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PARADIGMA

BARU PERTUMBUHAN JANIN


TERHAMBAT (PJT) DI BIDANG OBSTETRI

Johanes C.Mose

Department of Obstetrics and


Gynecology. Faculty of Medicine
Padjadjaran University
Bandung
DEFINITION of FGR

• Birth weight < 10th percentile for gestational age


• Birth weight< the 3rd, 5th, 10th centile
• Birth weight < 2,5 Kg
• Fetus who is SGA and displays other signs of
chronic hypoxia or malnutrition (Ville et al, 2003)
FGR in recent literatures
INSTITUTION/AUTHORS DEFINITION
. Baschat et al, . Combination of small AC and elevated UA
2007 Doppler BFR
. Cochrane 2013 . Failure to reach growth potential
. DIGITAT 2013 . EFW < 10th centiles for gestational age
. AOCOG 2013 . EFW < 10th centiles for gestational age
. RCOG 2013 . SGA : birth weight < 10th centiles
. SOGS 2013 . IUGR: EFW < 10th centiles on Ultrasound
. PORTO 2013 . EFW < 5th percentiles and Umbilical artery PI >
95th percentiles
. TRUFFLES 2013 . AC <10th percentiles and Umbilical artery PI
>95 percentiles
. Gordijin et al, . Combination of : AC < 3rd centiles, EFW < 3rd
2016 centiles, UtA >95th centiles, UA > 95th centiles
Kerangka Pikir
DEVELOPMENTAL PROGRAMMING
Next Generation ??

Source: Ricardo Uauy, et.al, 2011


Ferritin Low levels
Defective transport through placenta
Increased premature delivery

School education difficulties/


Low cognitive scores
need for special education

Major/minor motor Poor strength and


incompetence work capacity

Cerebral palsy
Minor neurological
dysfunction
Poor social competence

Behavioural problems Poor academic


(attention deficit hyperactivity performance
syndrome/Autism)
Low intelligence
score

Growth retardation Poor perceptual


IUGR male and female performance
children and adult
Poor visuo-motor
perception and motor
incompetence
Poor reading and
mathematics learning

Figure 7. Increased risk for various physical and neurodevelopmental problems in intrauterine growth restricted neonates when they reach their
childhood and adulthood. Figure Copyright Deepak Sharma.

78 CLINICAL MEDICINE INSIGHTS: PEDIATRICS 2016:10


IUGR: antenatal and postnatal aspects

Parkinsonism/ Lung abnormalities–


Alzihmer disease reactive airways disease

Immune dysfunction Metabolic


Syndrome X
Osteoporosis

Tybe 2 diabetes

Hypertension/obesity
Metabolic programming/Epigenetic
modification in antenatal period
Ischemic Heart
disease/Stroke
Postnatal abnormal nutrition
PCOD/premature
pubarche

Renal/Hepatic
Adult male and female disease

IUGR Neonate Depression, anxiety,


bipolar disorder,
Social problems/
schizophrenia
Poor cognitive
performance Cancer/
Short life span Hypercholesterolemia

Figure 8. Figure showing various adult disease the IUGR infant is prone to develop in his adulthood as per “Developmental origin of health and diseases
(DoHaD)”. IUGR infants undergoes epigenetic modification in-utero and postnatally have abnormal nutrition and growth leading to various disease of
adulthood in these infants. Figure Copyright Deepak Sharma.

Maternal factors Poor fetal growth/ Abnormal growth of


Maternal factors Poor fetal growth/ Abnormal growth of
IUGR fetus various organ system
Fetal factors like Renal

Placental factors
Less  cell in fetal Abnormal vascular
Genetic factors pancreas development

Fetal Hyperglycemia Hypertension

Poor fetal uptake of


glucose and amino
acid from mother
Metabolic syndrome X

Poor fetal growth


(Epigenetic
modification)

Postnatal excessive
nutrition

Abnormal postnatal
growth (obesity) Type 2 diabetes
Adult with decreased  mellitus
cell of pancreas

Figure 9. Barker Hypothesis (Thrifty phenotype) explaining the Fetal Origin of Adult Disease (FOAD) or “Developmental origin of health and diseases
(DoHaD)” in IUGR infants. Figure Copyright Deepak Sharma.
Table 7. Various “developmental origin of health and diseases
(DoHaD)” seen in IUGR neonates in adulthood.

v Hypertension
v Ischemic Heart disease/ Stroke
v Type 2 diabetes mellitus
v Kidney disease
v Liver disease
v Hypercholesterolemia
v Metabolic syndrome X
v Obesity
v Lung abnormalities- reactive airways disease
v Cancer- breast, ovarian, colon, lung, blood
v Schizophrenia/ Parkinsonism
v Alzheimer disease
v Polycystic ovarian syndrome, premature pubarche
v Shortened life span
v Depression, anxiety, bipolar disorder
v Immune dysfunction
v Osteoporosis
v Social problems
v Poor cognitive performance

Note: Adapted from Sharma D, Farahbakhsh N, Shastri S, Sharma P.


