18. IUGR and Rh-Isoimmunization - Dr. Kestela.pptx

IUGR and Rh-Isoimmunization

1. Fetal growth restriction Ketsela Lemma​ MD,MPH , ObGyn,Fetomaternal medicine subspecialist

2. Introduction FGR is a common pregnancy complication that worldwide is a leading cause of stillbirth, neonatal mortality, and short- and long-term neonatal morbidity .

3. -- introduction Fetal weight is determined by Inherent genetic growth poten - tial , and health of the fetus, capacity of the mother to supply adequate quality and quantities of substrates required for growth, ability of placenta to transport these nutritional substrates to the fetus .

4. --introduction The genetic growth potential varies from race to race and from individual to individual and this variation is evident in population studies of healthy term newborns. Normal fetuses at either extreme of this normal biological distribution curve will be combined with others whose growth has been restricted or accelerated due to patholog - ical influences

5. -- introduction problems in diagnosing and managing pregnancies with impaired fetal growth are substantial. confusion between small and healthy and those who have a pathological restriction in their growth, our inability to know what is the growth potential of a given fetus , occurrence of FGR in patients without recognizable high-risk factors, difficulties in estimating gestational age.

6. Any one dealing with FGR should adress the following 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? How to manage the pregnancies afflicted by pathological fetal growth restriction (PFGR)

7. Definition FGR is defined as the failure of the fetus to meet its inherent growth potential due to a pathological factor , most commonly placental dysfunction. Clinically, this is reflected by a drop in fetal size percentiles over the course of gestation. However , fetal growth potential is difficult to determine , and serial assessments of fetal size to detect a drop in fetal weight percentile are usually not available.

8. Instead , care providers most commonly have only a “snapshot” of fetal weight estimation at a given point in time. In clinical practice, small for gestational age (SGA), defined as estimated fetal weight (EFW) or abdominal circumference below a certain threshold such as the 10th or 3rd percentile, is most commonly used to suspect FGR .

9. The use of SGA as a proxy for FGR has several limitations that need to be recognized. First , most SGA fetuses are constitutionally healthy small fetuses, whose smallness is merely the result of their predetermined growth potential (i.e. false-positive diagnosis of FGR). Second, some growth-restricted fetuses, depending on their original growth potential and timing of insult, may remain above the percentile threshold described above and may thus not be SGA (i.e. false-negative diagnosis of FGR )

10. Third, the use of SGA as a proxy for FGR is limited by the accuracy of sonographic fetal weight estimation, which has an estimation error of up to ±15%–20 %. Fourth Inaccurate estimation of gestational age Finally, the diagnosis of SGA is highly dependent on the growth chart being used, which can therefore have a considerable effect on the proportion of fetuses or infants flagged as SGA in a given population.

11. SGA VS FGR Antenatal distinguishing between pathologically growth-restricted fetus and a constitutionally small one, however, is imprecise . In fact, only approximately 30 % of fetuses with an estimated fetal weight (EFW) less than the 10th percentile are pathologically growth restricted.

12. ACOG defines FGR when the sonographic EFW is less than the 10th percentile for gestational age on a standardised population growth curve ., FIGO

13. Epidemiology Overall, the incidence of FGR depends upon the definition and population being used. Using the ACOG definition of FGR based upon population growth charts, 10% of fetuses will be diagnosed However, only 20–30% of these fetuses are small because of a pathological restriction of their growth (PFGR) and a majority are normal small for gestational age

14. Classification of FgR Symmetric versus asymmetric FGR . Symmetric FGR , in which there is a proportional reduction in all of the biometric parameters, traditionally has been attributed to insults that occur early in pregnancy when the main component of fetal growth is cellular hyperplasia

15. A symmetric FGR , in which estimated fetal weight is below normal primarily because of a decrease in abdominal circumference (with normal skeletal and cranial dimensions), has conventionally been ascribed to placental disorders, which is thought to impair the normal process of cellular hypertrophy in fetal growth and deposition of glycogen in the fetal liver .

16. Causes of Fetal Growth Restriction C an be divided into three basic categories: maternal, placental and fetal factors Maternal Factors Maternal disease E specially ones that lead to alterations in uteroplacental perfusion. HDP ( preeclampsia, chronic hypertension and superimposed preeclampsia ) preexisting diabetes, renal disease and autoimmune disease

17. Inadequate nutrition. Minor alterations in maternal nutrition are unlikely to result in growth restriction. Extreme undernourishment , however, affects fetal development.

