Standardization in fetal growth restriction
Beune, Irene
DOI:
10.33612/diss.156487314
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Publication date: 2021
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Beune, I. (2021). Standardization in fetal growth restriction: Progression by consensus. University of Groningen. https://doi.org/10.33612/diss.156487314
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Chapter
1
General introduction
Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality and occurs in approximately 10% of pregnancies. It is characterized by the process in which a fetus does not reach its intrinsic growth potential due to placental insufficiency. Currently there is no undisputed method to estimate the (genetic) predispositions that determines the intrinsic growth potential of a fetus. It may be defined as the growth that the fetus can reach in optimal conditions. In suboptimal conditions the fetus can either experience growth acceleration (for example in diabetes) or growth restriction. Placental insufficiency is the common underlying mechanism of FGR in which oxygen and nutrient transport is suboptimal and the placenta is incapable of matching the needs of the fetus to
thrive.(1, 2) When placental insufficiency is present during a longer period of gestation, it results in a measurable abnormal size of the fetus: its size is below a defined cut-off at a particular gestational age in comparison to the population represented on reference charts. At the end-stage of placental insufficiency mild chronic fetal hypoxemia transgresses to acute severe hypoxemia that may cause intrauterine fetal death (IUFD). This is the typically observed pattern of the extreme phenotype in early-onset FGR. In these cases, the placen-tal insufficiency is caused by shallow implantation of the placenta in the maternal uterine wall.(3) It can be an isolated phenomenon, but is also seen in the context of chromosomal/ congenital malformations or intra-uterine infections when the underlying pathology also leads to placental insufficiency.(4, 5) To complicate matters, placental insufficiency may have a different pathway in late-onset FGR (>32 weeks of gestation), because placental and fetal reserves to withstand limitations in placental functions are more limited. In these situ-ations, acute hypoxemia (and fetal death) may occur before fetal growth is restricted below the defined cut-off for the population on reference charts.(6)
1
Effects of Fetal growth restriction
FGR is a risk factor for adverse perinatal outcome. Including a 3-7 times higher risk of IUFD.(7-12) The newborn who survived but was challenged by FGR during pregnancy still faces health risks, including mortality. Especially the risks of mortality and morbidity in the neonatal period are high in early FGR when birth is often iatrogenic preterm and additional risks apply.(13) Risks of major and minor morbidity and long-term health sequelae are not only strongly related to gestational age, but also to the level of starvation and hypoxemic status in FGR itself.(13)
The start of life with a status of prematurity, malnutrition and low birth weight (with a relatively higher body surface) results in a higher chance of hypoglycemia and hypothermia in the neonatal period.(14) Intra uterine compensation for FGR is preferential blood flow to the most important organs (brain, heart) and away from less important organs such as kidneys. This process results in suboptimal kidney development with reduced nephron endowment, which leads to less amniotic fluid and a higher chance of renal disease later in life.(15) During gestation this sustained vasoconstriction in the fetal peripheral vascular beds causes dysfunctional endothelial vasodilation and sympathetic hyperactivation. The consequent cardiac and arterial remodeling and systemic hypertension can still be seen in adulthood with a higher chance of hypertension and cardiovascular disease.(16-18) The chronic hypoxemic status and redistribution of blood flow away from the gastro-intestinal tract during pregnancy results in a vulnerable gut. When in the neonatal period enteral feeding is initiated there is an increased oxygen demand of the gastro-intestinal tract, with a higher risk of necrotizing enterocolitis and neonatal feeding disorders.(19, 20) Neonates that suffered FGR have a higher incidence of infections and sepsis, possibly caused by a depressed immunological state. Another complication of FGR is the increased risk of chronic lung disease, which is thought to be caused by chronic hypoxia affecting pulmonary devel-opment.(21, 22) Finally, intra-uterine starvation and adaptation of liver metabolism results in a negative metabolic profile with a higher prevalence of obesity and Diabetes Mellitus type 2 in adults and all the related cardiovascular comorbidities.(23, 24)
Small for gestational age vs. Fetal growth restriction
Small for gestational age (SGA) is often used as a proxy for FGR, which partly makes sense, because the lower the (birth)weight the higher the chance that FGR occurred (figure 1). Although there is significant overlap between SGA and FGR, the two terms refer to a princi-pally different condition. SGA describes a statistical deviation of size with the 10th percen-tile as the most common cut-off on population based growth charts to define (ab)normality. (25) This is not necessarily a pathological condition because approximately 40% of babies below that cut-off are small but healthy.(26) In contrast, in the case of FGR the condition is always pathological, but the baby not necessarily small. An appropriate for gestational age (AGA) or even a large for gestational age (LGA) fetus can be growth restricted, if their intrin-sic growth potential was higher.