Intrauterine growth restriction–part 2. J Matern Fetal Neonatal Med. 2016 Mar Fig
15:1–12. [Epub ahead of print] PubMed PMID: 26979578 with permission int
IUGR

Genetic factors Placental factors Fetal factors Maternal factors

Figure 1. IUGR can be the result of maternal, fetal, placental, genetic cause or can be combination of either of the combination. (Copyright images
Deepak Sharma).
e 2. Maternal causes for
Table 2. Maternal intrauterine
causes growthgrowth
for intrauterine restriction.
restriction. TableTable
3. Placental causes
3. Placental for for
causes intrauterine growth
intrauterine growthrestriction.
restriction.

v Maternal age (less than 16 years and more than 35 years) v Placental weight (weight less than 350 gram)
Maternal age (less than 16 years and more than 35 years)
v High altitude and maternal hypoxia
v Placental weight (weight less than 350 gram)
v Abnormal uteroplacental vasculature
igh altitude
v Low and maternal hypoxia
socioeconomic status and developing country v Abnormal uteroplacental
v Placental vasculature
dysfunction (PIH, pre-eclampsia)
v Ethnicity or race
ow socioeconomic status and developing country v v Thrombophilia-related
Placental dysfunction (PIH,uteroplacental
pre-eclampsia) pathology
v Maternal substance abuse (smoking both active and passive, v Confined placental mosaicism (CPM)
thnicity alcohol,
or race illicit drugs like marijuana or cocaine) v Thrombophilia-related
v Avascular villi uteroplacental pathology
v Maternal
Maternal substancemedication
abuse (smoking
(warfarin,both activeanticonvulsants,
steroids, and passive, v v Decidual
Confined placental
or spiralmosaicism (CPM)
artery arteritis
antineoplastic, anti-metabolite, and folic acid antagonists) v Multiple infarctions
lcohol,v illicit drugstolike
Moderate marijuana
heavy physicalorwork
cocaine) v Avascular
v Partialvilli
molar pregnancy
Maternal medication
v Maternal (warfarin, steroids,
pre-pregnancy height andanticonvulsants,
weight (BMI less than 20, v Decidual or spiral
v Syncytial knotsartery arteritis
weight less than 45 kg and more than 75 kg) v Chronic inflammatory lesions
ntineoplastic,
v Parity anti-metabolite,
(none and more than and 5folic acid antagonists)
birth) v Multiple infarctions
v Single umbilical artery
Moderate to heavy
v Inter physical
pregnancy work(less than 6 months or 120 months or
interval v Partial molarplacenta
v Abruptio pregnancy
Maternal more)
pre-pregnancy height and weight (BMI less than 20, v v Velamentous
Syncytial knots cord
v Previous delivery of a SGA newborn v Placental hemangioma
eightvless than 45reproductive
Assisted kg and more than 75 kg)(ART)
technologies v Chronic inflammatory
v Placental infectionslesions
(Placental malaria)
v Pregnancy
arity (none and morepoorthan 5 birth)
medical care v v Infectious
Single umbilicalvillitis
artery
v Pregnancy severe maternal starvation. v Multiple gestation
nter pregnancy
v Pregnancy interval
poor (less
weightthan
gain6 months or 120 months or v Abruptio placenta
v Chronic villitis of unknown etiology (CVUE)
more) v Maternal Bronchial asthma, cyanotic congenital heart diseases v Velamentous cord
v Reduced expression of enzymes for redox regulation (thiore-
v Hematologic and immunologic disorders (Acquired doxin, glutaredoxin)
revious delivery of a SGA
thrombophilias, suchnewborn
as anti-cardiolipin antibodies and lupus v Placental hemangioma
ssisted anticoagulant)
reproductive technologies (ART) v Placental infections (Placental malaria)
v Maternal medical disorders (hypertensive disorders (gesta-
regnancy poor medical care
tional and non-gestational), diabetes associated with vascul-
v Infectious villitis
regnancyopathy,severechronic
maternal
renalstarvation.
disease, systemic lupus erythematosus, v Thegestation
Multiple role of Insulin-like growth factor-II (IGF-II),
regnancyantiphospholipid
poor weight gain syndrome, sickle cell disease v Insulin-like
Chronic villitis ofgrowth
unknown factor binding
etiology (CVUE)protein-2 (IGFBP-2),
v Pathological conditions in pregnancy like preeclampsia and
Maternal diabetes
Bronchialassociated
asthma, cyanotic congenital heart diseases
with vasculopathy v Insulin-like
Reduced growthoffactor
expression binding
enzymes protein-3
for redox (IGFBP-3),
regulation (thiore- and
ematologic
v Maternal and immunologic disordersinfestations
infection and parasite (Acquired(TORCH, malaria, vasoactive
doxin, intestinal polypeptide (VIP) in IUGR have been
glutaredoxin)
tuberculosis, urinary tract infections and bacterial vaginosis) proved. In the various preclinical trials, mutation in IGF-II
hrombophilias, such as anti-cardiolipin antibodies and lupus
Curr Obstet Gynecol Rep (2013) 2:102–111 107