18. Toxins. Maternal cigarette smoking is a well-established risk factor for FGR, 3- to 10-fold increased risk for delivering an SGA neonate. Use of illicit substances such as cocaine, amphetamines and heroin also increases the risk for development of FGR.

19. Placental Factors Abnormal placental lobation , abruption, chorioangiomas and velamentous cord insertions also increase risk for development of FGR. Deficient endovascular trophoblast invasion of implantation site, inadequate extravillous trophoblast invasion of maternal spiral arterioles and maldevelopment of the villous and fetoplacental vascular tree.

20. Fetal Factors Genetic factors . Fetal aneuploidy is one cause of FGR, with 19 % of growth-restricted fetuses demonstrating an abnormal karyotype Structural anomalies. More than 22% of infants with congenital anomalies manifest concurrent FGR. I nfection ( viral or parasitic infections.) Cytomegalovirus (CMV ), rubella, toxoplasmosis and malaria are most often implicated. .

21. Traditionally , these infections, especially when they occur early in pregnancy, have been thought to result in FGR secondary to insults to cellular proliferation. More recent data suggest that the mechanisms are more complex than simple cytopathic effects arrest in placental vascularisation , impairment of placental transport Multiple gestation.

22. Consequences of Fetal Growth Restriction Extensive , traversing antenatal period to adulthood . Increases risks of perinatal morbidity and mortality, with a substantial increase in both as birth weight falls below the 6th percentile for gestational age Indicated preterm delivery attendant consequences of prematurity such as respiratory distress (RDS), intraventricular hemorrhage (IVH ) and necrotising enterocolitis (NEC) are significantly worse in FGR neonates.

23. Low Apgar scores, hypothermia, hypoglycaemia , hypocalcaemia , polycythaemia and impaired immune function. Higher incidences of chronic medical issues such as bronchopulmonarydysplasia (BPD), pulmonaryhypertension , neurodevelopmental delay and cerebral palsy. As adults, increased risk for cardiovascular disease , metabolic syndrome and obesity.

24. Screening Fundal Height Fundal height, a measure from the maternal pubic symphysis to the uterine fundus, is a commonly used measure to screen for FGR in routine obstetric prenatal care. Existing data, however, suggest that there is insufficient evidence to determine whether this measurement is effective in identifying FGR

25. Serum Analytes

26. Uterine Artery Doppler Uterine artery Doppler velocimetry is an indirect measure of uterine artery vascular resistance . As gestation advances in normal pregnancies, there should be a progressive decrease in uterine vascular resistance, which is thought to reflect adequate trophoblastic invasion into maternal spiral arterioles. This results in appropriate uteroplacental blood flow, which in turn also contributes to proper maternal endothelial function .

27. Different recommendation ACOG-not recommend RCOG recommends screening high-risk populations between 20 and 24 week U terine artery Doppler velocimetry is not recommended for routine screening in any trimester, and the ACOG and RCOG disagree about the utility of second trimester screening in high-risk populations.

28. Ultrasonographic Biometry Ultrasonographic biometry remains the mainstay of screening for FGR . However , despite the increase in detection rate, there is no evidence that this improves outcome.

29. Diagnosis Ultrasonographic Biometry Based upon the ACOG Practice Bulletin on Fetal Growth Restriction,the diagnosis of FGR is made when the combined biometric measurements result in an EFW of less than the 10th percentile for gestational age compared with an appropriate reference population. A crucial issue, however, is how to optimally define the ‘reference population’, which remains a controversial topic.

30. Evaluation After the Diagnosis of FGR Confirmation of Gestational Age Detailed Anatomic Ultrasound Evaluation of amniotic fluid Evaluation for Aneuploidy Aneuploidy should be considered especially in cases with early-onset FGR or when anomalies are present .

31. Evaluation for Infection Although various viral and parasitic infections have been associated with FGR, the ones most commonly associated are CMV and toxoplasmosis malaria should also be considered in high-risk populations. Identification of Risk Factors Fetal growth restriction may predate clinically evident preeclampsia , and evaluation for this is warranted in the setting of a new diagnosis of FGR. Identification of any modifiable risks factors such as cigarette smoking or substance abuse should alsobe undertaken.