When placental insufficiency is severe and early it becomes overt as a small sized fetus with placental insufficiency and redistribution of blood flow (to the brain) in the fetus mea-sured as Doppler changes on ultrasound examination. Doppler investigation in pregnancy measures the speed and direction of blood flow in blood vessels and can thereby indicate resistance in placental blood vessels and redistribution of the blood flow to the fetal brain. But when placental insufficiency occurs later in pregnancy, or is less severe, the signs are less obvious and size is not the best marker for the condition. This is particularly the case if FGR arises in late gestation because until then, the fetus has grown within normal ranges measured as between the 10th and 90th percentile on population based reference charts. Therefore, a decline in growth velocity in late pregnancy rarely causes the fetus’ size to drop below the used threshold for SGA.(27, 28)
In general, early FGR (defined as FGR <32 weeks of gestation) is easier to detect because
the signs are more remarked, but the management is more challenging. The maturation vs nutrition/oxygenation balance challenges the obstetrician to choose the best timing of delivery. To minimize the negative effects of (extreme) prematurity and minimize the risk of asphyxia and stillbirth. On the other hand, in late FGR (defined as FGR >= 32 weeks of
gestation) management is relatively simple as the fetal organs are more mature and the incidence of significant neonatal morbidity based on prematurity is low, but late FGR is hard to detect as size can be within normal ranges and Doppler examination is often normal, and therefore it is often missed.
1
Figure 1 Schematic representation of the possible overlap between FGR and SGA and between AGA
and LGA.
From an immediate survival perspective, the optimal birth weight on a population level is suggested to be between the 80th and 84th percentiles as IUFD of unknown causes (as-sumed to be most likely from placental insufficiency) is lowest in those percentiles.(29) This even suggests that in the majority of pregnancies, the placenta is incapable to facilitate the fetus to reach the intrinsic growth potential completely, which may be an adequate evolu-tionary strategy. Because of the risk of cephalopelvic disproportion in larger birth weight and resulting higher risk of birth trauma, instrumental delivery and asphyxia.
The dashed line reflects the 3rd percentile.
FGR Fetal growth restriction; SGA Small for gestational age; AGA Appropriate for gestational age; LGA Large for gestational age.
Gold standard
FGR is, because of its healthcare implications, a frequently studied condition in perinatal care. Most studies are primarily focused on prevention, detection, or management of the disorder. But, in the shared attempt to reduce the health risks of FGR, it has been over-looked that there is no consensus on the basic principles of the condition. In particular, because of the lack of a gold standard, there is significant heterogeneity in defining the disorder.
“Gold standard” is a term borrowed from economists. It signifies a monetary standard, un-der which the basic unit of currency was defined by a stated quantity of gold. The value of each country’s method of payment was weighed against the gold standard, which made it possible to compare these different currencies for international trading.(30) A gold standard for diagnostic tests denotes the best general accepted tool available at that time to com-pare different measures.(31) For example, histopathological assessment of small intestinal biopsy is the current gold standard to diagnose celiac disease.(32)
Currently, there is no undisputed method to define FGR. From this follows that research-ers found different solutions in how to study FGR, starting from how to define their study population, the disorder itself and which outcomes to study. Although important advances have been made, this heterogeneity hampered pooling of data and structural synthesis of available evidence. This resulted in delays in the improvement of medical care in FGR.
