
14
6 months
0
1 year
28
Other

85.71
84.52
8.33
79.76
19.05
19.05
26.19
4.76
54.76
5.95

21.43
0
7.14
1.19
1.19
30.95
0
2.38
7.14
1.19
19.05
4.76

57.14
33.33
9.52

92.86
2.38
0

I advice postpartum follow-up for


Sugar testing
Diet advice
Life style change
Contraception
Other
I advice the following protocol for sugar
testing
Random blood sugar
FBS/PPBS
50 g challenge
75 g challenge
WHO Testing
What in your opinion are the long-term
complications for a GDM mother?
None
GDM in next pregnancy
Type 2 diabetes
Major organ damage
Other
What in your opinion are the late
complications for the baby?
None
Childhood obesity
Adult onset of diabetes
Adult onset of hypertension
Adult onset of stroke
Adult onset of liver disease
Other
What is the service that you can avail of at
your clinical setup readily?
Endocrinologist
Dietician
Ultrasonologist
Senior obstetrician for second opinion
Neonatologist

%
549

94.05

417

71.43

431

73.81

466

79.76

56

9.52

63

10.71

327

55.95

42

7.14

104

17.86

90

15.48

1.19

396

67.86

542

92.86

63

10.71

14

2.38

63

10.71

410

70.24

417

71.43

146

25

69

11.9

1.19

%
355

60.71

369

63.1

556

95.24

361

61.9

473

80.95

4.76

all patients with home testing on a daily basis. Patient


education and counseling plays a key role in implementing this practice.
The study revealed that only 47.62% of doctors insisted
on for a self-monitoring at home using a glucometer
on a daily basis. As many as 41% of the clinicians said
that this was too cumbersome and patients will not

comply and therefore the venous sample estimate at


every 2-weekly visits was the only option left to them.
About 10% of the clinicians did not have a set protocol
for glucose monitoring even if the patient was being
administered insulin many times a day.
It is important that all clinicians who deal with these
patients spend time for patient education and coun-

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 137

Research Articles
RESEARCH
Divakar
H, et al. ARTICLES
Rising prevalence of gestational diabetes mellitus
seling and insist on strict monitoring of glucose at home
on a daily basis to regulate the insulin dosage as per the
sugar values, rather than adjusting the doses based on
fortnightly estimates. This is too infrequent for a proper
control.

b) Time and mode of delivery in


well-controlled patients
Many doctors (64.29%) said to interfere and deliver
by 38 weeks even if their patients were controlled and
only 35.71% of the doctors chose to wait for spontaneous labor. Among the doctors who said they would
wait for spontaneous labor, 54.8% considered waiting
up to 39 weeks and 28.6% of them would wait only
until 37 weeks of gestation. Preferred mode of delivery
was either elective LSCS (50%) or by induction of labor
(50%).
As per standard practice guidelines, delivery before full
term is not indicated unless there is evidence of macrosomia, polyhydramnios, poor metabolic control, or
other obstetric indications.14 The possibility that diagnosis of GDM may lead to increased obstetric intervention, including induction of labor and cesarean section15
is a concern. Continuation of the pregnancy in uncomplicated GDM to full term is acceptable provided
that indications from fetal monitoring are reassuring.
Contrary to this, majority of the doctors in the study
chose to electively intervene at 37, 38, or 39 weeks of
gestation. The reasons for opting for intervening could
probably be due to fear of not being able to institute the
fetal surveillance tests as frequently as the case would
demand and the inconsistent follow-up of the patient,
which could bring them in at a subsequent visit with
sudden silent intrauterine death. Most would opt for
elective intervention for the ease of monitoring during
labor, during daytime, when senior specialist help and
neonatal and lab facilities are available.

c) Awareness on neonatal
management
The neonates of mothers with GDM are at risk of all
the complications of infants born to mothers with overt
diabetes, particularly those infants born macrosomic
(birth weight >4 kg).16 Overall, 85.71%, 84.52%, and

138 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

79.76% of doctors agreed that neonates of mothers


with GDM would have macrosomia, hypoglycemia,
and RDS, respectively. In the Indian population, the
normal birth weight of a neonate is between 2.5 and
3.5 kg.17 In contrast, the doctors opined that the average
weight of neonates born to mothers with GDM was 3.5,
3, and 4 kg, larger than what they would expect, which
could be minimized by better and stricter control of
maternal sugar levels.
Only 60% of the clinicians had the luxury of the multispecialty team with dietician and endocrinologists.
This could explain the limitations in the maternal glycemic control due to lack of specialists input. It would
also mean that the primary obstetrician would have
to update themselves in offering these counseling and
advisesto match the better controls achieved in
higher centers with a multispeciality team.
About 57.14% of doctors transferred 1 of 10 infants to
NICU and 33.33% of doctors sent 5 of 10 infants to
NICU. This is alarming in the context where NICU
facilities are remote from the place of delivery. This
emphasizes the need for early screening/diagnosis/glycemic control and advice for transfer to a higher center
in select cases.

d) Postpartum follow-up
Gestational diabetic women require careful follow-up.
An oral glucose tolerance test with 75 g of glucose, using
WHO criteria should be performed at 68 weeks postpartum.18 Although many doctors (92.68%) advised
for 6 weeks of postpartum follow-up and 94.05% of
doctors advised for sugar testing, only 20% asked for
the WHO glucose challenge test and only 70% gave
some advice on lifestyle change and diet (Figure 2).
This is in spite of 92.86% being aware that T2DM
was the long-term complication in GDM mother
and 67.86% being aware that she could be vulnerable to GDM in next pregnancy. Indian women with
GDM have a high risk of developing diabetes (especially T2DM), and metabolic syndrome at a comparatively young age.18,19 They should be made aware of
the symptoms of hyperglycemia and advice should be
given about the importance of healthy eating and exercise patterns. Contraceptive advice and counseling

Research Articles
RESEARCH
ARTICLES
Divakar H, et al. Rising prevalence of gestational
diabetes
mellitus
regarding planning future pregnancies should be given.
Preventive measures against T2DM should start during
intrauterine period and continue throughout life from
early childhood.20 Being strict with counseling at the
postpartum visit with lifestyle modifications would go a
long way in containing the long-term problems, both to
the mother and the child.

3.

Pettitt DJ, et al. Gestational diabetes: infant and maternal


complications of pregnancy in relation to third trimester
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4.

Oats JN, Beischer NA. Gestational diabetes. Aust N Z J Obstet


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5.

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6.

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offspring. Baillieres Clin Obstet Gynaecol. 1991;5:485-492.

It is now recognized that it is the low- and middleincome countries that face the greatest burden of
diabetes. However, many governments and public
health planners still remain largely unaware of the
current magnitude, or, more importantly, the future
potential for increases in diabetes and its serious
complications in their own countries. This study raises
the challenge of translating the evidence from wellresourced research studies into initiatives that are
affordable and feasible, whether in richer or poorer
parts of the world.

7.

Silverman BL, et al. Impaired glucose tolerance in


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Pettitt DJ. Diabetes in subsequent generations. In: Dornhurst


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Simmons D, Robertson S. Influence of maternal insulin


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10.

Dornhorst A, et al. High prevalence of GDM in women from


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11.

Beischer NA, et al. Incidence and severity of gestational


diabetes mellitus according to country of birth in women
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Metzger BE, Coustan DR. Summary and recommendations of


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Seshiah V, et al. Pregnancy and diabetes scenario around the


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Rasmussen MJ, et al. The timing of delivery in diabetic


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1992;32:313-317.

15.

Hunter DJS, Keirse MJNC. Gestational diabetes. In: Chalmers


I, et al, ed. Effective Care in Pregnancy and Childbirth. Vol
1. Oxford: Oxford University Press; 1989:403-410.

16.

Maresh M, et al. Factors predisposing to and outcome of


gestational diabetes. Obstet Gynaecol. 1989;74:542-546.

17.

Paul VK, et al. Management of low birth weight babies. In:


Parthasarathy A, ed. IAP Textbook of Pediatrics. 2nd edn.
New Delhi: Jaypee Publications; 2002: 60.

18.

Yajnik CS, et al. High risk of diabetes and metabolic


syndrome in Indian women with gestational diabetes mellitus.
Diab Med. 2004;21:1257-1259.

19.

Krishnaveni GV, et al. Gestational diabetes and the incidence


of diabetes in the 5 years following the index pregnancy in
South Indian women. Diab Res Clin Pract. 2007;78:398-404.

20.

Tuomilehto J. A paradigm shift is needed in the primary


prevention of type 2 diabetes. In: Ganz M, ed. Prevention
of Type 2 Diabetes. England: John Wiley and Sons Ltd;
2005:153-165.

The study reveals the urgent need to improve quality


of diabetes treatment and care that is accessible and
community-based with multi-disciplinary teams and
patient-centered approach. On-going professional
development/training for diabetes care personnel
(health workers) and development of national clinical
guidelines for GDM are required. It is clear that what is
needed are not only initiatives to identify GDM as the
target group of women who are at high risk of developing T2DM, but also the group to whom appropriate
preventive measures can be provided by extended care
and counseling to prevent early onset of T2DM in the
present as well as the next generation.

Acknowledgments
We extend our sincere thanks to Ravishankar and Dr
Peter Pothula, BioQuest for their valuable IT and editorial guidance in the generation of this report.

References
1.

2.

Diabetes epidemic out of control. Press release [online] 2006


[cited December 04, 2006]. Available at: http://www.idf.org/
home/index.cfm. Accessed January 11, 2012.
OSullivan JB, et al. Gestational diabetes and perinatal
mortality rate. Am J Obstet Gynecol. 1973;136:901-904.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 139

Research Articles
RESEARCH ARTICLES

Homozygosity Mapping of a
Consanguineous South Indian
Keratoconus Family to the
Cytogenetic Region 14q11.2
Anandula Venkata Ramana, Rohit Shetty, Govindasamy
Kumaramanickvel, Ramesh N*

Abstract
Purpose: The objective of this study was to map the gene for
autosomal recessive keratoconus (KC). KC is a corneal thinning
condition that is frequently seen in ophthalmic practice. With
a strong genetic inheritance, KC is a steadily progressive, bilaterally nonsymmetrical, noninflammatory disease. It is an ecstatic
disease, where the paraxial stromal thinning and weakening
causes distortion, leading to conical shape of the cornea. The
disease might start with astigmatism and myopia. KC is a challenging problem and at times, frustrating to treat because of the
progressive nature of the disease.
Methods: In a consanguineous south Indian family, three
affected with KC, were subjected to complete ophthalmic
examination that included corneal topography and collection
of peripheral blood for gene mapping. The DNA was analyzed
using Affymetrix GeneChip SNP 6.0 and genome wide homozygosity mapping analysis.

*Correspondence
Dr Ramesh N
Department of Biotechnology,
JJ College of Arts and Science,
Pudukottai - 622422,
Tamil Nadu, India.
Phone: 04322-260103
Fax: 04322-260103
Email: ramanagene@gmail.com

Results: The regions of significant homozygosity in this family were


on chromosomes 12p13.1 and 14q11.2 and some of the singlenucleotide polymorphisms (SNPs) in this region were rs1544671
and rs3811259, respectively, but the latter showed a better association than the former.
Conclusion: The likelihood of the KC gene, in this south Indian
consanguineous family, to be in chromosome 14 is quite high
and was strongly associated with the SNP marker rs3811259 at the
cytogenetic region 14q11.2.
Key words: Homozygosity mapping, keratoconus, myopia

140 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Research Articles
RESEARCH
ARTICLES
Ramana AV, et al. Homozygosity mapping to the
cytogenic region
14q11.2

Introduction

Methodology

Keratoconus (KC) is a corneal ectasia that results in the


conical shape of the cornea. It is invariably bilateral,
noninflammatory disease. With different diagnostic
criteria utilized in a variety of studies, the prevalence
of KC varies from 8.8 to 54.4 per 100,000.1 However,
a study by Pearson et al,2 reported that the incidence
is 4 times higher in Indian subcontinent as compared
to Caucasians in Britain. Fullerton et al.3 showed that
such populations would be ideal for molecular genetic
studies and demonstrated in a Tasmanian small
size family. In a majority of patients, KC occurs as a
sporadic disease; however, a significant minority has a
strong family history with multiple members affected.
The prevalence of KC among the first degree relatives
were 15- to 67-fold higher than in the general population.4 In such highly inbred consanguineous or endogamous populations, homozygosity would be inherited
and because of which such rare autosomal recessive
disorders prevail.

Clinical

Both genetic and environmental factors are associated


with keratoconus.5 More than a dozen of syndromes
are associated with KC including Down syndrome,6
Leber congenital amaurosis,7 osteogenesis imperfecta,8
GAPO syndrome,9 and some subtypes of EhlersDanlos syndrome.10,11 Linkage analysis on autosomal
dominant and recessive families have identified various
loci (16q22.3-23.1, 20q12, 3p14-q13, 5q14.3-q21.1,
15q22.33-24.2, 17p13, and regions on chromosome 9,
4, 11, 12, and 14) for keratoconus. However, to date, no
mutations in any genes have been identified for any of
these loci. There is also evidence of VSX1 on 20p11.2
and SOD1 on 21q22.11 involved in the etiology of
keratoconus.12,13
Consanguineous marital practices were predominant
widely among fishermen community all over the world,
although now extinct in most part of Europe. However,
such practices are quite prevalent in the Middle East,
northern Africa, Pakistan, Bangladesh, and southern
India. Southern India has many such highly consanguineous recessive pedigrees with very rarely inherited
Mendelian disorders. We identified a consanguineous
family, three affected with KC, for gene mapping.