32. Ultrasound Serial biometry. Serial growth US examinations are used to assess both interval and overall fetal growth in pregnancies complicated by FGR . Although the optimal interval for repeat growth US examinations has not been established, experts suggest that repeat assessment should be performed between 2 to 4 weeks

33. Umbilical artery Doppler . Umbilical artery velocity waveforms are a reflection of placental vascular resistance, and secondary to ongoing angiogenesis of the fetoplacental vascular tree, demonstrate a progressive increase in diastolic flow as gestation progresses . Middle cerebral artery Dopplers .

34. Fetal venous Doppler. Evaluation of the fetal venous system is thought to reflect fetal ventricular function , with the premise that fetal acidosis will compromise cardiac function. In turn , this results in an increase in preload, and in conjunction with increased afterload secondary to placental vascular dysfunction, an absent or reversed a-wave (atrial contraction) within the ductus venosus (DV) or pulsations in the umbilical vein can be seen

35. Antenatal Testing Nonstress test and cardiotocography . Fetal heart rate ( FHR) characteristics are normally controlled through parasympathetic innervation , in which the vagus nerve innervates both the sinoatrial and atrioventricular nodes. This tonic influence results in decreased rates of firing, thereby controlling the FHR. The vagus nerve also transmits impulses that result in FHR variability . When a fetus is exposed to prolonged periods of uteroplacental insufficiency, a noradrenergic response through the fetal adrenals occurs . This supersedes vagal influence, leading to both fetal tachycardia and decreased variability . If this continues, there is ultimately myocardial depression that manifests as latedecelerations .

36. Biophysical profile . ,

37. Timing of Delivery Main goal of obstetric management of FGR is to attempt to time delivery when gestational age is maximized and exposure of a fetus to hypoxemia and acidemia is minimized.

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39. Rh- isoimmunization Ketsela L.

40. Isoimmunization is development of antibodies against antigens of another individual of same species. A ntigens present on human red blood cells (RBCs) are mainly ABO antigens (A, B, AB), rhesus D antigen (Rh-D) and infrequently other atypical rhesus (Rh) antigens like Cc, Ee , Kell (K), Duffy ( Fya ), Kidd ( Jka , JKb ). presence of particular antigens on RBCs confers an individual a specific blood group status. For example, if the RBCs of a person carry A, B and Rh-D antigens, the person’s blood group would be AB and Rh positive (expressed as AB positive) blood group

41. Rh isoimmunization is development of antibodies against Rh antigens present on surface of RBCs. Important Rh antigen responsible for majority of cases of severe Rh isoimmunization is Rhesus D antigen. O ther atypical Rh antigens with a potential to cause severe isoimmunization are c, E and Kell antigens. Rest of the Rh antigens (Duffy, Kidd, M and S) rarely cause significant problems

42. Pathophysiology An individual lacks antibodies against antigens, which are present on his own RBCs. However , if RBCs coated with different antigens (from another individual) gain entry into the circulation, reticuloendothelial sytem of recipient identifies these antigens on RBCs as foreign and mounts immune response to eliminate these cells .

43. A similar phenomenon occurs during Rh isoimmunization. Rh positive RBCs of the fetus gain entry into Rh negative maternal circulation via fetomaternal hemorrhage (FMH) resulting into formation of anti-D antibodies, which in turn pass to the fetus through placental circulation and destroy fetal RBCs to produce fetal anemia. FMH occurs throughout pregnancy and the amount of this hemorrhage increases with increasing gestation. Kleiheur – Betke test can detect fetal blood cells into maternal circulation by acid elution test.

44. Kleihauer – Betke Test- is the standard method to quantitate FMH The fetal blood has differential resistance to acid as compared to adult hemoglobin. A blood smear is prepared from the maternal blood and treated with the acid. This removes adult hemoglobin whereas fetal hemoglobin persists in the red cells. On subsequent staining, fetal cells appear rosepink in color whereas adult RBCs appear as ghost cells

45. Potential causes of FMH Unprovoked Idiopathicspontaneous Delivery Spontaneous abortion Ectopic pregnancy Abruption Antepartum haemorrhage Provoked Termination of pregnancy Amniocentesis Cordocentesis Chorionic villus sampling External cephalic version Trauma Manual removal of placenta

46. The Rh-D antigen on fetal cells, which is circulating in maternal blood, is recognized by maternal RES as foreign antigen. The RES responds with the formation of IgM antibodies against Rh-D antigen in small amount (initial response). Initial development of immunoglobulin is a slow process, and it can take anywhere from 5 to 15 weeks for a human antiglobulin titre to be detected after a sensitising event. With few exceptions, the maternal response to paternal antigen is not sufficient to have a significant effect on fetus in the sensitizing pregnancy