Table 1 Etiology of IUGR

Maternal factors Fetal factors Placental factors

Demographics: Genetic: Placenta:


Extreme of maternal age Trisomy 21, 18, 13 Placental abruption
Race Turners syndrome Placenta accreta
Low pre-pregnancy weight Deletion of chromosome 4, 5 Placental infarction
Poor maternal weight gain Genetic syndromes Circumvallate placenta
Obstetrical: Congenital malformations: Confined placental mosaicism
Short inter-pregnancy interval Congenital heart disease Placental hemangioma
Prior history of small for gestational age (SGA) CDH Placental chorangioma
Behavioral/environmental: Abdominal wall defect Diffuse chronic villitis
Smoking Anencephaly Fetal villous obliteration
Alcohol Infection: Umbilical cord:
Drug use TORCH Velamentous cord insertion
High altitude Malaria Single umbilical artery
Systemic disease: Others: Chlamydia, Mycoplasma, Listeria, TB
Hypertension (chronic hypertension, preeclampsia) Multiple pregnancy
Pregestational Diabetes
Renal disease
Anemia
Pulmonary disease
Congenital heart disease
Autoimmune disease
Antiphospholipid syndrome
GI disease (Crohn’s disease, ulcerative colitis, gastric bypass,
malabsorption)
Malnutrition
Transplant recipient (Renal)
Others:
Artificial reproductive technologies (ART)
Uterine factors (fibroid, müllerian anomalies)
Medications (anticonvulsants, beta blockers)
Angiotensin gene mutation

trimester serum screening can be associated with IUGR [68•]. Another simple tool commonly used in office includes
Curr Obstet Gynecol Rep (2013) 2:102–111 107

Table 1 Etiology of IUGR

Maternal factors Fetal factors Placental factors

Demographics: Genetic: Placenta:


Extreme of maternal age Trisomy 21, 18, 13 Placental abruption
Race Turners syndrome Placenta accreta
Low pre-pregnancy weight Deletion of chromosome 4, 5 Placental infarction
Poor maternal weight gain Genetic syndromes Circumvallate placenta
Obstetrical: Congenital malformations: Confined placental mosaicism
Short inter-pregnancy interval Congenital heart disease Placental hemangioma
Prior history of small for gestational age (SGA) CDH Placental chorangioma
Behavioral/environmental: Abdominal wall defect Diffuse chronic villitis
Smoking Anencephaly Fetal villous obliteration
Alcohol Infection: Umbilical cord:
Drug use
High altitude
Systemic disease:
TORCH
Malaria PLACENTAL FACTORS :
Others: Chlamydia, Mycoplasma, Listeria, TB
Velamentous cord insertion
Single umbilical artery

( Am J Obstet Gynecol. 2011 Mar; 204(3): 193–201.)


Hypertension (chronic hypertension, preeclampsia) Multiple pregnancy
Pregestational Diabetes
Renal disease
Anemia
Pulmonary disease
Congenital heart disease
DEFECTIVE DEEP PLACENTATION
Autoimmune disease
Antiphospholipid syndrome
GI disease (Crohn’s disease, ulcerative colitis, gastric bypass,
malabsorption)
Malnutrition
Transplant recipient (Renal)
Others:
Artificial reproductive technologies (ART)
Uterine factors (fibroid, müllerian anomalies)
Medications (anticonvulsants, beta blockers)
Angiotensin gene mutation
DEFECTIVE SPIRAL ARTERY
REMODELING
trimester serum screening can be associated with IUGR [68•]. Another simple tool commonly used in office includes
Table 3. Types of defective deep placentation in association with adverse pregnancy
outcomes

Type of myometrial spiral artery remodeling

Partial - Preterm labor


- Preterm PROM
- IUGR without hypertension

Absent - Preeclampsia

Absent with obstructive lesions - Preeclampsia with IUGR


- Abruptio placentae

PROM: premature rupture of membranes; IUGR: intrauterine growth restriction

THE “GREAT OBSTETRICAL SYNDROMES” ARE ASSOCIATED WITH


DISORDERS OF DEEP PLACENTATION
Ivo Brosens, MD, Robert Pijnenborg, PhD, Lisbeth Vercruysse, MSc, and
Roberto Romero, MD.