Members of the family underwent detailed ophthalmic


evaluation including corneal and fundus evaluations,
fluorescence angiography, horizontal corneal diameter
measurement, total axial length measurement, optical
coherence tomography, and full-field electroretinogram.

Pedigree
Detailed pedigree was taken from the proband, and
peripheral blood was collected from the affected as well
as unaffected members (Figure 1).

Figure 1. Pedigree of a four generation family associated with KC showing autosomal recessive inheritance. The striated symbol indicates members. The
open symbol indicates unaffected members.

Laboratory
Ten milliliters of heparinized blood was drawn from
affected patients and their parents after obtaining
written informed consent from both parents. DNA
was extracted using Machery & Nagel (M&N) Kit
according to the manufacturers instructions. High
throughput genotyping was done using Affymetrix
Gene Chip SNP 6.0. The protocol involves around 250
ng of total genomic DNA incubated with 10 units of
restriction endonuclease. The digested DNA is then
incubated with 0.25 M adaptor and DNA ligase. All
fragments resulting from restriction enzyme digestion, regardless of size, are substrates for adaptor ligation. A generic primer, which recognizes the adaptor

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 141

Research Articles
RESEARCH
ARTICLES
Ramana
AV, et al.
Homozygosity mapping to the cytogenic region 14q11.2
Table 1. Protocol for PCR Mix Concentration
Reagents
PCR buffer (10X)
dNTP (2.5 mM each)
MgCl2 (25 mM)
PCR Primer Xba (10 M)
AmpliTaq Gold (5 U/L)
H2O

Volume (L)
10
10
10
7.5
2
50.5

Concentration

250 M
2.5 mM
0.75 M
0.1 U/L

sequence, is used to amplify ligated DNA fragments.


The polymerase chain reaction (PCR) mix was prepared
(Table 1) and PCR reaction conditions are optimized
as follows: Initial denaturation at 94C for 3 minutes,
denaturation at 94C for 30 seconds, annealing at 60C
for 45 seconds, and extension at 68C for 15 seconds.
These three steps are followed by 30 cycles and final
extension at 68C for 7 minutes to selectively amplify
fragments in the 250 to 1100 bp size range. The amplification products are concentrated with a PCR purification column (Qiagen) and 80 g of DNA is digested
with fragmentation reagent (Affymetrix SNP 6.0 genotyping assay kit). Samples are labeled with 25 to 30
units of terminal deoxytransferase (Affymetrix SNP 6.0
genotyping assay kit) and 30 M biotinylated ddATP
(Affymetrix SNP 6.0 genotyping assay kit). Following
heat inactivation at 95C for 10 minutes, samples were
injected into microarray cartridges and hybridized overnight. Microarrays were washed in a fluidics station
(Affymetrix), followed by a staining protocol with
streptavidin avidin phycoerythrin (Molecular Probes),
and biotinylated anti-streptavidin (Vector Lab), and a
final wash of SSPE buffer. Microarrays were scanned
according to the manufacturers instructions (Affymetrix). The scanned data were analyzed using GeneChip
genotyping analysis software (GTYPE v.4.1), specifically designed to give highly automated SNP allele calls
for the Gene Chip mapping arrays. It provides an integrated analysis workflow to enable high content, high
throughput, and accurate mapping analysis.
The primary results were produced as a simple excel
spreadsheet. The results were then sorted by chromosome and genetic distance using a simple data sort
excel command. The column of sorted SNP allele
calls were copied. The sorted data were processed and
analyzed using ExcludeAR (Woods, 2004) program,

142 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

a freeware spreadsheet. The sorted primary SNP allele


data were pasted into ExcludeAR cell. ExcludeAR3 was
used for the interpretation of the data obtained from
three affected individuals and their parents (Figure 2).

Results
The regions of significant homozygosity in this family
were on chromosomes 12p13.1 and 14q11.2 and
some of the SNPs in this region were rs1544671 and
rs3811259, respectively. The regions of homozygosity in
chromosome 14q11.2 showed a better association than
the regions of homozygosity in chromosome 12 p13.1
(Figure 3).
The likelihood of the KC gene in this south Indian
consanguineous family to be in chromosome 14 is quite
high and is strongly associated with the SNP marker
rs3811259 at the cytogenetic region 14q11.2. Further
study is necessary to identify the disease-causing gene.

Figure 2. Schematic representation of high-density


SNP gene chip.
1

10

11

12

13

14

15

16

17 18 19 20 21 22
1.0 max
0.9 max
0.8 max
0.7 max
0.6 max

Figure 3. Whole genome linkage data.

Research Articles
RESEARCH
ARTICLES
Ramana AV, et al. Homozygosity mapping to the
cytogenic region
14q11.2

Discussion

6.

Despite knowing KC as a clinical entity for a considerable period of time in medical history, identification
of a major causative gene has been elusive for a while.
Genes such as VSX1, SOD1, COL4A3, and COL4A4
have been proposed as candidates based on the identification of disease-causing mutations to explain differential gene expression.14

Cullen, JF Butler HG. Mongolism (Downs Syndrome) and


keratoconus. Br J Ophthalmol. 1963;47:321-330.

7.

Elder MJ. Leber congenital amaurosis and its association


with keratoconus and keratoglobus. J Pediatr Ophthalmol
Strabismus.1994;31:38-40.

8.

Beckh U, et al. Autosomal dominant keratoconusas the chief


ocular symptom in Lobstein osteogenesisimperfecta tarda
(in German). Klin Monabl Augenheilkd. 1995;206:268272.

9.

Wajntal A, et al. GAPO syndrome (McKusick 23074): a


connective tissue disorderreport on two affected sibs and
on the pathologic findings in the older. Am J Med Genet.
1990;37:213-223.

10.

Kuming BS, Joffe L. Ehlers-Danlos syndrome associated with


keratoconus: a case report. S Afr Med J. 1977;52:403-405.

11.

Robertson I. Keratoconus and the Ehlers-Danlos syndrome:


a new aspect of keratoconus. Med J Aust. 1975;1:571-573.

12.

Heon E, et al. VSX1: a gene for posterior polymorphous


dystrophy and keratoconus. Hum Mol Genet. 2002;11:
10291036.

13.

Udar N, et al. SOD1: a candidate gene for keratoconus. Invest


Ophthalmol Vis Sci. 2006;47:3345-3351.

14.

Stabuc-Silih M, et al. Genetics and clinical characteristics


of keratoconus. Acta Dermatovenerol Alp Panonica Adriat.
2010;19:3-10.

15.

Liskova P, et al. Evidence for keratoconus susceptibility locus


on chromosome 14: a genome-wide linkage screen using
single-nucleotide polymorphism markers. Arch Ophthalmol.
2010;128:1191-1195.

16.

Gajecka M, et al. Localization of a gene for keratoconus


to a 5.6-Mb interval on 13q32. Invest Ophthalmol Vis Sci.
2009;50:1531-1539.

17.

Dash DP, et al. Fine mapping of the keratoconus with cataract


locus on chromosome 15q and candidate gene analysis. Mol
Vis. 2006;12:499-505.

Liskova et al15 have shown the linkage of 6 families with


multiple members affected to 14q24.3 and ruled out
mutation in VSX1 gene in the region.
Gajecka et al16 showed a 5.6 Mb region linkage on
chromosome 13q32. Bisceglia et al however, replicated
the region 5q21.2 and other regions in the genome in
their study. The clinical phenotype cataract with KC
was linked to chromosome 15q.17 Tang et al18 showed
linkage on chromosome 5q14.3-q21.1 in a multigeneration Caucasian pedigree. An autosomal dominant
KC in a Finnish family was located to 16q22.3-q23.1
region.19 The data clearly suggest that the consanguineous family studied was strongly associated with SNP
marker rs3811259 to chromosome 14q11.2 region.

References
1.

Edwards M, et al. The genetics of keratoconus. Clin


Experiment Ophthalmol. 2001;29:345-351.

2.

Pearson A, et al. Does ethnic origin influence the incidence


or severity of keratoconus?.Eye. 2000;14:625-628.

3.

Fullerton JM, et al. An associational approach using eight


affected individuals from Tasmania, Australia, maps a locus
for keratoconus. Am J Hum Genet. 1998;63(Suppl):160.

18.

4.

Wang Y, et al. Genetic epidemiological study of keratoconus:


evidence for major gene determination. Am J Med Genet.
2000;93:403-409.

Tang YG, et al. Genome wide linkage scan in a multigeneration


Caucasian pedigree identifies a novel locus for keratoconus
on chromosome 5q14.3-q21.1. Genet Med. 2005;7:397-405.

19.

5.

Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:


297319.

Tyynismaa H, et al. A locus for autosomal dominant


keratoconus: linkage to 16q22.3-q23.1 in Finnish families.
Invest Ophthalmol Vis Sci. 2002;43:3160-3164.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 143

Review
RESEARCH
Article
ARTICLES

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Neonatal Continuous Positive


Airway Pressure Ventilation
Koravangattu Sankaran*

*Correspondence
Dr Koravangattu Sankaran
Divisions of Neonatology and
Pediatric Infectious Diseases,
Department of Pediatrics,
University of Saskatchewan, Saskatoon,
Saskatchewan, Canada.

Continuous positive airway pressure (CPAP) is a mode


of ventilation in which positive pressure is delivered to
the airway throughout the respiratory cycle. It is a form
of continuous distending pressure coupled with positive
end expiratory pressure (PEEP) and continuous negative
expiratory pressure (CNEP), which provides low pressure distension of the lungs during expiration. CPAP,
over the years, has been proven to be an effective mode
of ventilation and therefore has gained widespread use
in the management of neonatal respiratory disease. In
this review, different delivery devices, pressure generating systems, and techniques of using CPAP have been
discussed. Indications for CPAP use and its advantages and limitations are also explored. Nasal intermittent positive pressure ventilation (NIPPV), which is the
augmentation of CPAP, is also discussed.
CPAP was first described in literature in 1971. This
mode of ventilation was first used on large mature
infants but over the years it has been applied to premature infants as well. Initially, treatment with CPAP was
delivered through an endotracheal tube as a precursor
up to extubation. Several other nasal delivery devices
have been tried with varying degrees of success through
the years. Delivery devices that are currently out of
favor are the face mask and head box with seal.

144

Nasal route is preferred as newborns are obligate nose


breathers.
Single nasal prongs, which are usually endotracheal tubes cut and placed 1 to 2 cm inside the
nose, have been used in many units. The specific
disadvantage of this method is leak of pressure
from the opposite nostril.
Binasal prongs are the most commonly used. They
are available in different sizes to ensure an optimal
fit. An appropriate fit is essential to prevent leakage
around the device (if too small) and trauma to the
nose (if too large or improperly fixed).
Nasal masks are less traumatic to the nose, internally. However, it could be difficult to maintain a
seal and they often press very hard against the face
of newborns.
All the nasal devices are limited to the fact that pressure is lost if the mouth is kept open. Chin straps and
pacifiers have been tried to minimize this problem.
Also, the delivery of CPAP has to be interrupted for
suctioning of the airway. Secretions plugging the device
can be problematic with suboptimal pressures being
delivered, leading to clinical deterioration of the infant
and possibly needless intubation. The most advantageous posture of the infant that will ensure maximal
delivery of CPAP to the lungs is yet to be determined.

Review Article
ARTICLES
Sankaran K.RESEARCH
Neonatal CPAP
ventilation
There are several ways of generating CPAP. These
CPAP systems include a conventional ventilator, an
underwater bubbling system, the infant flow driver,
and Benvenistes device. They work by supplying a
flow of gas that is used to generate the needed pressures. The actual amount of gas that reaches the alveoli
is dependent on the amount of leak in the system.
These leaks could be through the nose and around
the delivery device or through the infants mouth. The
amount of leakage can be quite significant and has been
indirectly measured by assessing esophageal or pharyngeal pressure while on CPAP. The optimal amount
of flow required remains unknown and ultimately
depends on the condition that is being treated, the size
of the infant, and the amount of leak in the system as
described above.
A CPAP system usually consists of a gas flow source,
oxygen blender, humidifier, an inspiratory and expiratory circuit, and a manometer. This system is then
attached to the delivery device of choice. The various
systems differ mainly in the expiratory circuits.

CPAP Using a Conventional


Ventilator
Conventional ventilator delivers a fixed amount of flow
to provide the desired positive pressure. It is the most
commonly used mode of delivering CPAP in neonatal
intensive care units, worldwide. Most standard ventilators have a CPAP feature.

Underwater bubble CPAP


Underwater bubble CPAP has been used since the
early 1970s. The tubing is immersed in sterile water
in a glass bottle to a specified depth to produce and
maintain the desired pressure. As gas flows through
the underwater seal, bubbling of the water sets the gas
into vibration and is postulated to create an oscillatory
effect similar but of less amplitude to that seen in high
frequency oscillation mode of ventilation. The CPAP
bubble system was compared to ventilator-derived
CPAP in intubated premature infants and was found
to decrease minute ventilation and respiratory rate and
possibly decrease the work of breathing and susceptibility to fatigue. It has not yet been studied in infants

using nasal delivery devices. The underwater bubbling


in this mode of CPAP generation serves as a visual cue
that the pressure is being appropriately supplied.