47. When there is second time exposure to this foreign antigen (during second pregnancy with an Rh-D positive pregnancy), the previously primed memory B cells respond more strongly with the formation of IgG antibodies (booster response). The initial response could be prevented if the fetal RBCs entering the maternal circulation are removed before they are detected by the maternal RES. This can be achieved by giving anti-D immunoglobulins to the mother so as to counteract appropriately for the FMH. This prophylaxis has drastically brought down the cases of isoimmunization throughout the globe

48. The IgM antibodies formed due to initial response cannot cross the placenta and gain entry into the fetal circulation and therefore do not affect the first sensitizing pregnancy. During the next pregnancy with Rh-D positive fetus, the IgG antibodies cross the placenta , bind to the Rh-D antigen on the fetal RBCs. These antibody-coated RBCs are trapped in the fetal spleen and are destroyed. This results in fetal anemia, the severity of which depends upon the amount of FMH and amount of antibody formation

49. Manifestations ( fetal response ) Rh isoimmunization of a pregnant mother may be responsible for varying severity of anemia in the fetus and newborn . Usually it is in the second or subsequent pregnancies that the fetus is affected. a fetus will initially have fetal anemia, this may manifest clinically as decreased fetal movements . If the condition persists and becomes more serious there would be extramedullary erythropoiesis in the liver and spleen- seen on ultrasound as hepatosplenomegaly .

50. In a profoundly anemic fetus initially there is increased cardiac output but hypoxic heart can no longer sustain and finally culminates in heart failure . manifested sonographically as hydropic changes like pleural effusion, pericardial effusion, ascites, subcutaneous edema and scalp edema . To compensate for reduced oxygen supply, placenta also enlarges which could be seen as placentomegaly on ultrasonography

51. By the time these hydropic changes are evident on ultrasound, it is quite late and fetus is very sick with a high fetal mortality. Therefore our aim remains to identify fetal anemia much before this terminal stage Fetal anemia is reflected on USG as increased middle cerebral artery (MCA) peak systolic velocity

52. Management Screening for Rh Isoimmunization Blood grouping and cross matching is performed in all pregnant women at the first visit If the woman is Rh-D positive no further testing for blood groups is required. When mother is Rh negative, the husband’s blood is tested for ABO grouping and Rh typing If the husband is Rh positive, virtually all guidelines recommend performing genotype of the father for Rh-D coding gene.

53. A homozygous father will inherit Rh-D gene to all his offspring and all the pregnancies will have potential for sensitization If the father is heterozygous, there is 50 % chance of fetus being Rh-D positive. Most of the western guidelines recommend finding the fetal blood group from circulating cell free fetal DNA in maternal blood When fetus is Rh-D negative no further testing required. If fetus is Rh-D positive, further follow- up is done

54. However in low income countries like ours the facilities for testing of zygosity for Rh-D gene and fetal blood group from circulating cell-free fetal DNA in maternal circulation are not available. Therefore a pregnancy, when mother is Rh-D negative and father is RhD positive, is considered potentially at risk of immunization. Small amount of FMH (total of less than 15 mL) is inevitable during the course of pregnancy.

55. To detect sensitization of mother, presence of anti-D antibodies in maternal circulation is usually detected by ICT It involves incubation of maternal serum with the RBCs carrying the particular Rh antigen against which the antibodies are being tested. Anti-human immunoglobulin is then added. It will cause agglutination of RBCs if they have adsorbed the antibodies

56. . The serial dilutions of maternal serum are mixed with the RBCs carrying D antigen and the reverse of maximum dilution which causes clumping of RBCs is denoted as the titer Mostly 1:16 or 1:32 is considered as the critical titer (potential to cause significant fetal anemia) which may vary with the laboratory. When ICT is negative the test is repeated every 4 week and if ICT is positive, mother is managed as an isoimmunized pregnancy.

57. Primary Prevention of Rh Isoimmunization For women who are not yet isoimmunized the aim is to prevent sensitization . It can be achieved by giving prophylactic dose of anti-D immunoglobulins to cover for the spontaneous fetomaternal hemorrhages and also any antepartum event which has potential to cause additional FMH

58. If no prophylaxis is given, it is estimated that 1 % of Rh-D negative women would develop antibodies by the end of first Rh-D positive pregnancy. Around 7–9 % of additional women would be sensitized at the time of delivery. Another 7–9 % would develop antibodies during 6 months following delivery.