Am J Obstet Gynecol. 2011 Mar; 204(3): 193–201.


DEFECTIVE DEEP PLACENTATION
THE GREAT OBSTETRICAL SYNDROMES
PPROM
PRETERM
PRE
ECLAMPSIA LABOR

ABRUPTION
PLACENTAE

GESTATIONAL
12 16 < 34 > 34
AGE (WEEKS)

LATE
SPONTANEOUS
ABORTION
DEFECTIVE
PLACENTATION
IUGR
THE “GREAT OBSTETRICAL SYNDROMES” ARE ASSOCIATED WITH DISORDERS
OF DEEP PLACENTATION
Ivo Brosens, MD, Robert Pijnenborg, PhD, Lisbeth Vercruysse, MSc, and
Roberto Romero, MD. Am J Obstet Gynecol. 2011 Mar; 204(3): 193–201.
of both symmetrical and asymmetrical IUGR at birth. This deficiency, IUGR results because of reduced uptake and uti-
type of IUGR results when early IUGR is affected further by lization of nutrients.12 In preclinical trials, it has been shown
placental causes in late pregnancy.6 that pancreatic agenesis of the fetus leads to fetal hyperglyce-
mia and this results in secondary decrease in the maternal–
Causes of IUGR fetal glucose concentration gradient; thus, there is a decrease
IUGR is the common end result of maternal, placental, in glucose transport to the fetus, leading to IUGR.13
fetal, or genetic factors, and IUGR can also result due to a Insulin-like growth factor-I (IGF-I) is positively regu-
combination of any of these factors (Fig. 1). Various maternal lated by glucose supply in the fetus. It has mitogenic properties

Table 1. Features of symmetrical and asymmetrical IUGR.

CHARACTERISTICS SYMMETRICAL IUGR ASYMMETRICAL IUGR


Period of insult Earlier gestation Later gestation
Incidence of total IUGR cases 20% to 30% 70% to 80%
Etiology Genetic disorder or infection intrinsic Utero-placental insufficiency
to foetus
Antenatal scan All are proportionally reduced Abdominal circumference-decreased
Head circumference, Abdominal circumference, Biparietal diameter, Head circumference,
Biparietal diameter and Femur length and femur length- normal
Cell number Reduced Normal
Cell size Normal Reduced
Ponderal Index Normal (more than 2) Low (less than 2)
Postnatal anthropometry Reductions in all parameters Reduction in weight
Weight, length and head circumference. Length and Head circumference- normal
(Brain sparing growth)
Difference between head and chest circumference Less than 3 cm More than 3 cm
in term IUGR
Features of malnutrition Less pronounced More pronounced
Prognosis Poor Good

Note: Adapted from Sharma D, Farahbakhsh N, Shastri S, Sharma P. Intrauterine growth restriction–part 2. J Matern Fetal Neonatal Med. 2016 Mar 15:1–12.
[Epub ahead of print] PubMed PMID: 26979578 with permission.
CLINICAL ASPECT
• SCREENING & PREDICTION
• DIAGNOSIS
• FETAL SURVEILLANCE
• MANAGEMENT
RISK FACTORS
CLINICAL ASPECT
PREDICTION &
SCREENING ,

DIAGNOSIS
SFH
MEASUREMENT
SIGNS AND SYMPTOMS
DOPLER USG

CTG EARLY ONSET LATE ONSET


IUGR IUGR

GESTATIONAL
12 16 < 34 > 34
AGE (WEEKS)
PREVENTION &

MANAGEMENT
TREATMENT
1. CLINICAL SCREENING & EARLY
DETECTION
• Identifying Risk Factors
• Measurement of Fundal
Height
• Uterine artery Doppler
CLINICAL SCREENING
A Risk factors
Ø Low socioeconomic environment
Ø Family history of IUGR
Ø Previous delivery of IUGR infant
Ø Cigarette smoking
Ø Low pre-pregnancy weight
Ø Poor maternal weight gain
Ø Medical complication of pregnancy
Ø Decreased fundal height
RISK FACTORS FOR IUGR
• DETECTABLE BEFORE CONCEPTION
- Previous fetal growth restriction
- History of chronic illness
- History of antiphospholipid syndrome
- Low maternal body mass index
- Substance abuse (including alcohol)
- Maternal hypoxia