Infant flow driver


Infant flow driver (IFD) has a unique patented design
that works in synchrony with the infants respiratory
effort. Fluid flip or coanda effect technology has been
applied in the fields of aerodynamics and jet engine
design. When the patient makes a spontaneous inspiratory breathing effort, the generator assists the patient by
converting air/gas flow to pressure energy and delivers
CPAP to the lungs. When the infant makes a spontaneous expiratory effort, pressure at the nasal attachment of the generator causes the flow to flip around and
leave the generator via the expiratory limb. When expiration stops, the flow flips back to the inspiratory position. By doing so, there is no mechanical impedance
and interference of flow seen in conventional CPAP.
Hence, the airway/system resistance is much lower and
the airway pressure remains constant. IFD has been
shown to reduce work of breathing more effectively
than conventional systems. It has also been shown
to decrease respiratory rate and oxygen requirement
compared to conventional CPAP systems. A nonstatistically significant trend toward reduced need for
mechanical ventilation, shorter clinical recovery time,
and shorter duration of treatment has been described.
Comparison of IFD with a conventional CPAP system,
however, showed no statistically significant difference
in preventing extubation failure in extremely low birth
weight infants (birth weight <1000 g). IFD therapy in
these infants was associated with fewer days on supplemental oxygen and shorter lengths of hospitalization.
This may be important in terms of further reducing the
cost associated with caring for these infants.

Benvenistes valve
Benvenistes valve, when applied to the nasal delivery
device of choice, vents expired air to the surrounding
atmosphere. This device eliminates the need for expiratory tubing, generates more constant pressure, and
may reduce over-distension of the lungs and consequent pneumothoraces. There have been no studies
comparing this device to other available CPAP systems.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 145

Review Article
RESEARCH
ARTICLES
Sankaran
K. Neonatal
CPAP ventilation
The breathing pattern of the neonate with respiratory
distress is quite disorganized. Some of the observed
patterns in them include increased respiratory rate,
active contraction of the inspiratory muscles during
expiration, active expiratory laryngeal narrowing and
tonic activity of the diaphragm, and intercostal muscles.
Premature infants have compliant chest walls causing
paradoxical breathing where the ribcage collapses
inward with the contraction of the diaphragm.
CPAP improves the breathing pattern in neonates
by increasing functional residual capacity and tidal
volume, thereby decreasing burden of breathing. It
also decreases chest wall compliance which is of added
importance in premature infants. CPAP increases the
mean airway pressure which decreases ventilation
perfusion mismatch. CPAP stents the upper airway,
decreases proximal airway resistance, reduces the physiologic dead space, improves synchrony of thoracoabdominal motion, and improves diaphragmatic function.
CPAP is therefore effective in the treatment of obstructive/mixed apnea of prematurity, respiratory distress
syndrome (RDS), respiratory distress of other etiology,
atelectasis, tracheomalacia, and other types of upper
airway obstruction, thus ensuring successful extubation.
In neonatal intensive care units across the world, CPAP
is being used more commonly as an alternative to intubation and intermittent positive pressure ventilation. By
using CPAP in the spontaneously breathing infant, the
adverse effect of intubation and mechanical ventilation
can be avoided. Intubation is associated with untoward
physiological responses to laryngoscopy such as desaturation, bradycardia, and hypotension with the added
risk of cerebral hemorrhage and neuronal injury in
premature infants. Mechanical ventilation predisposes
to atelectrauma, barotrauma, volutrauma, pneumothorax, inadvertent hyperventilation, and long-term side
effects such as stricture and subglottic stenosis. Nosocomial infections may be minimized by avoiding intubation. CPAP is easy to use, inexpensive and studies have
suggested decreased incidence of chronic lung disease
and mortality.

CPAP and RDS


CPAP has been shown to be effective in the treatment
of RDS even in low birth weight infants. In particular,

146 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

it has demonstrated effectiveness in resuscitation, avoidance of intubation, and facilitating weaning from the
ventilator. It is particularly attractive in the setting of
developing countries due to its ease of use and low cost.
For infants that are unable to tolerate CPAP alone due
to surfactant deficiency, in and out intubation for the
purpose of surfactant administration and extubation to
CPAP has been proposed and continues to be studied.
The downside to this practice is that intubation and its
untoward effects are inevitable. However, the effects
of short- and long-term ventilation may be avoided.
The use of nebulized surfactant has been suggested
in the literature but is yet to be studied. With more
infants receiving antenatal steroids, and there being
an improvement in antenatal and perinatal care, more
infants are likely able to tolerate CPAP alone. This idea
of CPAP only in premature infants is attractive because
intubation and surfactant administration are traumatic
and potentially destabilizing for them.

CPAP and Weaning from


the Ventilator
This is the area in which CPAP is mostly used. CPAP
has been proven effective in preventing failure of extubation.

CPAP and Resuscitation


The desired effects of CPAP such as stenting in upper
airways, increasing functional residual capacity (FRC),
reducing airway resistance, and decreasing work of
breathing, is likely to help open up the infants lungs
and keep them open immediately after birth. This may
improve the chances of success of resuscitation. The
IFDAS trial has looked at the use of CPAP right from
birth and found it to decrease the duration of mechanical ventilation. There was no difference in the incidence of chronic lung disease.

CPAP and Apnea of


Prematurity
The clinical management of apnea of prematurity is not
different today from what it was two decades ago. Three
classes of apnea of prematurity have been described

Review Article
ARTICLES
Sankaran K.RESEARCH
Neonatal CPAP
ventilation
central, obstructive, and mixed apnea. Central apnea is
still being treated with methylxanthines. Nasal CPAP
continue to be useful in the treatment of obstructive or mixed apnea. In mild cases, stimulation by the
bedside nurse persists. Alternative, noninvasive modes
of ventilation available for treatment of AOP are nasal
intermittent positive pressure ventilation (NIPPV) and
high-flow nasal cannula (12 L/min).
Studies show NIPPV to be as effective, or more so
than NCPAP. NIPPV is a technique of noninvasive
ventilations, in which a higher level of CPAP is delivered at intervals to simulate a ventilator breath. It is
used in conjunction with CPAP to augment its effect.
Two Cochrane reviews show that NIPPV is useful
in preventing failure of extubation and troublesome
apneas. Case reports of gastrointestinal perforation have
limited its widespread use. Reviewers, however, noted
that there have been no reports of this adverse effect
when the simulated breaths or backup rate is synchronized with the patients breaths.
The exact mechanism of action of NIPPV in improving
apnea of prematurity is yet to be elucidated. NIPPV is
not delivered directly into the lungs as in the case of
the intubated infant. In the scenario where the pressure
delivered is not synchronized, it may be delivered at any
point in the respiratory cycle. It is possible that NIPPV
works not merely as a ventilator breath but by altering
the respiratory mechanics and providing its benefit in
this way. More studies are needed to further define its
mode of action.

Limitations of CPAP
Use of CPAP does not come without its problems.
There is risk of pulmonary air leak, obstruction of the
nasal device by secretions, nasal irritation or injury,
and gastric distension. Over-distension of the lungs
can result in increased work of breathing, hypercapnia,
and decreased pulmonary vascular resistance resulting
in decreased cardiac output. CPAP therapy may simply
not work. CPAP is said to have failed when there is
unrelenting apnea, PaCO2>60 mmHg, pH<7.25, and
FiO2>0.6. These numbers are arbitrary and based
on clinical experience. It is important to consider the

infants age and presence of chronic lung disease. Older


infants with chronic lung disease may have increased
but compensated PaCO2 levels.

Contraindications to CPAP
The following contraindications are observed:
Ventilatory failure
Cardiovascular instability
Upper airway abnormalities (such as choanal
atresia, tracheo-esophageal fistula, diaphragmatic
hernia, and absent nose)
Unrelenting apneas

An Approach to the Use of


CPAP
The first step in the use of CPAP is choosing the
right patient, bearing in mind the indications,
contraindications, and limitations of CPAP.
Choosing the right situation such as resuscitation,
long-term management of respiratory distress,
post-extubation, apnea of prematurity, etc.
Choosing a CPAP system and deciding on whether
to augment CPAP with NIPPV. In our practice,
we regularly use conventional CPAP but use IFD
for infants with high risk of failure or we switch
to IFD with NIPPV with infants showing signs
of CPAP failure, especially those with unrelenting
apnea and bradycardia. A good system should
be appropriately warmed to body temperature
(37C) and humidified to prevent damage to nasal
mucosa.
Choosing a delivery device. The binasal prongs are
best supported in the literature for effectiveness.
New nasal masks are yet to be studied. It is essential that staff be trained in the correct placement of
delivery devices to avoid unnecessary injury to the
infant.
The pressure used is 4 to 10 cm of water. This
number is based on clinical experience. In our
practice, we use 6 cm of water routinely and
decrease to 4 cm of water when weaning.
Monitoring work of breathing, respiratory rate,

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 147

Review Article
RESEARCH
ARTICLES
Sankaran
K. Neonatal
CPAP ventilation
and oxygen requirements. If the infant has deterioration in clinical status, a blood gas test and chest
x-ray may be indicated. It is important to ensure
that the equipment is working appropriately and
the airway or nasal delivery device have not been
plugged by secretions prior to performing the above
investigations.
There is no available evidence to guide weaning or
discontinuation of CPAP. A trial of discontinuation
of CPAP can be attempted if the oxygen requirements substantially reduce or dyspnea resolves.
Different techniques have been used to get the
infant off CPAP. The CPAP may simply be stopped
and the child observed for deterioration; or low/
high flow oxygen by nasal cannula may be tried as
a more gradual, gentler weaning mode.
Recurrence of dyspnea, troublesome apneas, and
increasing oxygen requirement indicate the need to
recommence CPAP.
An infant that fails CPAP using the parameters
described above (see limitations of CPAP section) is
a candidate for intubation and ventilation.
In summary, CPAP is an effective and gentler mode
of ventilation. It is gaining widespread use in neonatal
intensive care units around the world. Due to its ease

148 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

of use and low cost, it is particularly suited for units in


the developing world. There are different nasal delivery
devices and CPAP systems available for use. The
infant flow system has been shown to be more effective in lowering respiratory rate, oxygen requirement,
and work of breathing. Infants with RDS/post-extubation, treated concomitantly with NIPPV, fare better
than those treated with CPAP alone. CPAP should be
considered for use in neonatal resuscitation, treatment
of respiratory distress syndrome, apnea of prematurity,
and to facilitate successful extubation. Surfactant-deficient infants can be managed with in-and-out intubation, delivery of surfactant, and extubation to CPAP as
an alternative to the traditional practice of intubation,
surfactant delivery, and mechanical ventilation.
More studies are in place comparing these treatment
modalities. CPAP is not for all infants and may sometimes fail, hence recognizing these situations are important. In such instances, mechanical ventilation may be
inevitable. It may be worth switching from conventional CPAP to the more effective infant flow device
with or without NIPPV before resorting to intubation
and mechanical ventilation as long as the baby is stable.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Fetal Medicine
Update
RESEARCH
ARTICLES
From the
Bangalore Fetal Medicine Centre

Fetal and Neonatal Outcome


of Congenital Cystic
Adenomatoid Malformation
Diagnosed in the Second
Trimester of Pregnancy
Shettikeri A, Radhakrishnan P*

Abstract

*Correspondence
Dr Radhakrishnan P
Bangalore Fetal Medicine Center,
Richmond Road, Bangalore, India.
Email: drprathima@bangalorefetalmedicine.
com

Congenital cystic adenomatoid malformation (CCAM) recently


renamed as congenital pulmonary airway malformation (CPAM)
is diagnosed antenatally when an ultrasound scan shows a
cystic or solid lung mass. The normal lung tissue is replaced
by a cystic piece of abnormal lung tissue which cannot carry
out normal functioning. Antenatally, CCAMs are classified into
three types. Type I CCAMs are macrocystic (>5 mm) and type
II CCAMs are microcystic, whereas Type III CCAMs appear as
a solid mass with mixed cystic and solid appearances. There
are several theories to explain the presence of abnormal lung
tissue. First theory suggests that it is due to the failure of bronchial structures to mature. Other explanation is overgrowth of
terminal bronchioles. Histological studies reveal it as imbalance
between cell proliferation and apoptosis (increased cell proliferation and decreased cell death). The incidence is about 1 in
4000 live births. Antenatal diagnosis provides an insight into the
in utero evolution of fetal lung lesions such as congenital cystic
adenomatoid malformation, bronchopulmonary sequestration,
and congenital lobar emphysema. Serial sonographic study
of fetuses with lung lesions has helped clinicians to define the
natural history of these lesions, determine the pathophysiologic
features that affect clinical outcome, and formulate management plans that are based on prognosis.
Key words: Congenital cystic adenomatoid malformation
(CCAM) antenatal, fetal CCAM, congenital pulmonary airway
malformation (CPAM)

149

Fetal Medicine Update


RESEARCH
Shettikeri
A, et ARTICLES
al. Fetal/Neonatal outcome of CCAM

Aim of the Study


To determine the postnatal outcome of antenatally
diagnosed congenital cystic adenomatoid malformation
(CCAM).

Study Design
All the fetuses that presented or were diagnosed to
have CCAM at Bangalore Fetal Medicine Centre from
2005 to 2010 were included and postnatal follow-up
was performed. This included 20 fetuses from 16 to 24
weeks of gestation.

