Intrauterine growth restriction: new concepts in antenatalsurveillance, diagnosis, and management

DR BHARTI PANT GAHTORI

Defining disorders of growth requires relating a given achieved growth to an expected growth.

INTRODUCTION

Within genetically set limits, the actual fetal growth judged by Fetal weight is determined by the - genetic growth potential which varies from race to race and individual to individual , - the health of the fetus with good fetal circulation, - the capacity of the mother to supply adequate quality and quantities of substrates ( O2 , glucose, aminoacids etc) required for growth, - and the ability of the placenta to transport these nutritional substrates to the fetus.

With a prevalence of the 5–8% in the general population, IUGR can complicate 10% to 15% of all pregnancies . - However, only 20–30% of these fetuses aresmall because of a pathological restriction of their growth (PFGR) and a majority are normal SGA -IUGR represents the second cause of perinatal mortality, after prematurity-It is related to an increased risk of perinatal complication as hypoxemia, low Apgar scores, and cord blood acidemia, with possible negative effects for neonatal outcome. -It is associated with increased risk of neurological, cardiovascular and metabolic diseases later in life.

EPIDEMIOLOGY

In practice, due to error in estimating gestational age, inaccuracy in weight estimation, and variation in true genetic potential, there will be no cut off that correctly separates normal and abnormal

IMPORTANT TERMS IN FETAL GROWTH DISORDER SGA simply refers to a weight for gestation below a given threshold, but a significant proportion of smallness is due to constitutional or physiological causes, The most commonly used definition of SGA is a birth weight below the 10th percentile for gestational age. IUGR SIGNIFIES THE PATHOLOGICAL CAUSE OF SAME CUTOFF

Endocrine regulation of fetal growth –IGF -1 IGF -2

FACTORS RESPONSIBLE FOR FETAL GROWTH

Placental regulation of fetal growth – Implantation and early placentation play crucial role

Genomic imprinting and fetal growth

Relative frequency of different etiologic factors in PFGR-Placental insufficiency 75–80%

-Maternal conditions not associated withplacental insufficiency 5%

-Fetal chromosome abnormalities 5%

-Multifactorial fetal abnormalities 2–3%

-Fetal infections 1%

MATERNAL CAUSES1. Associated with placental vascular insufficiency: -Preeclampsia -Chronic hypertension- Chronic renal disease- Connective tissue disorder-Diabetes with vascular lesions -Sickle cell anemia -Cardiac disease class III or IV -Multiple gestation -Autoimmune diseases, including: APS -Genetic disorders, including: phenylketonuria. 2. Not associated with placental insufficiency -Severe malnutrition -Smoking -Alcohol ingestion and recreational drugs -Hemoglobinopathies

placentalAlterations in the uteroplacental and fetal–placental circulations • Abnormal trophoblast invasion:• pre-eclampsia• placenta accreta.• Infarction ,villitis , hemorragic endovasculitis, • Abruption

• Placental location: placenta praevia.

• Tumours: chorioangiomas ,placental haemangiomas

• Abnormal umbilical cord or cord insertion: two-vessel cord.

FETALLack of substrate and inability to reach genetic potential• Genetic abnormalities, including:• trisomy 13, 18, or 21• turner’s syndrome• triploidy.• Congenital abnormalities, including:• cardiac, e.g. TOF, transposition of the great vessels• gastroschisis.• Congenital infection, including:• CMV• rubella• toxoplasmosis.• Multiple pregnancy. Inborn error of metablism

Classification of iugr – based on the symmetry among different anatomic structures. -Type I or symmetric FGR corresponds to fetuses that are symmetrically small and have normal H/A and F/A ratios.

Type II or asymmetric FGR corresponds to fetuses that have an AC that is smaller than the HC and the FL resulting in abnormally high H/A and F/A ratios.

Type III or intermediate FGR corresponds to fetuses that are initially symmetric but become asymmetric later in the pregnancy.

CLASSIFICATION BASED ON ORIGIN OF PROBLEM“Intrinsic”- FGR occurs when the fetuses are small due to fetal conditions such as viral infections or chromosomal abnormalities.

“Extrinsic” -FGR occurs when the growth failure is due to an element outside of the fetus such as a placental condition or a maternal disease.

“Combined”- FGR occurs when there are extrinsic and intrinsic factors causing the growth failure and

“Idiopathic” -FGR when the cause of the fetal growth failure is unknown.

BASED ON DOPPLER FINDINGS NOT BIRTHWEIGHT SOLELY

1) Small for gestational age (SGA) refers to those small fetuses with no discernible pathology and with normal umbilical artery and middle cerebral artery Doppler results;

2) Growth-restriction refers to small fetuses with recognizable pathology and abnormal Doppler studies; and

3) Idiopathic growth restriction applies to small fetuses with no discernable pathology and abnormal Doppler studies.28

ANOTHER PRACTICAL CLASSIFICATION

Early-onset FGR represents 20–30% of all FGR and is associated with gestational hypertension and/or pre-eclampsia in up to 70%.