• DETECTABLE DURING PREGNANCY


- Elevated MSAFP / hCG
- Drug ingestion (Coumarin, Hydantion)
- Vaginal bleeding
- Placental abnormalities
- Preterm labour
- Twin gestation
- Poor maternal weight gain
B SYMPHYSIAL FUNDAL HEIGHT (SFH)
MEASUREMENT

• Although it’s very helpful in predicting SGA,


single measurement has low predictive value.
• Sensitivity : 27 %
• Specificity : 88%
• Serial measurements may improve sensitivity
and specificity.
• Evidence level II and III, Recommendation
grade B
NORMAL
SGA =

CONSTITUTIONALLY
SMALL
IUGR
C ULTRASOUND SCREENING

• DOPPLER UTERINE ARTERY


• DIASTOLIC NOTCH
• BILATERAL : INCREASED IUGR
(RR: 33.7)
Sensitivity : 57.6 %
Specificity : 97.2 %
Uterine Artery Doppler

• Hasil Ultrasound color — Bentuk gelombang dari uterine


Doppler dari uterine artery artery normal pada usia kehamilan
dan iliac artery eksternal 24 minggu (aliran diastolik tinggi)
METHOD OF MEASURING UA PI
DIAGNOSIS
ULTRASOUND :
1. Fetal Size and Growth (Biometry)
2. Fetal Well being (Doppler)

MONITORING/ SURVEILLANCE

CARDIOTOCOGRAPHY
UMBILICAL ARTERY DOPPLER
NORMAL REDUCED

ABSENT REVERSED
Umbilical Artery (UA) Doppler
Middle Cerebral Artery (MCA) & Thoracic
Aorta Doppler
DUCTUS VENOSUS
Ductus Venosus

• Normal

• Reversed
EDF
UMBILICAL VENOUS PULSATIONS
MONITORING
&
EVALUATION
(Arduini D,et al,
1992)
(Baschat AA,
2004)
(Baschat AA, 2005)
Mari G, Hanif F, Drennan K, Kruger M. Staging of intra-uterine growth restriction fetuses. J
Ultrasound Med 2007;26:1469-1477
MANAGEMENT/INTERVENTION
Booking assessment
(first trimester)

Minor risk factors


Assessment of
Maternal age ≥35 years
fetal size and
IVF singleton pregnancy
umbilical
Nulliparity
al artery Doppler
BMI <20 Uterine rm
3 or more No in third trimester
BMI 25–34.9 artery
Smoker 1–10 cigarettes per day 3 or more
Doppler at
Low fruit intake pre-pregnancy Ab
20–24 weeks no
rm
Previous pre-eclampsia al Reassess
Pregnancy interval <6 months during
Reassess
Pregnancy interval ≥60 months third trimester
at 20 weeks
Institute serial
PAPP-A <0.4 assessment of
Major risk factors MOM (major) fetal size and
Maternal age >40 years
umbilical artery
Smoker ≥11 cigarettes per day Fetal echogenic Doppler
Paternal SGA bowel (major) Serial if develop:
Cocaine
Daily vigorous exercise One risk factor One risk factor assessment
of fetal size
Previous SGA baby Severe pregnancy
Previous stillbirth and umbilical
artery Doppler induced
Maternal SGA hypertension
Chronic hypertension from
Consider 26–28 weeks pre-eclampsia
Diabetes with vascular disease Unexplained APH
aspirin at
Renal impairment abruption
<16 weeks
Antiphospholipid syndrome
if risk
Heavy bleeding similar to menses
factor for
PAPP-A <0.4 MoM
pre-eclampsia

Women unsuitable for monitoring of


growth by SFH measurement
e.g. large fibroids, BMI >35

Risk assessment must always be individualised (taking into account previous medical and obstetric history and current pregnancy history). Disease progression or
institution of medical therapies may increase an individual’s risk.

Figure 2. Screening for Small–for–Gestational–Age (SGA) Fetus.


Note: Reproduced from: Royal College of Obstetricians and Gynaecologists. The Investigation and Management of the Small–for–Gestational–Age Fetus.
Green-top Guideline No. 31. London: RCOG; 2014, with the permission of the Royal College of Obstetricians and Gynaecologists.
IUGR: antenatal and postnatal aspects

SFH High risk of SGA fetus/neonate


Single measurement <10th customised centile Based on history, biochemistry or uterine
and/or serial measurements indicative of FGR artery Doppler

Fetal biometry
Single AC or EFW <10th customised centile
serial measurements indicative of FGR

UA Doppler
Refer
for
fetal medicine
specialist
opinion
Normal PI or RI >2 SDs, EDV present AREDV