Results
We had a total number of 20 fetuses presented with
CCAM diagnosed in the second trimester of pregnancy. One among them was a bilateral CCAM, and
the rest 19 fetuses were unilateral. Of the 19 fetuses,
eleven of the cases were right-sided CCAM and 8 were
left-sided CCAM. Eleven fetuses had mixed type of
CCAM, 5 were microcystic, and 4 were macrocystic.
Antenatal and postnatal follow-up was available in 19
out of the 20 fetuses. In one of the fetuses, in which
postnatal outcome was not available, the CCAM had
resolved on ultrasound scan examination at 36 weeks
with no residual changes. However, for the purpose
a

of this study, we have excluded this as the postnatal


confirmation of the babys well being is not confirmed
(Figure 1).
Four patients opted for termination of the pregnancy
due to development of fetal hydrops, polyhydramnios,
and deterioration in the condition of the fetus. One,
in addition had sacral agenesis; this probably was due
to high maternal blood glucose levels which was undetected till the time of fetal diagnosis. The sacral agenesis
was the main reason for termination. Fifteen infants
were delivered at term with complete resolution of
CCAM either antenatally (6/15; 40%) or postnatally
(9/15; 60%). All 6 infants that resolved antenatally were
around 29 to 34 weeks. This was confirmed by chest
x-ray/computed tomography (CT) scan performed
postnatally in 2 out of 6 infants. Two fetuses had spontaneous preterm deliveries at 32 and 36 weeks, but both
fetuses died within 7 days, and hence did not have
an opportunity to confirm with postnatal CT scan.
However, the remaining 2 infants are doing well postnatally, and hence chest x-ray/CT scan has not been
performed. Out of the 15 infants, 9 infants continued
to show ultrasound scan evidence of CCAM, however,
the size reduced significantly in all. Postnatal confirmation with chest x-ray or CT scan was performed in all
the infants. Resolution has been documented on chest
b

Figure 1. Cross section of fetal thorax showing hyperechogenic area in the left lung with medistinal shift to the
right (a) (highlighted in (b)).

150 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Fetal Medicine Update


RESEARCH
ARTICLES
Shettikeri A, et al. Fetal/Neonatal
outcome
of CCAM
Table 1. Outcomes of the Antenatally Detected
CCAMs
Total no. of CCAM

20

Live births

15

Lost to postnatal follow-up and


excluded

lent prognosis. Of the 15 live born infants, 2 succumbed


to complications related to prematurity rather than
CCAM. As in both these infants, there were no ultrasound evidence of CCAM just before delivery. Of the
remaining 13 infants that lived beyond 1 week of age,
all infants are doing well with maximum follow-up
period of 4 years till this study.

4/19 (21.1%)
Fetal hydrops

Terminations

Polyhydramnios
Associated sacral agenesis
Parents opted to terminate
6/15 (40%)

Antenatal resolution

Prematurity-related postnatal
death2

Postnatal resolution

9/15 (60%)

x-ray and/or CT scan at birth in 7 out of the 9 infants.


The remaining two infants have not had chest x-ray/CT
scan. However, both these infants are doing well at 3
months of age (Table 1).
Antenatal treatment with steroids and fetal intervention has been reported. However, none of the patients
had antenatal treatment, including the ones which had
antenatal resolution.

Conclusions
Our results suggest that spontaneous antenatal regression of the CCAM is common and has overall an excela

Although a normal postnatal chest x-ray does not indicate complete regression of CCAM, all the infants who
did not have chest x-ray have remained asymptomatic.
Asymptomatic infants with CCAM may be followed
up nonoperatively with no apparent adverse effects.
The decision and timing of an excision in an asymptomatic patient remains controversial among pediatric
surgeons. A CT scan is much more expensive than a
chest xray, and therefore this was a limiting factor for
not performing a CT scan in all the infants, especially
when they remain asymptomatic.

Discussion
CCAM has first been described by Chin and Tang in
1949. It is a rare hamartoma of the lungs that occurs
from unsystematic spread of tubular bronchioles and
enlarged alveolar tissue. This malformation can spontaneously regress, increase in size, or cause nonimmune
hydrops fetalis. Therefore, the differential diagnosis
should be made when echogenic lesions are seen in
the fetal lung at the prenatal period. About 90% to
95% of CCAMs are unilateral. When bilateral, diagb

Figure 2. Sagittal section of the fetal thorax showing CCAM (a). Color Doppler on the same shows no feeding
vessel from the aorta, which excludes pulmonary sequestration (b).

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 151

Fetal Medicine Update


RESEARCH
Shettikeri
A, et ARTICLES
al. Fetal/Neonatal outcome of CCAM

Summary of Antenatally
Diagnosed CCAM
USS appearances are typicalhyper/cystic
areas in the entire lung or part of the lung with
no feeding vessel from the aorta
About 10% would develop nonimmune
hydrops and then the prognosis is guarded;
hence serial follow-up scans are essential
40% resolve antenatally; the rest nonhydropic
show postnatal resolution
Fetal intervention in macrocystic CCAM
shows improvement in outcome
Postnatal CT scan is more specific in assessing
any residual abnormal lung tissue
If symptomatic, then surgical excision of
abnormal lung tissue may be necessary
In general, parents can be counselled that
prognosis for antenatally diagnosed CCAM is
good and in the ones which develop hydrops,
the mortality will be high. Hence, termination
of pregnancy is not recommended.
nosis of CHAOS (congenital high airway obstruction
syndrome) should be borne in mind. When CCAM
is right sided, diaphragmatic hernia of right side
containing the liver should be considered as a differential diagnosis. This must be confirmed on fetal MRI
(magnetic resonance imaging) as prognosis for the two
conditions is very different. In the absence of hydrops,
CCAM has more than 95% of survival rate. CCAM
with hydrops along with expectant management has a
mortality rate of more than 95%. Macrocystic CCAM
shunting has 65% of survival rate.
Antenatal resolution of CCAM is seen in about 50%
of the cases. Neonatal chest x-ray is reported normal in

152 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

50% of the cases. Lung mass is identified in more than


90% of the cases by CT scan in antenatally diagnosed
CCAMs. Hence, we strongly recommended a postnatal
CT or a follow-up CT scan, (if the infant is asymptomatic) in all the cases of antenatally diagnosed CCAM,
irrespective of the infant being symptomatic or asymptomatic. Delivery at a tertiary care center is a must as
few of the infants develop respiratory distress.
Intrauterine amelioration is frequent, but surgery is
often necessary as these lung masses are prone to infection, pneumothorax, and have a tendency for malignant
degeneration (broncho alveolar carcinoma, pulmonary
blastoma, rhabdomyosarcoma). Respiratory function
can be brought to normal functioning with long-term
follow-up (Figure 2).

References
1.

Chin KY, Tang MY. Congenital adenomatoid malformation


of one lobe of a lung with general anasarca. Arch Pathol Lab
Med. 1949; 48:221-229.

2.

Rajiv C, et al. Congenital cystic adenomatoid malformation


associated with ipsilateral eventration of the diaphragm. Clin
Brief. 2006;73:832-834.

3.

Janka GE, Schneider EM. Modern management of children


with hemophagocytic lymphohistio-cytosis. Br J Hematol.
2004;124:4-14.

4.

Rothenberg S. Congenital lung malformations, update and


treatment. Rev Med Clin Condes. 2009;20(6):734-738.

5.

Davenport M, et al. Current outcome of antenatally diagnosed


cystic lung disease. J Pediatr Surg. 2004;39(4):549-556.

6.

Ierullo AM, et al. Neonatal outcome of antenatally diagnosed


CCAM. Ultrasound Obstet Gynaecol. 2005;26(2):150-153

7.

Tran H, et al. CCAM monitoring the antenatal and short term


neonatal outcome. J Obstet Gynaecol. 2008;48(5):462-466.

8.

Adzick NS. Management of fetal lung lesions. Clin


Perinatol. 2009;36(2):363-376.

9.

Laje P, Liechty KW. Postnatal management and outcome


of prenatally diagnosed lung lesions. Prenat Diagn.
2008;28(7):612-618.

RESEARCH
Quiz
ARTICLES

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Picture Quiz
Can you make the correct diagnosis?

Figure 1

Figure 2

Figure 3

Figure 4

153

Quiz
RESEARCH
Picture
Quiz

ARTICLES

Picture Quiz Answers


Figure 1: Facial palsy
A left facial palsy is present in this term baby. This is a lower motor neurone lesion, which may result from pressure
in utero or following forceps delivery. If the nerve fibers are not torn, recovery occurs after a few weeks but the eye
may need special care during this time.

Figure 2: Beckwith syndrome


These infants are of high birth weight with macroglossia, exomphalos, and visceromegaly. Characteristic linear
creases are present in the ear lobe. Hypoglycemia is common and may be severe and persistent.

Figure 3: Potter syndrome


Bilateral renal agenesis results in oligohydramnios with fetal compression. Pulmonary hypoplasia is present. There
are characteristically low set ears, a receding chin, and beaked nose. Such infants are frequently stillborn, or die in
the early neonatal period.

Figure 4: Pierre-Robin syndrome


Mandibular hypoplasia leads to posterior displacement of the tongue, and a rounded palatal cleft. Obstruction of the
upper airways may occur but this can be relieved by bringing the tongue forward. Feeding requires extra patience.
Growth results in a normal profile.

154 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Quiz
RESEARCH
ARTICLES
Self-assessment
Quiz

Self-assessment Quiz
Which of the following statements are true?
1. In females, the urogenital sinus gives
rise to
a. Urethra
b. Bartholins glands
c. Cervix
d. Trigone of the bladder
e. Gartners duct
2. Breech presentation is associated with
a. Prematurity
b. Polyhydramnios
c. Oligohydramnios
d. Hydrocephaly
e. Anencephaly
3. In a pregnant, insulin-requiring diabetic,
the following changes are irreversible
a. Worsening of retinopathy
b. Hypertension
c. Worsening of renal disease
d. Increase in insulin requirements
e. Atherosclerosis in uterine spiral arteries
4. In a pregnant patient with diabetes
mellitus
a. Glycosuria is a reliable sign of poor control
b. The blood glucose should be maintained at
approximately 9 mmol/L

c. Persistent hyperglycemia is worse than occasional hypoglycemia


d. All patients should be admitted to hospital to
establish tight control of the blood sugar concentration
e. Patients must be delivered by 38 weeks of
gestation
5. The grand multiparous patient is more at
risk of
a.
b.
c.
d.
e.

Varicose veins of the legs


Iron deficiency anemia
Operative delivery
Face presentation
Cord prolapse

6. A high head at term could be due to


a.
b.
c.
d.
e.

Fundal fibroid
Wrong dates
Placental abruption
Cephalopelvic disproportion
Occipitoposterior position

7. Disseminated intravascular coagulation


(DIC) is associated with
a.
b.
c.
d.
e.

Pre-eclamptic toxemia
Placental abruption
Amniotic fluid embolism
Hydatidiform mole
Intrauterine fetal death

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 155

Quiz
RESEARCH ARTICLES
Self-assessment
Quiz

Self-assessment Quiz Answers


Question 1: A, B

Question 5: All are true

The urogenital sinus gives rise to the structures of the


vulva, urethra, and most of the bladder. The Trigone
of the bladder is formed from the distal portion of
the ureteric buds as the ureters are absorbed into the
bladder. The cervix is a Mullerian structure. Gartners
duct is the remnant of the Wolffian duct in the female.

A grand multipara is in her sixth or subsequent pregnancy. Iron deficiency anemia is common and varicose
veins of the legs tend to worsen with each pregnancy.
The lower ratio of uterine muscle to fibrous tissue
makes unstable lie, malpresentation, malposition, cord
prolapse, uterine rupture, and operative delivery more
likely.

Question 2: All are true


Twenty-five percent of fetuses present by the breech
at 30 weeks, but only 3% at term. Fetal abnormalities
such as hydrocephaly and anencephaly often present by
the breech because of the better fit in the pelvis. Polyhydramnios and oligohydramnios are associated with
fetal abnormality, but also make the fetus too mobile
and immobile, respectively, increasing the incidence of
breech presentation.

Question 3: A
Although all of these changes take place to a greater or
lesser extent in pregnancy, they are all reversible with
the exception of diabetic proliferative retinopathy. It is
for this reason that known diabetics must be investigated for retinopathy and treated if it is found early in
the pregnancy.

Question 4: C
Because of the increased glomerular filtration rate,
glycosuria is common in pregnancy and is an unreliable measure of blood glucose concentration. Blood
sugar should ideally be kept below 7 mmol/L. Transient
hypoglycemia has little effect on pregnancy. Management is at home; when patients are admitted they
become more difficult to control because of the alteration in their activity levels. The objective is to avoid
iatrogenic prematurity and with good control, delivery
should be after 38 weeks.

156 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Question 6: B, D, E
In a primigravida patient, the fetal head engages from
36 weeks of gestation. In multiparous patients the head
may not engage until labor is commenced. A high head
at term may be found because of wrong dates or for fetal
or maternal reasons. The fetus may be too big (hydrocephaly or cephalopelvic disproportion) or present with
a large diameter (occipitoposterior position). There may
be something else in the pelvis (the placenta, fibroids
in the lower part of the uterus, ovarian masses, full
bladder, and full rectum).