Late-onset FGR, which represents approximately 70–80% of cases of FGR, shows a weaker association with hypertensive disorders of the pregnancy, roughly 10%

Classification according to age of onset plus doppler findings

CLASSIFICATION BASED ON TIMING

IDENTIFICATION OF PATIENT AT RISK

1) Maternal socio-economic condition and nutritional status 2) Maternal smoking , alcohol intake , teratogen intake or substance abuse in past and present 3) Previous history of growth restriction or still birth - 50% increased risk of severe growth restriction - Stillbirths before 32 weeks’ gestation have a particularly strong association with IUGR. 4) Medical disorders 5) Diabetes -Preeclampsia is observed in 15-20% of pregnancies complicated by type 1 diabetes mellitus without nephropathy and approximately 50% in the presence of nephropathy.6) Low PAPP-A , two vessel cord and multiple pregnancy7) IVF pregnancy

Screening in first trimesterBiochemical markers. In the first trimester, an unexplained low pregnancy-associated plasma protein A or human chorionic gonadotropin (hCG) is associated with an increased risk of placental-related diseases such as IUGR or preeclampsia. Early growth restriction. Low first-trimester measurement of crown-rump length in pregnancies dated by the last menstrual period is also linked with FGR. Slow growth between the first and second trimester is able to identify a subgroup of slow-growing babies that are at increased risk of perinatal death before 34 weeks’ gestation, in most cases with growth restriction.

Biochemical markers - an unexplained elevation of serum alpha-fetoprotein, hCG, or inhibin-A is also associated with these adverse outcomes.

Uterine artery Dopplers -. Uterine Doppler evaluation in the second or first trimester hasbeen proposed as a screening tool for early-onset IUGR,with detection rates of about 75% and 25%, respectively, for a false-positive rate of 5-10%. These sensitivities are higher for predicting early IUGR associated with preeclampsia and lower for late IUGR.

SCREENING IN SECOND TRIMESTER

Different strategies combining maternal risk factors, blood pressure, and biochemical markers have been published with detection rates greater than 90% for early-onset preeclampsia and associated IUGR

SCREENING IN THIRD TRIMESTERSerial fundal height assessment

Routine/intermittent third-trimester ultrasound biometry

Serial ultrasound biometry. For pregnancies at risk due to past or current situation , serial assessment of estimated fetal weight or abdominal circumference is the best predictor of FGR as assessed by neonatal morphometry. Therefore, serial biometry is the recommended gold standard

ULTRASOUND PARAMETERS

Serial ultrasound biometry. For pregnancies at risk, serial assessment of estimated fetal weight or abdominal circumference is the best predictor of FGR as assessed by neonatal morphometry

Amniotic fluid. A metaanalysis 132 of 18 randomized studies demonstrated that an amniotic fluid index of less than 5 is associated with abnormal 5 minute Apgar score but failed to demonstrate an association with acidosis.Longitudinal studies in early-onset IUGR fetuses have shown that the amniotic fluid index progressively decreases.

Routine/intermittent third-trimester ultrasound biometry. Sensitivity of AC for detecting a birthweight less than the 10th centile ranges from 48% to 87%, with specificity from 69% to 85%. For estimated fetal weight, sensitivities of 25-100% have been reported, with a specificity of 69-97%.

First, the standard is customized for sex as well as maternal characteristics such as height, weight, parity, and ethnic origin based on-one size does not fit all theory.Second, pathological factors such as smoking, hypertension, diabetes, and preterm delivery are excluded to predict the optimum weight that a baby can reach at the end of a normal pregnancy.Third, the term optimal weight and associated normal range is projected backward for all gestational age points, using an ultrasound growth based proportionality curve It is calculated by computer software

CUSTOMISED GROWTH CHART – THREE PRINCIPLES

FETAL DOPPLERS

CARDIOTOCOGRAPHY

MANAGEMENTFor the practicing obstetrician, these problems can be summarized in following five important questions: ?? How to recognize that the fetus is small ?? How to differentiate between the fetuses that are small and healthy and the fetuses that have pathological growth restriction? ?? Which is the appropriate fetal surveillance method and follow up interval ??? How to manage the pregnancies afflicted by pathological fetal growth restriction (PFGR) as per their staging of deterioration ? ?? How to optimize the timing and mode of delivery

Fetal deterioration and monitoring in early onset iugr

Fetal deterioration and monitoring in late mild fgr

MANAGEMENT OF IUGR

FETAL AND NEONATAL PROBLEMSASSOCIATED WITH FGRANTEPARTUM COMPLICATIONS are an increased incidence of stillbirth, oligohydramnios, and antepartum fetal distress.

INTRAPARTUM COMPLICATIONS are fetal hypoxia, acidosis, and high rate of cesarean delivery.