Importance and challenges of detection of
Fetal growth restrictionSGA, let alone FGR, is a frequently missed diagnosis, with up to >80% not detected antena-tally.(33) Implementation of a standard biometry ultrasound at 30 weeks of gestational age in antenatal care improved the detection from 19% to 32% in the large Dutch IRIS study. (34) However, improved detection of SGA does not necessarily lead to improved perinatal outcome.(33-35)
1
The risks of inaccurate diagnosis of FGR, are on one hand overtreatment of the healthy SGA and on the other undertreatment of the unidentified FGR fetus, especially the ones with ‘normal’ growth/weight. For example, in case of a healthy small SGA baby, the monitoring of the pregnancy is intensified. Sometimes, especially in case of early SGA, additional (in-vasive) examination is offered like an amniocentesis with a small risk of preterm prelabour rupture of membranes (PPROM) and consequent delivery or infection. Also, it can be deci-ded to induce labor on false grounds with (relative) prematurity as a consequence. Further-more, after birth the child is exposed unnecessarily to invasive procedures such as glucose monitoring. On the other hand, the lack of vigilance that comes with under-diagnosis of FGR may result in under-treatment and (otherwise preventable) adverse events, such as (in the worst case) imminent fetal death.
One of the reasons that detection strategies and interventions have no effect on relevant adverse outcomes, may be that the study population is diluted by healthy SGA. Distinguish-ing true FGR from healthy SGA is important to focus on the group at risk for adverse out-come and to protect the healthy SGA from unnecessary, potentially harmful, interventions. Parameters that are used to make this differentiation focus on growth velocity, measures of placental function such as redistribution of blood flow in the fetus (to the brain). This is reflected in a low resistance in the middle cerebral artery, a process that is termed brain sparing.(36-39) However, extreme SGA, below the 3rd percentile on population based refe-rence charts is by itself a risk factor for poor outcome, even in the absence of other abnor-mal findings.(40)
Growth velocity is measured by sequential ultrasounds with a focus on declining growth or crossing of growth percentiles on reference charts. Placental function is generally measured by Doppler waveform analysis of the umbilical artery, uterine artery and ductus venosus (in early FGR). Serum biomarkers, usually reflecting protein secretion of the placenta, are currently frequently studied and promising in predicting placenta development and (dis) function, they are expected to gain importance in the future.
During pregnancy, detection of true FGR can prevent imminent IUFD by offering monitoring and optimize timing of delivery. Early adequate management directly after birth could help in preventive therapy for adverse long-term outcome.(41, 42) The recurrence risk of FGR rates up to 40%.(43) When correctly identified in the first pregnancy, the monitoring in the subsequent pregnancy can be adjusted and preventive measures can be taken (for example, prescribing acetylsalicylic acid). If the 10th percentile is used as cut-off to define a history of ‘FGR in previous pregnancy’ a mother who delivered a baby with a birthweight above the 10th percentile will not be prescribed acetylsalicylic acid in a next pregnancy, nor will the pregnancy be monitored adequately with sequential ultrasound scans, advised in high-risk pregnancies for FGR.(44, 45)
Definition of Fetal growth restriction
The diagnosis of FGR can be made during pregnancy in the fetus in singleton or multiple pregnancy, after birth in the newborn or after fetal demise in the stillborn. In each situation, other parameters are available and used to come to the diagnosis or to exclude it. Ante-natally, ultrasound biometric and Doppler measurements are mainly used, in the newborn period absolute weight and biometric measurements can be used whereas in the stillborn no functional measurements can be used and (postmortem) pathological parameters are more important.
FGR in singleton pregnancy
Historically terms like intrauterine growth restriction or fetal growth retardation were used. When the diagnosis is made during a singleton pregnancy the term fetal growth restriction is the most accurate term to use. It describes the subject of concern (the fetus), by defini-tion already intrauterine, and the failure to reach its growth potential without the connota-tion of mental retardaconnota-tion.