Repeat ultrasound Repeat ultrasound Repeat ultrasound


(fortnightly) Weekly Twice weekly Weekly Daily
AC and EFW1,2 UA Doppler
AC and EFW1,2 UA Doppler AC and EFW1,2 UA Doppler
MCA Doppler after 32 weeks DV Doppler
[cCTG]3

Delivery Delivery Delivery


Offer delivery by 37 weeks with the Recommend delivery by 37 weeks Recommend delivery before 32 weeks after
involvement of a senior clinician Consider steroids if delivery by CS steroids if:
Recommend delivery by 37 weeks if Consider delivery >34 weeks if static growth – abnormal DV Doppler and/or cCTG
MCA Dopper PI <5th centitle over 3 weeks provided ≥24 weeks and EFW >500g
Consider delivery >34 weeks if static growth Recommend steroids if delivery is by CS Recommend delivery by 32 weeks after steroids
over 3 weeks (as per RCOG guidance) Consider delivery at 30–32 weeks even when
Recommend steroids if delivery is by CS DV Doppler is normal
(as per RCO guidance)

Figure 3. The Management of the Small–for–Gestational–Age (SGA) Foetus.


Notes: Reproduced from: Royal College of Obstetricians and Gynaecologists. The Investigation and Management of the Small–for–Gestational–Age Fetus.
Green-top Guideline No. 31. London: RCOG; 2014, with the permission of the Royal College of Obstetricians and Gynaecologists. 1Weekly measurement
of fetal size is valuable in predicting birthweight and determining size-for-gestational age. 2If two AC/EFW measurements are used to estimate growth, they
should be at least 3 weeks apart. 3Use cCTG when DV Doppler is unavailable or results are inconsistent – recommend delivery if STV 3 ms.
Abbreviations: AC, abdominal circumference; EFW, estimated fetal weight; Pl, pulsatility index; RI, resistance index; UA, umbilical artery; MCA, middle
cerebral artery; DV, ducts venosus; FGR, fetal growth restriction; EDV, end-diastolic velocities.
MANAGEMENT OF IUGR
1. EARLY DETECTION OF HIGH RISK FACTORS
2. ELIMINATION OF CONTRIBUTING FACTORS
3. SERIAL MATERNAL AND FETAL SURVEILLANCE
4. CORTICOSTEROID & MgSO4 ADMINISTRATION
4. TIMELY INTERVENTION
5. CARE OF IUGR NEONATE BY AN EXPERIENCE
NEONATOLOGIST
Obstetrics & Gynecology:
August 2010 - Volume 116 - Issue 2, Part 1 - pp 402-414
doi: 10.1097/AOG.0b013e3181e9322a
Reviews
Prevention of Preeclampsia and Intrauterine Growth Restriction With Aspirin Started in Early Pregnancy: A Meta-Analysis

Bujold, Emmanuel MD, MSc; Roberge, Stéphanie MSc; Lacasse, Yves MD, MSc; Bureau, Marc MD; Audibert, François MD,
MSc; Marcoux, Sylvie MD, PhD; Forest, Jean-Claude MD, PhD; Giguère, Yves MD, PhD
Abstract

OBJECTIVE: To estimate the effect of low-dose aspirin started in early pregnancy on the incidence of preeclampsia and
intrauterine growth restriction (IUGR).
DATA SOURCES: A systematic review and meta-analysis were performed through electronic database searches (PubMed,
Cochrane, Embase).
METHODS OF STUDY SELECTION: Randomized controlled trials of pregnant women at risk of preeclampsia who were
assigned to receive aspirin or placebo (or no treatment) were reviewed. Secondary outcomes included IUGR, severe
preeclampsia and preterm birth. The effect of aspirin was analyzed as a function of gestational age at initiation of the
intervention (16 weeks of gestation or less, 16 weeks of gestation or more).
TABULATION, INTEGRATION, AND RESULTS: Thirty-four randomized controlled trials met the inclusion criteria, including
27 studies (11,348 women) with follow-up for the outcome of preeclampsia. Low-dose aspirin started at 16 weeks or
earlier was associated with a significant reduction in preeclampsia (relative risk [RR] 0.47, 95% confidence interval [CI]
0.34–0.65, prevalence in 9.3% treated compared with 21.3% control) and IUGR (RR 0.44, 95% CI 0.30–0.65, 7% treated
compared with 16.3% control), whereas aspirin started after 16 weeks was not (preeclampsia: RR 0.81, 95% CI 0.63–1.03,
prevalence in 7.3% treated compared with 8.1% control; IUGR: RR 0.98, 95% CI 0.87–1.10, 10.3% treated compared with
10.5% control). Low-dose aspirin started at 16 weeks or earlier also was associated with a reduction in severe
preeclampsia (RR 0.09, 95% CI 0.02–0.37, 0.7% treated compared with 15.0% control), gestational hypertension (RR 0.62,
95% CI 0.45–0.84, 16.7% treated compared with 29.7% control), and preterm birth (RR 0.22, 95% CI 0.10–0.49, 3.5%
treated compared with 16.9% control). Of note, all studies for which aspirin had been started at 16 weeks or earlier
included women identified to be at moderate or high risk for preeclampsia.
CONCLUSION: Low-dose aspirin initiated in early pregnancy is an efficient method of reducing the incidence of
preeclampsia and IUGR.
ASPIRIN TREATMENT WORKS, IF STARTED EARLY