Question 7: All are true


Pre-eclamptic toxemia, placental abruption, amniotic
fluid embolism, hydatidiform mole, and intrauterine
fetal death are all associated with disseminated intravascular coagulation. In all these conditions a clotting
screen should be a routine investigation. Treatment
involves close liaison with and advice from the doctors
in the hematology department.

Abstracts from
RESEARCH
ARTICLES
Literature

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Evaluation of Potential Factors


Predicting Attainment of Full Gavage
Feedings in Preterm Infants

Chorioamnionitis and Cerebral Palsy

Shulman RJ, et al.

Meta-analysis including 15 studies revealed significant


associations between clinical chorioamnionitis or histological chorioamnionitis and cerebral palsy. For clinical
chorioamnionitis (chi1 = 13.91; P<.001) with a pooled
odds ratio of 2.42 (95% CI, 1.523.84), and for histological chorioamnionitis (chi1 = 6.86; P = .009) with a
pooled odds ratio of 1.83 (95% CI, 1.172.89). The data
suggested increased risks of 140% and 80% for neonates
exposed to clinical chorioamnionitis or histological
chorioamnionitis, respectively.

Neonatology. 2011;99:38-44.

In this prospective study, authors determined the potential relationship of attainment of full gavage feedings
and feeding volume with clinical measures and noninvasive GI tests. In 50 prospectively followed neonates,
authors found the number of GRV >2 mL/kg tended to
decrease with postnatal age (P = .06). Lactase activity
and feeding volume in milliliters per kilogram per
day prior to achieving full feedings were correlated
(P=.007, L = 0.164). There was no correlation between
feeding outcomes and GRV (mL/day), GRV>50%,
GRV>2 mL/kg, small bowel, colonic, or whole bowel
permeability, fecal calprotectin concentration, gastric
emptying, or abdominal distention.

Lactate Dehydrogenase Predicts


Hypoxic Ischemic Encephalopathy
in Newborn Infants
Karlsson M, et al.
Acta Pdiatrica. 2010;99:1139-1144.

In this prospective case-control study, authors investigated the utility of plasma lactate dehydrogenase
(LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) during the first 12 hours
after birth in predicting hypoxic ischemic encephalopathy (HIE) and adverse neurodevelopment outcome in
newborn term infants with intrapartum signs of fetal
distress. A total of 123 neonates with perinatal asphyxia
including 41 neonates with different degree of HIE
and 123 term control were included in the study. Using
ROC curves, a cut-off level of 1049 U/L for LDH was
the best predictor of HIE (sensitivity 100% and specificity 97%) and for long-term outcome after HIE. If
further studies confirm this finding, this may prove to
be an important tool for diagnostic confirmation and
prognostication of neonates with perinatal asphyxia.

Shatrov JG, et al.


Obstet Gynecol. 2010;116:387-392.

Comparison Between One and


Three Doses a Week of Recombinant
Erythropoietin in Very Low Birth
Weight Infants
Vzquez Lpez MA, et al.
J Perinatol. 2010.

Authors compared transfusion requirements and erythropoietic response in preterms between schedules of
rEPO administration once or three times per week,
using the same weekly dose. A total of 119 preterm
VLBW infants were enrolled in the trial. Infants receive
either subcutaneous rEPO at 250 units/kg per dose,
three times weekly for 6 weeks (Group 1 = 60, n) or
750 units/kg per dose, once weekly for 6 weeks (Group
2, n = 59). Data revealed, incidence of blood transfusion were similar between the two groups; however,
hemoglobin levels were lower at end of study in Group
2 (10.6 1.5 g/dL vs 11.5 1.4 g/dL; P<.003). Finally,
at end of study, reticulocyte counts and serum transferring receptor values increased and serum ferritin values
decreased, without significant differences between the
two groups. Incidence of complications was similar in
both groups. Thus, the once-weekly rEPO schedule for
very low birth weight infants proved as effective as the
three times weekly schedule, in relation to erythropoietic stimulus and transfusion requirement.

157

Abstracts from Literature

RESEARCH ARTICLES

Does Sustained Lung Inflation at


Birth Improve Outcome of Preterm
Infants at Risk for Respiratory Distress
Syndrome?
Lista G, et al.
Neonatology. 2011;99:45-50.

In 89 prospectively enrolled infants with respiratory distress [gestational age (GA) 28.1 2.2 weeks]
compared to historical control group, authors evaluated the efficacy of sustained lung inflation (SLI, 25
cm H2O, sustained for 15 s) in improving the respiratory outcome. Data suggest, the SLI group had less
need for (51% vs 76%, P<.0001) and shorter duration of mechanical ventilation (5 11 vs 11 19
days, P = .008), a more frequent occurrence of exclusive nasal continuous airway pressure support (49 vs
24%, P<.0001) and INtubation-SURfactant-Extubation (INSURE) treatment (16% vs 3%, P = .01), less
need for surfactant (45% vs 61%, P = .027) and postnatal steroids (10% vs 25%, P = .01), a shorter duration
of oxygen therapy (21 27 vs 31 31 days, P = .016),
and finally, a lower occurrence of bronchopulmonary
dysplasia in survivors (7% vs 25%, P = .004). Authors
concluded that the application of a sustained lung inflation at birth in preterm infants with respiratory distress
may decrease the need for mechanical ventilation
without inducing evident adverse effects.

Lung Lavage with Dilute Surfactant


for Meconium Aspiration Syndrome:
A Randomized Trial
Dargaville PA, et al. On behalf of the lessMAS Trial Study Group.
J Pediatr. 2011;158(3):383-389.

The therapy for meconium aspiration syndrome


(MAS) is essentially supportive. The use of innovative
therapies such as high-frequency oscillatory ventilation and inhaled nitric oxide did not result in a reduction of the duration of ventilation or oxygen therapy.
Bolus surfactant therapy for MAS has little effect on
mortality, risk of pneumothorax, or duration of intubation, but reduces the need for extracorporeal membrane
oxygenation (ECMO).

158 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Previous findings, retrieved from experimental and


clinical studies, suggested that therapeutic lung lavage
with dilute surfactant may alter the course of disease by
removing some of the inhaled meconium from the air
spaces. Meconium recovery appears optimized with a
total lavage fluid volume of 30 mL/kg and an aliquot
volume of 15 mL/kg, with open suction and chest
squeezing.
On these bases, the international lessMAS Trial Study
Group has conducted a randomized controlled trial to
evaluate the efficacy of lung lavage and to assess the
potential effect of this strategy on the duration of respiratory support, oxygen therapy, and/or hospitalization. Ventilated infants with MAS were randomized to
receive lung lavage with two 15 mL/kg aliquots of dilute
surfactant or no lavage (control group). The lavage fluid
was a 1:5 dilution of surfactant in saline (final concentration 5 mg/mL). Control subjects received standard
care, which in both groups included high-frequency
ventilation, nitric oxide, and ECMO, where available.
In total, 66 infants were randomized. Median duration
of respiratory support was similar in infants who underwent lavage and control subjects (5.5 days vs 6.0 days).
Similarly, requirement for high-frequency ventilation
and nitric oxide did not differ between the groups.
Post-hoc analysis showed that fewer infants who
underwent lavage died or required ECMO: 10%
(3/30) compared with 31% (11/35) in the control
group (OR, 0.24; 95% CI, 0.0600.97). Lavage
transiently reduced oxygen saturation without
substantial heart rate or blood pressure alterations.
Mean airway pressure was more rapidly weaned
in the lavage group after randomization.
In conclusion, this randomized study demonstrated
that dilute surfactant lavage is achievable in ventilated
infants with severe MAS and a high risk of mortality.
Although this strategy does not appear to alter the duration of respiratory support, it may produce a reduction
in mortality, especially in units not offering ECMO.
Further trials enrolling a larger number of infants
would help to more precisely define the effect on
survival.

Short
RESEARCH ARTICLES
Communications

PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Prenatal Diagnosis of Apert


Syndrome in Second Trimester:
A Case Report
Shubha R Phadke,* Kausik Mandal, Prajnya Ranganath

*Correspondence
Dr Shubha R Phadke,
Professor, Department of Medical Genetics,
Sanjay Gandhi Postgraduate Institute of
Medical Sciences,
Lucknow - 226013, India
Phone: 0522-668004, 668700, 668800, 668900
Extension no. 4325
Email: Subha@sgpgi.ac.in
shubharaphadke@gmail.com

Abstract
Apert syndrome is an autosomal dominant disorder characterized by craniosynostosis, distinctive dysmorphic facial features, limb abnormalities, and developmental delay, resulting
from a dominant mutation in FGFR2 gene. This study reports a
case of Apert syndrome diagnosed prenatally based on the
results of antenatal ultrasonography at 26 weeks of gestation
and molecular testing.
Key words: Apert syndrome, prenatal diagnosis, FGFR2 gene

Introduction

Case Report

Apert syndrome (OMIM #101200) is an autosomal


dominant disorder characterized by coronal craniosynostosis, midface hypoplasia, and symmetrical syndactyly of the hands and feet (often described as mitten
glove syndactyly), associated with varying degrees
of developmental delay. Apert syndrome is caused by
dominant mutations in the FGFR2 gene, which occur
de novo in majority of the cases. The typical combination of craniosynostosis and syndactyly makes it easy to
diagnose Apert syndrome in an affected child, but antenatal detection is difficult as an abnormal skull shape
may not always be evident in the fetus and the characteristic facial profile and syndactyly can be easily missed
unless carefully looked for. Reported in this study is an
antenatally diagnosed case of Apert syndrome, detected
as early as 26 weeks of gestation and confirmed by
FGFR2 mutation analysis.

A 29-year-old primigravida presented to the center


at 26 weeks of gestation for a routine antenatal ultrasonographic evaluation. Except for 2 episodes of mild
vaginal bleeding in the second and sixth months of
gestation, the pregnancy otherwise was uncomplicated.
There was no history suggestive of any teratogenic
exposures during the pregnancy. Neither the pregnant
woman nor her partner (aged 32 years) had any known
chronic medical illness. There was no history of consanguinity or any significant illness in the family. Previous
fetal ultrasounds done at other centers at 10, 17, and
25 weeks of gestation were reported to be normal. The
antenatal ultrasound done at the center at 26 weeks of
pregnancy showed a live fetus with growth parameters
appropriate for the gestational age and a normal amniotic fluid volume. The intracranial anatomy appeared
distorted with tear drop-shaped lateral ventricles and a

159

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RESEARCH
Phadke
SR, et al.ARTICLES
Prenatal diagnosis of Apert syndrome
highly placed third ventricle, suggestive of agenesis of
the corpus callosum. In addition, a long and prominent
forehead; a flat facial profile; appearance of mittenhand, suggesting syndactyly of the hands, disorganized
phalanges; and bilateral short halluces were noted in the
fetal ultrasonogram (Figure 1: a, b, c).

The common mutations in the FGFR2 gene (S252W


and P253R), known to cause Apert syndrome, were
diagnosed by PCRRFLP (polymerase chain reactionrestriction fragment length polymorphism) technique.
The S252W mutation was found to be present in the
fetal DNA. The fetal karyotype was normal.

These findings led to the possibility of Apert syndrome


in the fetus. After appropriate genetic counseling of
the couple, a placental biopsy sample was obtained
for molecular genetic testing of the FGFR2 gene and
amniocentesis was performed for fetal karyotyping.

After intrauterine demise at 29 weeks of gestation, the


fetus was brought for a detailed autopsy evaluation.
Fetal autopsy revealed facial dysmorphism including
frontal bossing, a flat occiput, ocular hypertelorism,
proptosis of the eyes, a flat nasal bridge, a beaked nose,

b
e

Figure 1. a, b, c: Prenatal ultrasonogram showing the flat face, prominent and long forehead, mitten hands,
syndactyly of the toes, and short and broad great toes.
d, e, f, g: Postmortem examination findings in the fetus: Acrocephaly, flat facial profile, ocular hypertelorism, low
set ears, anteverted nares, and syndactyly of the hands and feet.

160 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

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RESEARCH
ARTICLES
Phadke SR, et al. Prenatal diagnosis
of Apert
syndrome
and low set ears. Oral cavity examination showed a high
arched palate with a median groove and absent uvula.
There was complete syndactyly of the second, third,
and fourth fingers and partial syndactyly of the fourth
and fifth fingers of both the hands. The halluces were
bilateral, short, and broad, and in both feet there was
syndactyly of the second, third, and fourth toes (Figure
1: d, e, f, and g). The external genitalia were of a normal
male infant. The heart, lungs, gastrointestinal tract,
and genitourinary organs appeared normal. Skeletal
survey revealed bony disorganization of the hands and

feet with syndactyly. A postnatal computerized tomography (CT) scan with three-dimensional reconstruction showed the characteristic facial profile, partially
closed coronal sutures, a wide open sagittal suture, bony
syndactyly, and duplicated hallux bones (Figure 2).