FGR in twin pregnancy
In twin pregnancy, there can be fetal growth restriction of either of both twins. The first, the so called ‘selective growth restriction’ refers to a condition where a conflict of interest in placental volume appears in mostly monochorionic twins. In this condition two fetuses are sharing one placenta; this placenta is then shared unequally. This selective fetal growth restriction puts the obstetrician in a complex monitoring-management decision model because one of the fetuses is unaffected by abnormal growth. Thus, early delivery will help the growth restricted twin, who is already affected by the condition, and additionally cau-sing serious prematurity related neonatal morbidity in the normally grown, healthy twin.
Growth restriction in the newborn (GRN)
Growth restriction in the newborn is diagnosed after birth in the live born and refers to the same condition as FGR, which is the antenatal version. Although the placenta function ceased, GRN still refers to the pathological condition during pregnancy due to placental insufficiency.
1 Growth restriction in IUFD
This refers to the condition of FGR that occurred prior to death in utero. The diagnosis of growth restriction diagnosis can be made prior to demise or in retrospect after delivery of the stillborn, which limits the diagnostic options because functional measurements cannot be applied because the placenta does not function anymore and biometric measurements, such as birth weight, are less accurate because of the weight loss during the intra-uterine interval after demise.
How to develop a definition, in lack of a gold standard?
In lack of a gold standard, and in lack of the opportunity to generate empirical evidence and thereby find absolute “truth”, expert consensus is the next best way to make decisions. Con-sensus is commonly used in daily medical care, patients (who hardly ever exactly match the patient for whom a protocol was developed) are treated based on consensus of the medical team in charge. This group-discussion and decision making on management and monitoring of patients based on knowledge and experience, eventually results in a shared strategy and clinical protocols. These group-discussions are however prone to bias. It is prone to authora-tive influences, is affected by local culture and has a high situational variability. For example, the opinion of the head of the department is weighed differently from the opinion of young-est intern. Also, the composition of the team highly influences the consensus outcome.(46) To be able to compare cohorts and improve care there has to be consensus on basic levels. For example, to be able to test the outcome of FGR, there has to be consensus on how to de-fine the condition. Consenting does not necessary mean that one fully agrees to it, it means there are no reasonable objections and one decides to consent and conform.
There are formal strategies to achieve and test consensus. These strategies are not methods to create new knowledge, but make the best use of already available information.
Figure 2 Illustration of the Pythia the High Priestess of the Temple of Apollo at Delphi Delphi procedure
The Delphi procedure was originally named after the oracle of Delphi; the high priestess of the Temple of Apollo at Delphi (Figure 2). By the end of 7th century BC the oracle was excelling and she was consulted until the 4th century AD. The oracle would answer questions put to her by visitors wishing to be guided in their future actions. The Delphic Oracle was the most prestigious and authoritative oracle among the Greeks, and she was the most powerful woman of the classical world.(47)
1
In current practice, a Delphi procedure is a consensus building procedure and the method of choice when the answer to a specific question cannot be answered by (empirical) evi-dence alone, in absence of a gold standard. It was originally developed by RAND coopera-tion in the 1950’s for informed intuitive judgment in forecasting of technology.(48) A Delphi procedure is a systematic interactive group communication process to reach consensus in an expert panel. The Delphi procedure acknowledges the value of an experts’ opinion, and his or hers experience and intuition. The strength of the procedure is highly influenced by selection of genuine- and ‘in the field’ respected experts.