59. Therefore around 17 % women would become sensitized by the second pregnancy The most effective strategy to reduce the incidence of Rh isoimmunization has been the introduction of antenatal and at birth anti-D prophylaxis. The occurrence of Rh-D sensitization in last few week of an uncomplicated pregnancy has been stated to be the single most reason for remaining cases of isoimmunization .

60. It may be due to either the inability to cover the potential events causing FMH or inadequate dose of anti-D. Therefore, clear instructions regarding the event-specific doses and timing could almost eliminate this condition. Also transfusion of Rh-D positive blood to Rh-D negative woman should be avoided and blood should be properly cross matched before transfusion so as to avoid possibility of isoimmunization against other minor red cell antigens.

61. Antenatal Prophylaxis If ICT is negative at the first visit, it is repeated at four weekly interval and if it remains negative on subsequent testing, prophylactic dose of anti-D immunoglobulin is given (300 lu deep intramuscularly) at 28–32 week of pregnancy. This will take care of the small amount of FMH and prevent isoimmunization . . One dose versus two doses There are various thoughts regarding the one dose of 300 lu at 28 week versus two doses of 100–120 lu each at 28 and 34 week .

62. Doses for different types of procedures In addition to routine prophylaxis, different situations which are considered to increase risk of FMH should be covered by anti-D prophylaxis. After checking for maternal blood type and antibody screening, 120–150 lu of intramuscular anti-D injection is given for the following obstetric conditions within 12 week of pregnancy Threatened abortion; miscarriage; induced abortion; ectopic pregnancy; molar pregnancy; and chorionic villus sampling

63. After 12 week of pregnancy, 300 lu of intramuscular anti-D for following conditions: All above conditions after 12 week; amniocentesis; external cephalic version; antepartum hemorrhage; retained placenta; and blunt trauma over the abdomen . Usually these doses prevent development of isoimmunization and take care of up to 15 mL of fetal RBCs.

64. Where severe FMH is suspected, Kleihauer – Betke test could be done to measure the amount of FMH and accordingly dose can be adjusted. Additional 10 lu of antiD should be given for every additional 0.5 mL of fetal RBCs in maternal circulation.

65. A few investigators have observed that if Rh negative mother does not deliver by 40 week and she has received prophylaxis at 28 week (12 week ago), the circulating antiD is not enough to take care of FMH occurring at this time and advise a second dose of anti-D at 40 week. However, there is not enough evidence and it is not a routine practice.

66. Postpartum Prophylaxis The FMH which occurs at the time of delivery is covered by prophylactic anti-D within 72 h of birth. A dose of 300 lu of anti-D is given when the baby’s blood group is Rh-D positive. If anti-D dose is missed within 72 h, it can be given up to 28 days of delivery with some benefit Secondary Prevention of Rh Isoimmunization Early Diagnosis Once ICT for Rh-D antibodies becomes positive in critical titer, pregnancy is managed as isoimmunized pregnancy.

67. The aim is to detect fetal anemia at the earliest and also to avoid events likely to increase the FMH (like external cephalic version, external trauma over the abdomen or invasive testing ). Weekly monitoring is performed with the antibody titer and ultrasonography . Ultrasound is performed for MCA-PSV and for any evidence of fetal hydrops (scalp edema, pleural effusion, pericardial effusion, ascites, and skin edema).

68. Antibody titers of 1:128 are considered to cause significant fetal anemia and once these titers are reached, the pregnancy is monitored closely by MCA-PSV Median values for MCA-PSV is for healthy nonimmunized pregnancies at different gestations are recorded and 1.5 MOM values are calculated. MCA-PSV above 1.5 MOM is considered to be associated with significant fetal anemia and is an indication for cordocentesis and intrauterine transfusion (IUT ).

69. Intrauterine Transfusion (IUT ) IUT is considered to be most effective in management of isoimmunized pregnancy where fetus is anemic and not mature enough to be delivered . If IUT is not done, fetus is at the risk of developing hydrops and dying in utero.

70. Tertiary Prevention of Rh Isoimmunization Once the baby has delivered, baby is carefully monitored for severe anemia and jaundice, and if required, postnatal exchange transfusion would save the baby . Prognosis Rh isoimmunization is one condition which had got a very good prognosis if managed properly and in expert hands.

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