Start ≤16 weeks


PE by ~ 50% Preterm PE by89%
IUGR by ~ 55%
Clinical Nutrition xxx (2018) 1e6

Contents lists available at ScienceDirect

Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Original article

Severe vitamin D deficiency in the first trimester is associated with


placental inflammation in high-risk singleton pregnancy
Qianqian Zhang a, 1, Hao Chen b, 1, Yi Wang a, Chen Zhang a, Zhen Tang a, Hong Li a,
Xiaoyi Huang a, Fengxiu Ouyang c, Hefeng Huang a, **, Zhiwei Liu a, *
a
International Peace Maternity and Child Health Hospital of China Welfare Institution, School of Medicine, Shanghai Jiao Tong University, Shanghai 20030,
China
b
Departments of Neonatology, Children's Hospital of Shanghai, School of Medicine, Shanghai Jiao Tong University, Shanghai 20040, China
c
Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong
University, Shanghai 200092, China

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Vitamin D deficiency during pregnancy is a worldwide epidemic. This study aimed
Received 13 November 2017 to identify whether vitamin D deficiency in early pregnancy is associated with placental inflammation in
Accepted 23 June 2018 high-risk pregnancy.
Methods: This study comprised 23,396 women who provided serum samples in the first trimester for
Keywords: vitamin D analysis from January 2015 to December 2016. Among them, 2648 women with high-risk
Vitamin D
pregnancy underwent placental pathologic examination. Women were divided into placental inflam-
Placental inflammation
mation positive (PIP) and placental inflammation negative (PIN) groups based on placental pathology.
High-risk pregnancy
Neonatal outcome
Multivariate logistic regression was used to evaluate the relationship between vitamin D levels and
placental inflammation.
Results: We found that severe vitamin D deficiency in early pregnancy was associated with placental
inflammation. Maternal vitamin D levels were significantly lower in the PIP group than those in the PIN
group (P ¼ 0.025). Compared with the highest quartile of vitamin D levels, risk for placental inflam-
mation was significantly higher in women with extremely low vitamin D levels (<5th percentile;
P ¼ 0.012). The effect estimate was slightly decreased but still significant (P ¼ 0.027) after adjusting for
maternal age, gestational age at birth, birth weight, infant sex, and sample collection season. In addition,
compared with the PIN group, the incidences of adverse neonatal outcomes, including sepsis (0.5% vs
2.4%) and fetal intrauterine infection (5.7% vs 15.6%), were significantly higher in the PIP group than that
in the PIN group (P < 0.001).
Conclusions: Severe vitamin D deficiency in the first trimester is a risk factor for placental inflammation
in high-risk pregnancy.
© 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Article Navigation

Maternal Vitamin D Deficiency During Pregnancy


Elevates the Risks of Small for Gestational Age and Low
Birth Weight Infants in Chinese Population
Yuan-Hua Chen, Lin Fu, Jia-Hu Hao, Zhen Yu, Peng Zhu, Hua Wang, Yuan-Yuan Xu, Cheng Zhang,
Fang-Biao Tao , De-Xiang Xu

The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 5, 1 May 2015, Pages
1912–1919, https://doi.org/10.1210/jc.2014-4407
Published: 01 May 2015 Article history
Obstet Gynecol. Author manuscript; available in PMC 2015 Jan 1. PMCID: PMC3914014
Published in final edited form as: NIHMSID: NIHMS542703
Obstet Gynecol. 2014 Jan; 123(1): 40–48. PMID: 24463662
doi: 10.1097/AOG.0000000000000049

Maternal Vitamin D Status and Small-for-Gestational-Age Offspring in


Women at High Risk for Preeclampsia
Alison D. Gernand, PhD, MPH, RD, Hyagriv N. Simhan, MD, MS, Steve Caritis, M.D., and Lisa M. Bodnar, PhD,
MPH, RD
Alison D. Gernand, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA;
Contributor Information.
Corresponding author and author for reprint requests: Lisa M. Bodnar, University of Pittsburgh Graduate School of Public Health, A742
Crabtree Hall, 130 DeSoto St, Pittsburgh, PA, 15261, 412.624.9032 (voice), 412.624.7397 (fax), bodnar@edc.pitt.edu