The procedure consists of multiple rounds, in which the statements become more specific and precise in each round to stimulate convergence of opinion until consensus is reached. Anonymized results on group level of the previous round are presented to the panel mem-bers who completed the previous round in the subsequent round (Figure 3 ). In the subse-quent round the same items are presented for rating of their importance once more, with the group results in mind the panel members re-rate the items. This results in convergence of opinion. Anonymization prevents group pressure and influence of (socially) dominant individuals. Participating experts can revise their opinion at any point in the procedure because the procedure is an electronic questionnaire, this is less likely to occur in group discussions.(49, 50)
A Delphi procedure does not result in ‘’the absolute truth” and the results are inferior to empirical evidence. It is a dynamic process that is dependent on the wisdom (or foolish-ness) of the crowd (the selected experts) and in the future new insights and evidence will arise, in that case the procedure could be repeated to again establish consensus.
Figure 3 Schematic overview of the Delphi procedure
Objective
In this thesis, the aim is to come to a solid set of basic principles in which a definition for growth restriction is determined for singleton and twin pregnancies in the perinatal period. It is determined what basic principles should be adhered to when studies are designed for fetal growth restriction. Furthermore, the underlying methodology for consensus proce-dures is tested. Panel evaluations Round n Monitoring and feedback Panel evaluations Round n + 1 Report Drop-out
1
Outline of thesis
The thesis was structured following four research questions, which result in eight chapters.
Part 1: What are the effects of fetal growth restriction?
Part 2: Why is there a need for standardization in fetal growth restriction studies and
medi-cal care?
Part 3: Is there a possibility to come to consensus regarding how to diagnose fetal growth
restriction antenatal, postnatal and after fetal demise?
Part 4: How to improve the methodology in consensus procedures?
To address these research questions, seven studies were conducted. Chapter 2 is a review
of the outcomes of severe, early growth restriction. Chapter 3 describes an overview of
used building consensus methods and the need for standardization in FGR. Chapter 4 is an
overview of literature in definitions of FGR in singleton pregnancies over time presented in an editorial. Chapter 5-8 are describing Delphi procedures to come to consensus on
defi-ning FGR in singleton and twin pregnancies, FGR diagnosed in the newborn and FGR in in-tra-uterine fetal demise. In twin pregnancy, the procedure was also used to gain consensus on monitoring, management and outcome reporting. Chapter 9 is describing a study to test
the validity of the face-to-face consensus round in core outcome set development metho-dology. This was tested in two core outcome set procedures.
Illustration of the problem in personal life
It is 2019, me and two dear friends are pregnant and expecting to give birth. I was fortunate that there has never been any sign of fetal growth restriction in my pregnan-cy. My friends, however, were less lucky and both struggled with insecurities and fears due to the implications if the risk of harm for their babies would become reality. Friend A was 20 weeks pregnant when the baby was diagnosed with Tetralogy of Fallot (ToF) and a fetal size under the 3rd percentile. A normal QF-PCR and array was found in amniotic fluid retrieved at amniocentesis. During her pregnancy, the baby continued to grow on the same percentile, and there were no abnormal Doppler patterns. At 40 weeks of gestational age she was induced and delivered a girl with ToF, without syndro-mal abnorsyndro-malities and a birth weight on the 1st percentile.
Friend B had an uncomplicated pregnancy until 35 weeks of gestational age. Sequential fundal height measurements in primary midwifery care raised the suspicion of FGR. She was referred for a biometry ultrasound, which showed an estimated fetal weight (EFW) on the 5th percentile with a normal Doppler pattern. Structural ultrasound at 20 weeks had shown a growth within normal ranges and no structural abnormalities. Because there was no known pattern of fetal growth until that time, it was decided to induce birth at 38 weeks of gestational age. She delivered a boy with a birth weight be-low the 3rd percentile and a general scraggy impression suggesting it had been growth restricted.
Reflection
Both friends experienced the diagnostic difficulty that obstetricians face and how this translates into different definitions of the problems and varying strategies. During the pregnancy of friend A, the physicians doubted the diagnosis FGR. As the growth of the baby was repetitively according its own percentile, and there were no abnormal func-tional parameters (such as Doppler abnormalities). It was also questioned if the same definition could be used as in pregnancies without congenital abnormalities.
Friend B was suggested that the weight of the fetus could very well be physiologically small and consistent with expectations given her own posture, being petite herself.
1
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