Discussion
Few reports of successful prenatal diagnosis of Apert
syndrome by antenatal ultrasonography have been
published.1 However, basing the diagnosis on the fetal
ultrasonogram alone can be erroneous and molecular

Figure 2. a, b, c: Postnatal CT scan showing the characteristic facial profile, partially closed coronal sutures,
wide open sagittal suture, bony syndactyly, and duplicated hallux bones.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 161

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RESEARCH
Phadke
SR, et al.ARTICLES
Prenatal diagnosis of Apert syndrome
testing of the FGFR2 gene should ideally be performed
to confirm the diagnosis.2,3 A sequential diagnostic
approach combining three-dimensional computed
tomography scan and molecular testing in cases wherein
fetal sonography alone is not conclusive, has also
been recommended.4 Quintero-Rivera et al reported
a newborn diagnosed to have Apert syndrome after
birth, whose only abnormality detected in a prenatal
ultrasound was agenesis of the corpus callosum, which
has been detected prenatally in the present case too.
Following the review of the central nervous system
findings of 30 patients with Apert syndrome, it was
suggested that a careful diagnose for hand malformations of Apert syndrome should be carried out in any
fetus detected with agenesis of corpus callosum or mild
ventriculomegaly in the antenatal sonogram.5
Mutation detection prenatally helps not only in confirmation of the diagnosis but also in genetic counseling.
Though most mutations in cases of Apert syndrome
arise de novo, germline mosaicism may give rise to
recurrence in the family, and thereby detection of mutation in the proband helps in early prenatal testing in the
next pregnancy. Two common mutations in the FGFR2
gene, S252W (p.Ser252Trp) and P253R (p.Pro253Arg),
account for 98% of the cases of Apert syndrome, with
the S252W mutation detected in 71% of the cases and
P253R in remaining 26%.6,7 As both these mutations

162 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

can be tested using simple PCR-RFLP technique, all


cases with prenatally detected features suggestive of
Apert syndrome, especially the mitten-hand anomaly,
should be tested for these two mutations.

References
1.

Kaufmann K, et al. Ultrasound detection of Apert syndrome:


a case report and literature review. Am J Perinatol.
1997;14:427-430.

2.

Skidmore DL, et al. Prenatal diagnosis of Apert syndrome:


report of two cases. Prenat Diagn. 2003;23:1009-1013.

3.

Athanasiadis AP, et al. Apert syndrome: the current role of


prenatal ultrasound and genetic analysis in diagnosis and
counselling. Fetal Diagn Ther. 2008;24:495-498.

4.

Mahieu-Caputo D, et al. Prenatal diagnosis of sporadic Apert


syndrome: a sequential diagnostic approach combining threedimensional computed tomography and molecular biology.
Fetal Diagn Ther. 2001;16:10-12.

5.

Quintero-Rivera F, et al. Apert syndrome: what prenatal


radiographic findings should prompt its consideration? Prenat
Diagn. 2006;26:966-972.

6.

Ferreira JC, et al. Second-trimester molecular prenatal


diagnosis of sporadic Apert syndrome following suspicious
ultrasound findings. Ultrasound Obstet Gynecol. 1999;14:
426430.

7.

Park WJ, et al. Analysis of phenotypic features and FGFR2


mutations in Apert syndrome. Am J Hum Genet. 1995;57:
321328.

Short Communications
RESEARCH ARTICLES

Congenital Sternal Cleft with


Pectus ExcavatumA Case Report
Dr Somashekhar AR,* Dr Ranjana R

Abstract

*Correspondence
Dr Somashekhar AR
Associate Professor, Pediatrics,
Department of Pediatrics,
MS Ramaiah Medical College,
Bangalore-560054. India

This study reports a rare case of congenital sternal cleft in association with pectus excavatum. In neonates with cleft sternum, the
sternal bars can be easily approximated by simple sutures due
to flexibility of cartilagenous thorax. If reconstruction is delayed,
increased rigidity of the chest wall and physiologic accommodation of the thoracic organs to the circumference of the chest
render simple approximation impossible, without serious compromise of the heart and lungs.
Key words: Pectus excavatum, sternum/abnormalities, sternum/
surgery

Introduction
Sternal cleft is a very rare midline defect. Incomplete
sternal clefts are more common than the complete ones.
In this challenging anomaly, the underlying mediastinal structures (particularly heart and great vessels)
can be easily injured by external trauma. In addition,
the deformity is cosmetically unpleasant and quite
alarming to young patients and their families.
Although the embryology of the thoracic wall is well
known, the etiology of cleft sternum remains unclear.
Failure of fusion of the lateral sternal bands by an early
disturbance affecting the midline mesodermal structures between the sixth and ninth gestational week is
a possible outcome. However, no familial, teratogenic,
or nutritional factors have been identified as a potential
cause. Cleft sternum is categorized into complete and
incomplete forms depending on the degree of separation
of the lateral sternal bands. Its association with craniofacial hemangiomas and omphalocele is common.

Cleft sternum could be prenatally diagnosed by ultrasonography. During the neonatal period, surgical
correction should be performed where the direct
suturing of the sternal halves is possible and the thorax
can accommodate the thoracic viscera. At an older
age, surgical repair is feasible, but it may require additional measures, such as sliding chondrotomies of the
adjacent costal cartilages and notching of the sternal
bars, to facilitate the approximation. Lung herniation
at the base of the neck should be corrected by uniting
the cervical muscles. The first postoperative day is most
critical owing to acute reduction of the mediastinal
space. Long-term results are satisfactory.

Case Report
A term female neonate, born through normal vaginal
delivery to a 32-year-old gravida 3, para 2 mother, was
noted to have a chest wall abnormality at birth. The
neonate was therefore admitted to neonatal intensive

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RESEARCH AR
ARTICLES
Somashekhar
, et al. Conginital sternal cleft with pectus excavatum
care unit. There were no prenatal complications and
the family history was unremarkable. Second trimester
sonographic findings were reportedly normal. The other
siblings of the neonate were normal and the parents had
a nonconsanguineous marriage. There was no history
of drug intake during pregnancy, which would have
an adverse effect on the fetus. The neonate was wellnourished and active with birth weight of 3 kg; head
circumference 34 cm; and length 48 cm. There were no
reports of cyanosis, pallor, or edema.
A defect in the anterior chest wall, extending from the
suprasternal notch to about 1 cm below the xiphoid
process was noted, associated with paradoxical movement of the chest wall during respiration. A blackish
raphe, extending from xiphoid to umbilicus, was
present. A transverse ridge of scar tissue in the region of
hyoid bone was observed and the strap muscles appeared
to be adherent to it. A distinct bulge of the heart was
noted while the baby was crying. Apex beat was localized to the left 4th intercostal space, 1/2 inch medial to
the midclavicular line. Respiratory system was normal
and so was the abdominal examination. X-ray of the
chest showed sternal cleft. A surgical correction for the
sternal cleft was advised and performed after thorough
investigations to rule out other conditions that could
affect the prognosis, post operation.

predilection, with female infants outnumbering male


infants, especially when the cleft is accompanied by a
combination of supraumbilical raphe and facial hemangiomas. Clinically, infants with a sternal cleft have a
concave midline thoracic defect, which can be associated with paradoxical movement of the chest wall
during respiration. The changes in intrathoracic pressure resulting from this paradoxical movement can
cause displacement of the heart and large vessels and
impairment of venous return. As a result, the infants
may have symptoms of right ventricular overload,
cyanosis, dyspnea, and arrhythmias. Furthermore, the
infants have reduced aeration of the lungs and decreased
force of the cough reflex, which may lead to recurrent
upper respiratory tract infections. Additionally, cardiac
pulsations can sometimes be seen through the thin
and ulcerated skin that overlies the defect. Complete
absence of the sternum, as opposed to a sternal cleft,
is usually seen in other fetal anomalies such as ectopia
cordis or pentalogy of Cantrell (also known as thoracoabdominal ectopia cordis). The pentalogy of Cantrell
consists of defects of lower sternum and midline
supraumbilical abdominal wall, deficiencies of the
diaphragmatic pericardium and anterior diaphragm,
and intracardiac anomalies. A left ventricular diverticulum may also be present.

Discussion

Conclusion

Sternal clefts can be classified into 3 categoriessuperior, inferior, and complete. The superior cleft defect,
which is the most common variant encountered, is
almost always an isolated abnormality but can occasionally be associated with cervicofacial hemangiomas.
The defect is either a U-shaped defect with the cleft
ending at the level of the fourth costal cartilage, or a
V-shaped defect with the sternum cleft at the xiphoid
process. Although the embryologic development of the
sternum has been studied in detail, the etiology of cleft
sternum is unknown.

The superior cleft is the most common variant. Inferior clefts, conversely, are almost always associated with
severe developmental defects, especially ectopia cordis
and pentalogy of Cantrell. The complete form of this
anomaly is the rarest type and usually associated with
the most severe anomalies such as double central incisors, congenital heart defect, neck webbing, bicornuate uterus, and minor anomalies including long face
with hypotelorism and craniofacial hemangiomas. In
neonates, approximation of sternal bars with simple
sutures without the complications of cardiac compression is the preferred procedure.

Some hypotheses include chronic nutritional deficiency, lack of riboflavin during pregnancy, and disruption of the HoxB4 gene.1 Most clefts occur sporadically,
although autosomal recessive familial association has
been reported. Some series have found a skewed sex

164 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

References
1.

Complete congenital sternal cleft associated with pectus


excavatum. [Medline] Ravitch MM. Congenital deformities
of the chest wall and their operative correction.

Short Communications
RESEARCH ARTICLES

Congenital ChylothoraxAn
Evidence-based Approach
Ramesh T,* Vishwanath J, Pejaver RK

Abstract
*Correspondence
Dr Ramesh T
#40C, Roja Illam,
Near Angaleeswari Amman Temple,
Ashok Nagar Extn., Moolapalayam,
Erode, Tamil Nadu, India.
Email: drtr_ero@yahoo.co.in

Points to remember

Chylothorax is the presence of chyle in the pleural space. It is


the most common cause of isolated pleural effusion in neonate.1
The etiology of chylothorax in neonates is usually unknown, but
sometimes it is associated with Noonans, Turners, and Downs
syndrome. It can be secondary to trauma, surgery, or pulmonary
lymphangiectasias. We report a neonate presented with congenital chylothorax.
Key words: Chylothoraxcongenital, medical and surgical
management

Chylothorax is the most common cause of isolated


pleural effusion in neonates.
Medical management includes intercostal
drainage, dietery modification, total parenteral
nutrition, and octreotide infusion.
Surgery is the option for refractory cases.
Supportive measures like rehydration, management of electrolyte abnormalities and infection are
very important.

Case report
A 23-year-old primigravida, who is Rh positive without
any medical illness like hypertension, diabetes mellitus,
heart disease was referred to our hospital in the 3rd
trimester of pregnancy for evaluation of polyhydramnios and isolated left-sided pleural effusion of the fetus
which was detected by routine antenatal ultrasonogram
(USG).
Maternal serology, hepatitis B surface antigen (HBSAg),
Venereal Disease Research Laboratory (VDRL) were
found negative. As the pleural effusion was progressive, elective lower segment cesarean section was done
at 35 weeks of pregnancy after giving steroids. Term
infant (girl) was born with birth weight of 2.8 kg and

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Congenital chylothoraxAn evidence-based approach
an Apgar test scored 4 and 6 at 1 and 5 minutes of age,
respectively. The infant needed resuscitation with bag
and mask ventilation followed by bag and tube ventilation. There were no dysmorphic features or congenital anomalies found. X-ray of the chest of the neonate
was showing gross left-sided pleural effusion with mediastinal shift toward right side. Intercostal drainage
was done and approximately 100 mL of straw colored
fluid was drained. Pleural fluid was sent for analysis.
Indwelling thoracic tube was placed for continuous
drainage of the pleural fluid.

oped intercurrent infection, which was treated with


appropriate antibiotics. The infant continued to have
large amounts of chylous secretion even after 1 week of
continuous intercostal drainage. In view of the above
said complications, the infant was started on amedium
chain triglycerides (MCT) oil supplementation and
octreotide infusion 1 g/kg/h, which was increased
to 2 g /kg/h. Chyle secretion came down after 3 to 4
days and ICD was removed on day 11 of life. The infant
was normoglycemic during octreotide infusion and was
discharged on day 23 of life in stable state.

Blood group of the infant was B positive, and peripheral smear study was found to be normal.

Discussion

Initial blood culture revealed no growth. Echocardiogram was done which revealed small PDA (Patent
Ductus Arteriosus) with L to R shunt and small PFO
(Patent Foramen Ovale) with L to R shunt. There was
no pericardial effusion. USG of abdomen and chest was
done which revealed no ascites and no effusion on the
right pleural space. TORCH screening was negative;
high-resolution computed tomography (HRCT) of the
chest was carried out to rule out other causes of isolated
pleural effusion and it was found normal. Chromosomal studies were deferred as there was no features of
dysmorphism.
Pleural fluid analysis was done on day 1 of life which
showed count of 900 cells, 100% lymphocytes, protein
2.7 g%, sugar 55 mg%, fat globules were absent and
no growth was observed on culture. Pleural fluid triglyceride (TGL) level was done on day 5 of life, which
was 489 mg% (N<100 mg%), which confirmed chylothorax. By this time, the infant was on enteral feeds in
increasing quantities and the pleural fluid had turned
milky in appearance. The infant was ventilated for 3
days and then weaned off from ventilator. During the
first week of life, the infant developed hyperkalemia
which was treated with k + free fluid and K-bind. By
the end of first week, the infant lost 400 g of weight
(approximately 20%) which was associated with severe
dehydration and electrolyte abnormalities (hyperkalemia and hyponatremia). Dehydration was corrected
with extra fluid. Twenty percent albumin infusions
were given to build up the nutrition. The infant devel-

166 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Presence of chyle in the pleural space is called chylothorax. Incidence of congenital chylothrax is 1 in 10,000
to 15,000,2 with male female ratio of 2:1.3 It was first
described by Pisek and Linner in 1917.