Copyright notice

The publisher's final edited version of this article is available at Obstet Gynecol
See other articles in PMC that cite the published article.
THE GREAT OBSTETRICAL SYNDROMES
PPROM
PRETERM
PRE
ECLAMPSIA LABOR

ABRUPTION
PLACENTAE

GESTATIONAL
12 16 < 34 > 34
AGE (WEEKS)

LATE
SPONTANEOUS
ABORTION
DEFECTIVE
PLACENTATION
IUGR
RISK FACTORS

PREDICTION &
SCREENING ,

DIAGNOSIS
SFH
MEASUREMENT
SIGNS AND SYMPTOMS
DOPLER USG

CTG EARLY ONSET LATE ONSET


IUGR IUGR

GESTATIONAL
12 16 < 34 > 34
AGE (WEEKS)

CORTICOSTEROIDS
MgSO4
PREVENTION &

CALCIUM
TREATMENT

ASPIRIN
VITAMIN D

TOP (DELIVERY)

TOP (DELIVERY)
FOLATE
LMWH
METFORMIN
PRAVASTATIN
1. Calcium : 1,5-2 gram/day
CALCIUM

ASPIRIN

VITAMIN D

FOLATE

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day
CALCIUM
2. ASPIRIN 150 mg/day started at 12- 16
weeks of pregnancy
ASPIRIN

VITAMIN D

FOLATE

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day

CALCIUM 2. ASPIRIN 150 mg/day starting at 12- 16 weeks of


pregnancy

ASPIRIN 3. Vitamin D : 4000 IU/day starting at 12-16 weeks


of pregnancy

VITAMIN D

FOLATE

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day
CALCIUM
2. ASPIRIN 150 mg/day starting at 12- 16 weeks of
pregnancy

ASPIRIN 3. Vitamin D : 4000 IU/day starting at 1-16 weeks


of pregnancy

VITAMIN D 4. Folic Acid 400 ug/day

FOLATE

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day
CALCIUM
2. ASPIRIN 150 mg/day starting at 12- 16 weeks of
pregnancy

ASPIRIN 3. Vitamin D : 4000 IU/day starting at 12-16 weeks


of pregnancy

VITAMIN D 4. Folic Acid 400 ug/day

5. As indicated for Thrombophilia (SLE or APS)

FOLATE

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day
CALCIUM
2. ASPIRIN 150 mg/day starting at 12- 16 weeks of
pregnancy

ASPIRIN 3. Vitamin D : 4000 IU/day starting at 12- 16


weeks of pregnancy

VITAMIN D 4. Folic Acid 400 ug/day

5. As indicated for Thrombophilia (SLE or APS)

FOLATE 6. As indicated for prior insulin dependent DM or


PCO

LMWH

METFORMIN

PRAVASTATIN
1. Calcium 1,5-2 gram/day
CALCIUM
2. ASPIRIN 150 mg/day starting at 12- 16 weeks of
pregnancy
ASPIRIN 3. Vitamin D : 4000 IU/day starting at 12- 16
weeks of pregnancy

VITAMIN D 4. Folic Acid 400 ug/day

5. As indicated for Thrombophilia (SLE or APS)


FOLATE 6. As indicated for prior insulin dependent DM or
PCO

LMWH 7. As indicated for metabolic syndrome (obese,


hyperlipidemia)

METFORMIN

PRAVASTATIN
MANAGEMENT OF IUGR : SUMMARY
1. Elimination of contributing factors, ie:
Hypertension, infections, alcohol, smoking,
drug abuse, etc.
2. Bed rest, optimally on left side & O2 therapy
3. Vitamin D & Dietary supplementation
4. Calcium 1-2 gm/day, Aspirin 150 mg/day,
Pravastatin, Metformin, Folic Acid, LMWH, etc
5. Corticosteroids at < 36 weeks
6. MgSO4 for fetal brain protection (< 32 weeks)
7. Fetal functional assessment (Doppler, CTG, BPP)
8. Termination Of Pregnancy (TOP) when :
- Doppler : - A/RED umbilical artery
- A/RAV (absent or reversed
arterial contraction) of ductus
venosus.
- UV pulsation
- Olygohydramnion
- Abnormal CTG
- Abnormal BPP
- pH < 7,2
(Evidence level I a, Recommendation A)
9. Mode of delivery :
Caesarean Section : - Premature
- Fetal distress (point 9)
Induction for vaginal delivery :
- Term pregnancy
- Intrapartum continuous monitoring (Ia, III, C)
- Deliver in a unit with optimal neonatal expertise
and facilities are available ( Evidence IV, C)