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Multiple Pregnancy

Multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care, or multifetal gestation, is a pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care with more than 1 fetus. Multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care with more than 2 fetuses is referred to as a higher-order multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care and the most common type of multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care is a twin pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care. Due to advanced maternal age and evolving assisted reproductive technology Assisted Reproductive Technology Clinical and laboratory techniques used to enhance fertility in humans and animals. Reproductive Ethical Issues, the rates of multiple pregnancies have steadily increased over the past 3 decades. However, rates have slowly plateaued with the increase of the single embryo Embryo The entity of a developing mammal, generally from the cleavage of a zygote to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the fetus. Fertilization and First Week transfer. The perinatal mortality Mortality All deaths reported in a given population. Measures of Health Status and morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status rates of twin pregnancies are 3–7x higher than singleton pregnancies primarily because of higher rates of preterm delivery. Multiple pregnancies also carry a higher risk of obstetric complications such as congenital Congenital Chorioretinitis anomalies, preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders, and gestational diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus. Multiple pregnancies are classified as high-risk and require astute obstetric care.

Last updated: 3 Dec, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care is a pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care with more than 1 fetus.

Table: Important terminology of multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
Term Definition
Zygosity Refers to the genetic makeup of a twin pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
Monozygotic twins
  • Result from division of a single zygote Zygote The fertilized ovum resulting from the fusion of a male and a female gamete. Fertilization and First Week
  • Share the same genetic material
  • Identical twins
Dizygotic twins
  • Result from 2 separate eggs fertilized by 2 separate sperm
  • Share approximately 50% of the genetic material
  • Fraternal twins
Chorionicity The number of chorions (equal to the number of placentas)
Amnionicity The number of amnions surrounding the fetuses

Epidemiology

Statistics of the United States:

  • Twin births account for: 
    • 3% of live births 
    • 97% of multiple births
    • Dizygotic twins: 70% of all twin gestations in the absence of assisted reproductive technology Assisted Reproductive Technology Clinical and laboratory techniques used to enhance fertility in humans and animals. Reproductive Ethical Issues
    • ↑ Rate of monozygotic twins with assisted reproduction
  • Triplet and higher-order multiple births: 
    • 87.7 per 100,000 births
    • Approximately 80% are associated with medically assisted conception.

Risk factors

  • Prior history of multiple pregnancies
  • History of twins in the maternal family
  • Maternal weight and height: Women with a BMI BMI An indicator of body density as determined by the relationship of body weight to body height. Bmi=weight (kg)/height squared (m2). Bmi correlates with body fat (adipose tissue). Their relationship varies with age and gender. For adults, bmi falls into these categories: below 18. 5 (underweight); 18. 5-24. 9 (normal); 25. 0-29. 9 (overweight); 30. 0 and above (obese). Obesity ≥ 30 kg/m2 and ≥ 165 cm are at ↑ risk for dizygotic twin births.
  • ↑ Maternal age
  • Parity Parity The number of offspring a female has borne. It is contrasted with gravidity, which refers to the number of pregnancies, regardless of outcome. Pregnancy: Diagnosis, Physiology, and Care
  • Racial and ethnic variation:
    • ↑ In Nigeria 
    • ↓ In Japan
  • Assisted reproductive technology Assisted Reproductive Technology Clinical and laboratory techniques used to enhance fertility in humans and animals. Reproductive Ethical Issues or ovulation Ovulation The discharge of an ovum from a rupturing follicle in the ovary. Menstrual Cycle induction drugs

Classification and Diagnosis

Classification

  • Dizygotic twins are always dichorionic-diamniotic.
  • Monozygotic twins are classified based on the timing of cleavage after fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week (timing of cleavage determines chorionicity and amnionicity). 
Table: Classification of monozygotic twins
Time of cleavage after fertilization Fertilization To undergo fertilization, the sperm enters the uterus, travels towards the ampulla of the fallopian tube, and encounters the oocyte. The zona pellucida (the outer layer of the oocyte) deteriorates along with the zygote, which travels towards the uterus and eventually forms a blastocyst, allowing for implantation to occur. Fertilization and First Week Classification Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency
1–3 days Dichorionic-diamniotic 20%–25%
4–8 days Monochorionic-diamniotic 70%–75%
9–12 days Monochorionic-monoamniotic 1%–5%
≥ 13 days Monochorionic-monoamniotic (conjoined twins) Very rare

Diagnosis

Signs and symptoms:

  • Exaggerated early pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care symptoms (e.g., hyperemesis gravidarum)
  • Symphyseal-fundal height is greater than expected for gestational age Gestational age The age of the conceptus, beginning from the time of fertilization. In clinical obstetrics, the gestational age is often estimated as the time from the last day of the last menstruation which is about 2 weeks before ovulation and fertilization. Pregnancy: Diagnosis, Physiology, and Care.
  • ↑ Abdominal girth
  • ↑ Weight gain compared to singleton pregnancies

Ultrasound findings:

  • ≥ 2 fetuses and ≥ 2 heart activities 
  • Dichorionic-diamniotic:  
    • Lambda sign: a thick, triangular protrusion of tissue leading up to the intertwin membrane
    • Thick intertwin membrane
    • 2 separate placentas
  •  Monochorionic-diamniotic:
    • T sign: the interface between 2 amniotic membranes
    • Thin intertwin membrane
    • Single placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity
  • Monochorionic-monoamniotic:
    • No intertwin membrane
    • Single placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity

Management

General care

Multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care is considered a high-risk pregnancy High-Risk Pregnancy Prenatal Care.