Etiology
Exact etiology is not known. Congenital malformation
in the thoracic duct,4 hyperextension of spine in intrauterine life which compresses the thoracic duct are the
proposed explanations. Secondary causes include birth
trauma, cardiac surgeries, diaphragmatic repair, like
Noonans, Downs, Turners syndrome, local causes
like pulmonary lymphangiectasias, pulmonary sequestration, hamartoma, infections like viral and bacterial
pneumonias5 (CMV, Adeno, group B streptococcal). In
this case, no specific etiology could be made out.

Clinical Presentation
Usually neonate presents with birth asphyxia due to
large pleural effusion which interferes with expansion
of lung. If the effusion is large, it results in pulmonary hypoplasia and PPHN. The mediastinum will be
shifted to contralateral side and the ipsilateral lung will
have dull note on percussion and breath sounds will be
absent.

Diagnosis
Diagnosis of chylothorax is made by antenatal USG
or by postnatal x-ray chest. It is important to look for
other features of hydrops fetalis like ascite, skin edema.
Chylothorax is usually diagnosed in the presence of

Short Communications
RESEARCH ARTICLES
Ramesh T, et al. Congenital chylothoraxAn evidence-based
approach
plural effusion with triglyceride level >1.1 mmol (>100
mg%) and a cell count >1000 cells/mL with a predominance of lymphocytes6,7(approximately 80%). Presence
or absence of TGL, fat globules in pleural fluid depends
upon the feeding habit of the baby. In neonates, who is
not on enteral feeds, diagnosis of chylothorax is made
by detecting lymphocytes in the pleural fluid. In our
case, initial evaluation shown 900 cells100% cells
lymphocytes and fat globules were absent, whereas on
day 5 (after starting feeds) triglyceride levels were high
(489 mg%).
HRCT chest is the best modality to detect secondary
causes of chylothroax like pulmonary lymphengiectasias, hamartomas, and pulmonary sequestrations. In
our case, HRCT chest was normal. If there is associated ascites, work up should be done for immune and
nonimmune hydrops like karyotyping, TORCH
screening, metabolic work up to rule out storage disorders, Hb electrophoresis, echocardiogram, and ECG.
In our case, extensive work up for nonimmune hydrops
was deferred in view of isolated pleural effusion and
pleural fluid analysis had confirmed chylous nature.
However, TORCH screening, echocardiogram were
done and were normal.

Management

Algorithm for Management of Congenital Pleural Effusion

Isolated pleural effusion

Look for ascites, skin edema

Pleural fluid analysis

Hydrops fetalis

>1000 cells, >80% Lympho

Evaluate immune and


non-immune hydrops

>100 mg% TGL (only after starting feeds)

Chylothorax

HRCT to rule out secondary causes


Intercostal drainage
(or)
Repeated thoracentesis

No improvement after 1 week.


Dietary modificationspecial preparations (like pregestimil, portagen)

Antenatal
It includes thoracocentesis or thoraco amniotic
shunting.8 Indications for thoracoamniotic shunting
include USG evidence of mediastinal shift, inversion
of diaphragm and intrathoracic pressure more than
39 mmHg. The aim is to reduce the complication of
PPHN or reduce the need for mechanical ventilation or
prevent the development of hydrops fetalis.

Postnatal
Conservative
1. It includes mechanical ventilation for respiratory
failure.
2. Continuous thoracostomy tube drainage (or)
repeated thoracentesis: lung expansion tamponading the defect and prevent further fluid
accumulation.

MCT oil supplementation

Total parenteral nutrition

Octreotide infusion

*Supportive measures

Persistent drainage >46 weeks

Surgical treatment: pleurodesis, pleural abrasion, thoracic duct ligation

*Includes correction of dehydration, electrolyte abnormalities, and


metabolic acidosis, IV antibiotics, 20% albumin infusion.

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RESEARCH
Ramesh
T, et al. ARTICLES
Congenital chylothoraxAn evidence-based approach
3. Dietary modification: Preparations containing
long chain triglycerides (LCT) are absorbed
into the lymphatic system which results in
excess chyle formation and chyle leakage.
Avoiding LCT and adding MCT in diet results
in less chyle formation and leak.9 Examples:
Pregestemil lipil, portagen, or pepti junior.
These preparations should be used at least for
2 weeks. But these preparations are not easily
available in our country. Other option is total
parenteral nutrition.
4. Somatostain analogue: octreotide infusion.

References
1.

Koksal N, et al. Congenital chylothorax. Turk J Med Sci.


2000;30:307-309.

2.

Van Aerde J, et al. Spontaneous chylothorax in newborn.


Am J Dis Child. 1984;138:961-964.

3.

Bukowski R, Saade GR. Hydrops fetalis. Clin Perinatol.


2000;27(4):1007-1031.

4.

Van Straaten HL, et al. Chylothorax in the neonatal period.


Eur J Pediatr. 1993;152;2-5.

5.

Ozkan H, et al. Congenital chylothorax. Turk J Pediatr.


1996;38;113-117.

6.

Vera B, et al. Chylothorax in children, guidelines for


diagnosis and management. Chest. 1999;116;682-687.

7.

Chandra K, Randall DC. Neonatal pleural effusion. Arch


Pathol Lab Med. 2005;130;22-23.

8.

Masami Y, et al. Intrathoracic pressure in congenital


chylothorax; keystone for the rationale of thoracoamniotic
shunting? Fetal Diagn Ther. 2007;22:169-171.

9.

Jalili F. Medium chain triglycerides and total parenteral


nutrition in the management of infants with congenital
chylothorax. S Med J. 1987;80:1290-1294.

10.

Sivasli E, et al. Spontaneous neonatal chylothorax treated


with octreotide in Turkey. A case report. J Perinatol.
2004;24:261-262.

11.

Lanterbach R, et al. Somatostatin treatment of spontaneous


chylothorax in an extremely low birth weight infant. Eur
J Pediatr. 2005;164:195-196.

12.

Brissaud O, et al. Congenital idiopathic chylothorax in


neonates; chemical pleurodesis with povidone iodine (
Betadine). Arch Dis Fetal Child Neonatal Ed. 2003;88:F
531.

13.

Requet M, Badia A. Surgery for chylothorax. Rev Pneumol


Clin. 2004;60(2):104-108.

10,11

Exact mechanism of action in chylotorax is not known


but it is believed that the reduction in splanchnic blood
flow reduces the thoracic duct flow and decreases chyle
formation. It is used in the dose of 14 g/kg/h.

Surgical management
It includes pleurodesis talc, fibrin glue, povidone
iodine,12 plural abrasion, and ligation of the thoracic
duct.13

Complications
Babies with chylothorax may develop dehydration
and metabolic acidosis because of excessive fluid and
sodium loss. They are prone to malnutrition, failure
to thrive, hypoalbuminemia, and infection because of
loss of lymphocytes, immunoglobulins, and albumin
in chyle. In this case, the infant had weight loss, severe
dehydration, and infection which was corrected with
20% albumin, extra fluid and Intravenous (IV) antibiotics.

168 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Short Communications
RESEARCH ARTICLES

Presternal Bronchogenic Cyst:


A Rare Site for a Rare Neonatal
Tumor
Aftab Ahmed, Padmalatha Kadamba, Manjiri Somshekar, Pratima

*Correspondence
Ahmed A,
Assistant Professor,
Department of Pediatric Surgery,
M.S. Ramaiah Medical College,
Bangalore, India.
Email: draaftab@rediffmail.com

Abstract
A 9-month-old child presented with a swelling in front of the
sternum that was seen since neonatal age. Complete excision
was done. Histopathology confirmed the diagnosis as bronchogenic cyst.

Introduction
Bronchogenic cysts are rare congenital anomalies with
prevalence ranging from 1 in 42,000 to 1 in 68,000.1
Subcutaneous bronchogenic cysts are even rarer, as
less than 70 cases have been reported.2 We report a
case of subcutaneous bronchogenic cyst in front of the
sternum.

Case report
A 9-month-old female child presented with a history of
swelling in front of the sternum which was present since
birth. This swelling had remained quiescent till 2 weeks
before the diagnosis. The 0.5-cm diameter swelling
had sudden increase in size associated with pain. The
infant was treated with antibiotics and analgesics for a
week. Meanwhile, an ultrasound scan showed a cystic
lesion measuring 1 cm in diameter. The swelling had a

punctum and was adherent to the skin. There was no


discharge from the punctum.
The cyst was excised in totality. It extended deep up
to the sternum but was not adherent to it. It was thick
walled and contained purulent material. Histopathology of the specimen revealed fibrocollagenous
tissue with the cyst wall lined by pseudo stratified ciliated columnar epithelium. The surrounding area had
seromucinous glands and smooth muscle tissue. No
cartilage or lymphoid tissue was found. Therefore, a
diagnosis of bronchogenic cyst was made. No recurrence was found on follow-up of 3 months (Figure 1).

Discussion
Bronchogenic cysts are formed due to abnormal development of the ventral foregut.3 During the 5th week
of gestation, the laryngotracheal groove separates the
primitive foregut into ventral and dorsal parts.4 Ventral

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RESEARCH
Ahmed
A, et al.ARTICLES
Presternal Bronchogenic Cyst
a

Figure 1. Cyst lined by ciliated columnar epithelium with surrounding seromucinous glands: (a) high power;
(b) low power view.

component forms the lung buds and dorsal component forms the foregut by the 7th week of gestation.
Bronchogenic cysts arise from the lung buds during
this phase. Bronchogenic cysts in subcutaneous tissue
of the anterior chest wall may arise due to migration
of the intra-thoracic bronchogenic cysts or due to the
pinching off effect of the developing sternal bars
during their fusion on the developing lung parenchyma.4 Migration of the sequestered tissue can occur
as the embryo developes. Therefore, bronchogenic
cysts can be found as far as abdominal cavity or superiorly upto the chin, they may be found in the neck
(suprasternal is the most common site in the neck), the
presternal area, or the scapula region.4 But, the most
common extra pulmonary location of bronchogenic
cysts is the mediastinum.4
Bronchogenic cysts which are cutaneous are noticed in
the neonatal age or in early childhood. They are usually
asyptomatic but may develop symptoms of inflammation as in our case. Some may have a fistulous tract
draining mucoid material.4 Rarely, they may develop
into muco-epidermoid carcinoma or melanoma.4,5
Pedunculated bronchogenic cysts have been reported.
Males are four times more affected than females.
Differential diagnosis includes thyroglossal cyst,
branchial cyst, cutaneous ciliated cyst, epidermal inclusion cyst, dermoid cyst, and trichilemmal cyst.2 The

170 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

diagnosis of the above conditions would depend on


histopathology and location of the lesions. Bronchogenic cysts are lined by respiratory epithelium with
smooth muscle cells, mucus glands, and cartilage.
Thyroglossal cysts are midline cervical swellings, not
seen in the neonatal age and have thyroid follicles on
histology. Branchial cysts commonly occur along the
sternomastoid muscle; histologically these have stratified squamous epithelium and lymphoid tissue. Cartilage is absent in these cysts. Cutaneous ciliated cysts are
seen in females in the lower extremities. Dermoid cysts
occur along suture lines and have epidermal appendages in them.
Metaplastic change to squamous epithelium due to
chronic inflammation has been reported by Ho Sung,
Hyun Jin Son, and Myoung Jae Kang4 in bronchogenic
cysts. Lymphoid aggregates have been described in
cutaneous bronchogenic cysts by Beyer et al.4
Bronchogenic cysts need to be completely excised
as recurrence of the cyst can occur. Besides, this also
prevents the chances of malignant transformation into
muco-epidermoid tumor or melanoma.

Conclusion
Bronchogenic cysts in skin are rare swellings that are
not suspected before surgery. One should consider
this condition in the differential diagnosis of swell-

Short Communications
RESEARCH
ARTICLES
Ahmed A, et al. Presternal
Bronchogenic
Cyst
ings found in neonates if present in the locations as
mentioned above. Histopathology is required for diagnosis of the condition. Complete excision is necessary to
prevent recurrence, inflammation, or chances of malignant transformation.

2.

Vivek Manchanda AM, et al. Subcutaneous bronchogenic cyst.


J Cutaneous Aesthetic Surg. 2010;Sept-Dec;3(3):181-183.

3.

Kundal AK, et al. Scapular bronchogenic cyst. J Indian Assoc


Pediatr Surg. 2008;13:147-148.

4.

Park, HS et al. Cutaneous bronchogenic cyst over the


sternum. Korean J Pathol. 2004;38:333-336.

References

5.

Tanita M, et al. Malignant melanoma arising from cutaneous


bronchogenic cyst of the scapular area. Int J Pediatr
Otorhinolarygol. 2001;57(2):145-148.

1.

Schouten van der Velden AP, et al. A bronchogenic cyst


under the scapula with the fistula on the back. Pediatr Surg
Int. 2006;22:857-860.