NEONATAL COMPLICATIONS are multiple and include hypoglycemia, hyperbilirubinemia, meconium aspiration, persistent fetal circulation,hypoxic-ischemic encephalopathy, hypocalcemia,hyperviscosity syndrome, and necrotizing enterocolitis

PROPOSED TREATMENT OF IUGROXYGEN – No rolePLASMAVOLUME EXPANDERS – no role BETA MIMETICS - Larger, well-designed studies are needed to evaluate the effects of betamimetics on fetal growth. Since there is potential for adverse effects due to the pharmacological characteristics of this group of drugsBED REST IN HOSPITAL- There is not enough evidence to evaluate the use of a bed rest in hospital policy for women with suspected impaired fetal growth.AMNIOINFUSION - Amnioinfusion with saline solution should be one of the initial steps in the intrapartum management of the PFGR fetus with decreased amniotic fluid volume or early MSL. SILDENAFIL ( NO promoter ) – Phosphodiesterase inhibitors. The enzyme phosphodiesterase breaks down cGMP, an enzyme critical to the effect of NO. But sildenafil reduces its breakdown thereby more NO for vasodilatation ( Johal 2014 )

TAKE HOME MESSAGE- Always determine the correct gestational age . - Patients with high-risk factors, unreliable dates, and abnormal or difficult to assess uterine growth are at risk for carrying small fetuses.

-In the majority of cases the clinical findings and ultrasound measurements allow only the diagnosis of “small fetus.” The majority of small fetuses are healthy. Only a modest proportion of small fetuses are truly undernourished or PFGR.

- To distinguish between fetuses that are small and healthy and PFGR it is necessary to use serial growth charts and Doppler assessment of the uterine, umbilical, and mid cerebral artery resistance.Dopplers are not only diagnostic but prognostic

- Uterine artery, UA, and MCA Doppler do not identify all PFGR fetuses. Doppler technology is exclusively for the identification of PFGR because of placental insufficiency. Small fetal size in the presence of normal uterine, umbilical, and midcerebral Doppler rules out placental insufficiency .- The most important surveillance tests to follow the PFGR fetus are the FHR monitoring by CTG and the umbilical and cerebral Doppler. As long as the FHR monitoring is normal and the Doppler does not show fetal decompensation (ADF or RDF) expectant management is adequate.- The placentas of all PFGR babies should be examined by a competent placental pathologist. In many cases the placenta will provide evidence regarding the etiology of the problem.-The earlier in gestation IUGR is detected, the greater the possibility of developmental problems later in life. The worst prognosis is for IUGR secondary to congenital infections, congenital abnormalities, and chromosomal defects

Staging system and management·      Stage 0 SGA fetuses have a good prognosis. They are managed as outpatient with Doppler assessment every 2 weeks. If the Doppler remains normal, delivery is recommended at term. If the Doppler becomes abnormal, these fetuses are managed as Stage I IUGR fetuses.·      Stage I IUGR fetuses are considered to have mild growth restriction, and affected mothers who are without preeclampsia are usually managed as outpatients. Antenatal corticosteroids should be given at time of diagnosis. In these fetuses, twice-weekly antenatal testing is recommended. If the non-stress testing (NST) remains reactive and the AFI remains >5.0 cm, delivery is recommended at 37 weeks’ gestation. If the umbilical artery Doppler becomes absent, these fetuses should be managed as Stage II IUGR.·      Stage II IUGR fetuses should be managed as inpatients. During hospital admission, the fetuses should undergo daily antenatal testing with twice-daily NST and daily biophysical profile (BPP). If the NST remains reassuring and the BPP score remains between 6 and 8 of 8, continuation of expectant management is recommended. In addition, antenatal corticosteroids should be given at time of diagnosis. Delivery is recommended at 34 weeks. If any of the aforementioned NSTs become non-reassuring or if the BPP score is 4 of 8 on 2 occasions at least 4 hours apart, immediate delivery is recommended. Delivery should occur via cesarean delivery because fetuses with an absent/reversed flow of the umbilical artery will not tolerate labor induction.·      Stage III IUGR fetuses are managed the same as Stage II except for delivery at 32 weeks’ gestation, regardless of gestational age at time of diagnosis. As with Stage I and II, antenatal corticosteroids should be given at time of diagnosis.The advantage of the above scoring system is its simplicity. Only fetal biometry, sonographic interrogation of three fetal vessels, and the amniotic fluid index are needed. It also allows classification of all small fetuses. Of note is that if the umbilical artery and middle cerebral artery Doppler is normal, it is determination of flow velocity waveforms of the ductus venosus is unnecessary because it will be normal as well. The presence of IUGR in the setting of preeclampsia should not deter standard management of preeclampsia. It is important to note the rate of mortality in the staging system.29 No deaths occurred in Stage 0 or Stage I fetuses, whereas the mortality for stage III fetuses is high (50% if there was reversal of flow in the ductus venosus; 85% mortality was observed when reversal of flow in the ductus venosus was present in combination with one of the other parameters that characterize stage III), whereas the mortality in stage II IUGR fetuses was intermediate between stages I and III (Figure 4). Also, studies have shown that fetuses can survive for days or weeks with reversal of flow in the ductus venosus.29 A recent preliminary study reported that fetuses with reversal of flow in the ductus venosus will not necessarily be acidemic at birth.30 In addition, the majority of affected pregnancies have an AFI <5 cm before fetal demise occurs (Figure 5). These data came from a study in which we were able to follow very early IUGR fetuses up to the time of demise because the patients had declined intervention.