Pulmonary Function Outcomes in Bronchopulmonary Dysplasia


Through Childhood and Adulthood
Hayes Jr D, et al.
Prim Care Respir J. 2011;pii: pcrj-2010-02-0014-R1

Bronchopulmonary dysplasia (BPD) results from prematurity and surfactant deficiency with contributing factors such as barotrauma, volutrauma, and oxygen toxicity determined by supportive mechanical ventilation care and infection. Taken together, these factors result in chronic inflammation with
recurring cycles of lung damage and repair that impair alveolarization and vascularization in developing lungs.
Studies show that pulmonary complications continue to exist in early to late childhood. For instance, chronic
airway obstruction typically persists in former premature infants with classic BPD during early childhood and
can be associated to air trapping in infants with new BPD. The airway obstruction is typically fixed (ie, unresponsive to 2-agonists). The mechanism of development of fixed airway obstruction is most likely related to early
life structural changes in the airways. Preterm children with a history of BPD more commonly have abnormal
pulmonary function (ie, significant reduction in FVC, FEV1, and FEF25-75) along with bronchodilator responsiveness as compared to preterm children without BPD and children born term. Several studies have evaluated
the physiological response to exercise in late childhood and overall showed a reduction in performance and a
worsening in respiratory parameters in children with a history of BPD. In addition, a study showed that exerciseinduced bronchospasm occurred in 50% of the BPD group.
Very few studies have assessed pulmonary function of BPD survivors reaching the adult years. They
continue to show different degrees of pulmonary function changes, primarily due to airway obstruction. These complications include chronic pulmonary function impairment, reduced exercise capacity,
and more rapid deterioration of lung function than in normal subjects as adolescents and young
adults. In addition, the diagnosis of asthma and use of asthma inhalers is significantly more prevalent among patients born prematurely than controls. Screening by computer tomography of adult
patients (age 1733 years) showed that 84% of survivors of moderate and severe BPD had emphysema.
Follow-up studies of preterm infants with BPD show that long-term pulmonary complications resulting from
airway structural changes persist into adulthood.
The new BPD in postsurfactant era has different pathophysiological changes and different radiological and clinical presentations. These differences between classic and new BPD may also influence long-term pulmonary
outcomes, with less possible impairment in the latter case. This is an important issue for primary care physicians
who will be involved with the care of these patients.

PERINATOLOGY Vol. 12 No. 4 JanMar 2012 171

RESEARCH ARTICLES

Upcoming Events
8th Annual Pediatric Clinical Trials Conference
Date: May 2 to 4, 2012

The Contribution of Epigenetics in Pediatric


Environmental Health

Venue: Philadelphia, Pennsylvania, United States

Date: May 30 to June 1, 2012

For more details, visit: http://www.marcusevansch.com/Pediatric2012_Event

Venue: San Francisco, California, USA


For more details, visit: http://www.regonline.com/cehn

Issues of Obstetrics, Gynecology and


Perinatology

Neonatal Pharmacology

Date: May 17 to 18, 2012

Date: June 7 to 9, 2012

Venue: Yalta, Ukraine

Venue: Washington, DC, United States

For more details, visit: http://www.nbscience.com/16.html

For more details, visit: http://contemporaryforums.com/Live-CEConferences/2012/Neonatal-Pharmacology/

The 2nd Global Congress for Consensus in


Pediatrics & Child Health

Date: May 17 to 20, 2012


Venue: Moscow, Russian Federation
For more details, visit: http://www.cipediatrics.org

Royal College of Paediatrics and Child Health


(RCPCH) 2012 Annual Conference
Date: May 22 to 24, 2012
Venue: Glasgow, United Kingdom

Dedicated to Pediatrics

For more details, visit: http://www.rcpch.ac.uk/conference2012

46th Annual Meeting of the Association


for European Paediatric and Congenital
Cardiology
Date: May 23 to 26, 2012
Venue: Istanbul, Turkey
For more details, visit: http://www.aepc2012.org/Welcome-1-.html

The 12th International Child Neurology


Congress and the 11th Asian and Oceanian
Child Neurology Congress
Date: May 27, 2012 to June 1, 2012
Venue: Brisbane, Australia
For more details, visit: http://www.icnc2012.com

172 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

A quarterly newsletter dedicated to Pediatrics


20,000+ copies circulated every quarter
To subscribe, write to
publications@himalayahealthcare.com

Instructions to
RESEARCH
Authors
ARTICLES

Perinatology

Vol. 12 No. 4 JanMar 2012

Journal of Perinatal and Neonatal Care

Instructions to Authors
Perinatology, one of the few journals dedicated to the emerging
multidisciplinary field of perinatal medicine, is published quarterly.
The journal publishes original articles, brief reports on clinical and
laboratory observations, case reports of substantiate value, invited
editorials, invited papers on recent advances, clinical diagnosis,
announcements of meetings, and summary reports of conferences.
The journal is multidisciplinary and welcomes articles in English from
metabolic specialists, clinical biochemists, obstetricians, neonatologists, pathologists, geneticists, endocrinologists, neurologists, developmental pediatricians, and any other person whose work is related
to metabolic disorders and genetics.
The articles should not exceed 2500 words, with not more than six
figures, tables, and photographs. Brief reports and case reports
should not exceed 1200 words, with not more than two tables and
figures or photographs and six references. Brief accounts of new
observations can also be presented as letters not exceeding 400
words.
Guidelines to be followed while preparing and submitting a manuscript are given below.
MANUSCRIPT CHECKLIST
Typescript and other inputs
Send original (unpublished and not submitted elsewhere)
manuscript along with two photocopies to the address* given
below
Send a softcopy (CD) of the manuscript in MS Word format
Send two sets of illustrations, photographs, and drawings
Line art/graphs/illustrations should be provided in .eps
or .ai format or in a camera-ready form with redundant
areas trimmed
Line drawings can be submitted as photographic prints or
high-quality photocopies. All other illustrations should be
black-and-white photographic prints
Resolution of photographs or their scanned copies should
be 300 or more dpi
If the subjects of the photographs are identifiable, either
their eyes should be masked or their written permission to
use the photograph should be submitted along with the
typescripts
Color illustrations can be used if essential to the article
Provide complete details of the corresponding author,
including address for communication, telephone and fax
numbers, and email address
Keep a copy of the manuscript for your reference
Statements/permissions
Include statements signed by each author on:
Authorship criteria and responsibility
Financial disclosure
Copyright transfer
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permission has been obtained from all persons named in the
Acknowledgment
Include research or project support/funding in an acknowledgment

* The Managing Editor Perinatology


Scientific Publications Division
The Himalaya Drug Company
Makali, Bangalore,
Karnataka, India 562123

Include written permission from each individual identified as a


source for personal communication
Include informed consent forms for identifiable patient descriptions, photographs, and pedigrees
Include written permission from publishers and authors to
reproduce or adapt previously published illustrations and
tables
Postsubmission
An acknowledgement will be sent against the receipt of the
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Manuscripts not accepted for publication will not be returned
Editor has the right to make necessary changes in the manuscript and also to reduce the length of the manuscript, if
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Two copies of the journal will be provided to the author free of
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MANUSCRIPT FORMAt
Titles and subtitles
Titles should be short, concise, specific, and informative.
Abstract
Abstract of a research paper summarizes the main points of an
article: (1) the study objective and background, (2) the study design
and methods, (3) results, and (4) conclusion.
Key words
Key words are descriptors representing the key topics presented in
the article.
Introduction
The introduction should provide the objective of the study and state
the hypothesis or research question, how and why the hypothesis
was developed, and why it is important.
Methods
This section includes a description of:
Study design or type of analysis and period of study
Condition, factors, or disease studied
Details of sample (eg, study subjects and the setting from which
they were drawn)
Intervention(s)
Outcome measures
Statistical analysis
Results
The results given in the manuscript should be specific and relevant to
the research hypothesis.
Discussion
This section should be a formal consideration and critical examination of the study. The results should be considered in this section in
the context of other studies.
Conclusion
This section summarizes the consensus statement. It may include
benefits and harms of the study. The type of future studies, if appropriate, should be mentioned here.
Acknowledgments
Acknowledgments are considered to be a continuation of the text
and precede the references. Only those who have made substantial
contributions to the study and/or preparation of the paper should
be acknowledged. The source(s) of grant support, equipment, and
drugs should be included.

173

Instructions to Authors
RESEARCH ARTICLES
References
Authors cite a reference:
To support their arguments or lay the foundation for their theses
As a source of information or to credit other authors
General Style Points (US Spelling and Style)
Use American English, ize spelling
Numbers under 10 are spelled out, except for measurements
with a unit (8 mmol/L) or age (6-week old), or when in a list with
other numbers (14 dogs, 12 cats, and 9 gerbils)
Use list comma. For example: The bishops of Durham, Canterbury, Bath and Wells, and York were invited. OR I used to
help my mother with the cooking, cleaning, washing and
ironing, and yard work
Use double quotes: Generally, quotes are outside punctuation.
For example: poliomyelitis is commonly referred to as polio.
For range use to in text, for example 40 to 50 mg, and (en
dash) in parenthesis (3547 cm)
Use P value as: P = .05, P<.005, P>.05 (no 0 before period and
P is capital and italics; no space between the symbols (<,>)
and P; rule of exception: insert space before and after the
symbol =)
Closed-up em dash should be used for parenthetical
phrases
Parenthesis style: First priority is parenthesis followed by square
bracket, that is, ([]), (World Health Organization [WHO])
Date: December 5, 2008 (US style)
Foreign words listed in Merriam-Websters online dictionary
should not be italicized and hyphenated (in vitro, in vivo, etc.)
Tables
All tables should be cited in the text and it should be in
sequential order
Table should be cited as Table 1/Tables 1 and 2/Tables 1 to 3 (or
Tables 13, inside parenthesis)
Table caption should be provided and its first part should be in
bold form as given below
For example:
Table 1. Table Caption in Title Case (no full point at the end)
Figures
All figures should be cited in the text and it should be in
sequential order
Figure should be cited as Figure 1/Figures 1 and 2/Figures 1 to 3
(or Figures 13, inside parenthesis)
Figure caption should be provided and its first part should be in
bold form as given below
For example:
Figure 1. Figure caption in sentence case. (Note the full point at the
end.)
Abbreviations
Most abbreviations should be spelled out at first mention (in text);
some very common abbreviations need not be expanded. Abbreviations should not be introduced in titles.
Some notes on the use of abbreviations are given below.
In general, use uppercase letters without period for acronyms
and initialisms such as CHF, GFR, and WBC and also for routes of
administration and dosage schedules such as PO, IV, BID, and
TID. Some abbreviationssuch as PhD and pHdo contain
lowercase letters
Use abbreviations consistently. In general, write out the term or
phrase at first mention, followed by the abbreviation in parentheses; use only the abbreviation thereafter

174 PERINATOLOGY Vol. 12 No. 4 JanMar 2012

Write lowercase abbreviations without period; et al and vs


are examples. Rule of exception: Use lowercase abbreviations,
preceded by a comma and followed by a full point at the end
of etc. For example: sun, moon, etc.
Write for example or that is, preceded and followed
by a comma, if it is not the beginning of the sentence, in
a running text. Write eg or ie followed by a comma
when used in parenthesis (ie, or eg,)
Genus and species
Italicize when used in singular: Species, variety or subspecies,
genus (eg, first occurrence in textEscherichia coli; following
occurrencesE coliwithout any period)
Use lowercase (unless it is not a beginning of the sentence) and
nonitalic style for plural form of organisms
Bacillus

bacilli

Staphylococcus

staphylococci

Streptococcus

streptococci

Units
Use standard abbreviations for units of measure.
References
All references should be cited in the text, tables, or figures in consecutive numerical order (as presented in the text) by means of
superscript Arabic numerals, outside punctuation.
Article in journals
Typical entry for journal with more than two authors (if more than
two authors, list first author, then et al).
For example:
Hunter DJ, et al. Plasma organochlorine levels and the risk of breast
cancer. N Engl J Med. 1997;337(suppl 1):1253-1258.
Morris LA. The risk revolution: an experimentation of the regulatory
environment [editorial]. J Am Pharm Assoc. 2001;41:S5-S10.
Books
Author name: Same as journal.
Aronoff GR, et al. Drug Prescribing in Renal Failure. Vol. 1. 4th edn.
Philadelphia, PA: American College of Physicians; 1999:39.
Dukes MNG, Aronson JK, eds. Meylers Side Effects of Drugs. 14th
edn. Amsterdam, Netherlands: Elsevier; 2000:xvi-xvii.
Other published material
Electronic media
Perneger TV, et al. Randomized trial of heroin maintenance programme for adults who fail in conventional drug treatments. TBMJT
[serial online]. 1998;317:20-24. Available at: http://www.bmj.com/
cgi/content/full/317/7150/13. Accessed March 4, 2003.
Rennie D, Guyatt G, eds. Users Guides to the Medical Literature:
A Manual for Evidence-Based Clinical Practice [book online].
Chicago, IL: AMA Press; 2002. Available at: http://www.usersguides.
org/textbooks.asp. Accessed February 26, 2004.
Unpublished material
Do not include material that has been submitted for publication but
has not yet been accepted. This material, with its date, should be
noted in the text as unpublished data, as follows:
For example:
These findings have recently been corroborated (Mariman, unpublished data, January 1996).

RNI Regd No. KARENG/1999/35

Printed and published by Dr Pralhad S Patki on behalf of The Himalaya Drug Company, Makali, Bangalore - 562123.
Published at The Himalaya Drug Company, Makali, Bangalore - 562123.
Printed at Sri Sudhindra Offset Process, No. 27/28, DT Street, 8th Cross, Malleshwaram, Bangalore - 560003.
Edited by Dr Ranjan K Pejaver.

MAG (3) NPP/43/2011/12

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