  • Prenatal care Prenatal care Prenatal care is a systematic and periodic assessment of pregnant women during gestation to assure the best health outcome for the mother and her fetus. Prenatal care prevents and identifies maternal and fetal problems that adversely affect the pregnancy outcome. Prenatal Care requires: 
    • More frequent prenatal visits
    • More frequent ultrasounds to monitor fetal growth
    • Adequate maternal nutrition
    • Monitoring for maternal complications (e.g., gestational diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus and preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders)
    • Monitoring for fetal complications (e.g., congenital Congenital Chorioretinitis anomalies)
  • Chorionicity determination is essential in the 1st trimester:
    • Aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS in appropriate counseling of associated risks
    • Becomes less accurate after the beginning of the 2nd trimester

Mode of delivery

  • Depends on several factors, including:
  • Multiple pregnancies with > 2 fetuses are almost always delivered by cesarean section.
  • Triplet pregnancies may be delivered vaginally by experienced obstetricians.

Timing of delivery in uncomplicated cases

For twins the timing for delivery depends on chorionicity and amnioniticy:

  • Dichorionic-diamniotic: 38 0/7 weeks–38 6/7 weeks
  • Monochorionic-diamniotic: 34 0/7 weeks–37 6/7 weeks
  • Monochorionic-monoamniotic: 32 0/7 weeks–34 0/7 weeks

Maternal Complications

Multiple pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care presents higher risk to develop complications such as:

  • Hyperemesis gravidarum
  • Gestational diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus 
  • Hypertensive pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care disorders (e.g., preeclampsia Preeclampsia A complication of pregnancy, characterized by a complex of symptoms including maternal hypertension and proteinuria with or without pathological edema. Symptoms may range between mild and severe. Pre-eclampsia usually occurs after the 20th week of gestation, but may develop before this time in the presence of trophoblastic disease. Hypertensive Pregnancy Disorders)
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Excessive weight gain
  • Postpartum hemorrhage Postpartum hemorrhage Postpartum hemorrhage is one of the most common and deadly obstetric complications. Since 2017, postpartum hemorrhage has been defined as blood loss greater than 1,000 mL for both cesarean and vaginal deliveries, or excessive blood loss with signs of hemodynamic instability. Postpartum Hemorrhage (due to uterine atony or lacerations)
  • Miscarriages
  • Placental abnormalities Placental abnormalities Normal placental structure and function are essential for a healthy pregnancy. Some of the most common placental abnormalities include structural anomalies (such as a succenturiate lobe or velamentous cord insertion), implantation anomalies (such as placenta accreta and placenta previa), and functional anomalies (such as placental insufficiency). Placental Abnormalities (e.g., placenta previa Placenta Previa Abnormal placentation in which the placenta implants in the lower segment of the uterus (the zone of dilation) and may cover part or all of the opening of the cervix. It is often associated with serious antepartum bleeding and premature labor. Placental Abnormalities)
  • Increased risk for cesarean delivery Cesarean Delivery Cesarean delivery (CD) is the operative delivery of ≥ 1 infants through a surgical incision in the maternal abdomen and uterus. Cesarean deliveries may be indicated for a number of either maternal or fetal reasons, most commonly including fetal intolerance to labor, arrest of labor, a history of prior uterine surgery, fetal malpresentation, and placental abnormalities. Cesarean Delivery

Fetal Complications

Affecting all multiple pregnancies

  • Preterm labor Preterm labor Preterm labor refers to regular uterine contractions leading to cervical change prior to 37 weeks of gestation; preterm birth refers to birth prior to 37 weeks of gestation. Preterm birth may be spontaneous due to preterm labor, preterm prelabor rupture of membranes (PPROM), or cervical insufficiency. Preterm Labor and Birth and birth:
    • Resulting in prematurity Prematurity Neonatal Respiratory Distress Syndrome and associated complications such as:
      • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
      • Intracranial hemorrhage Intracranial hemorrhage Subarachnoid hemorrhage (SAH) is a type of cerebrovascular accident (stroke) resulting from intracranial hemorrhage into the subarachnoid space between the arachnoid and the pia mater layers of the meninges surrounding the brain. Most sahs originate from a saccular aneurysm in the circle of willis but may also occur as a result of trauma, uncontrolled hypertension, vasculitis, anticoagulant use, or stimulant use. Subarachnoid Hemorrhage
      • Sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
      • Cerebral palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies
    • Women with multifetal gestation are 6x more likely to give birth preterm.
  • Congenital Congenital Chorioretinitis anomalies 
  • Low birth weight
  • Discordant growth
  • Neonatal death

Monochorionic twins

Twin-to-twin transfusion syndrome:

  • Occurs in 10%–15% of monochorionic twins
  • Due to arterio-venous anastomosis with imbalanced blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure
  • Blood flows in a fixed direction from 1 fetus (donor) to another (recipient)
  • Donor twin: 
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Growth restriction
    • Oligohydramnios Oligohydramnios Oligohydramnios refers to amniotic fluid volume less than expected for the current gestational age. Oligohydramnios is diagnosed by ultrasound and defined as an amniotic fluid index (AFI) of ‰¤ 5 cm or a single deep pocket (SDP) of < 2 cm in the 2nd or 3rd trimester. Oligohydramnios 
  • Recipient twin: 
    • Polycythemia Polycythemia An increase in the total red cell mass of the blood. Renal Cell Carcinoma
    • Polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios
  • 5 stages (each stage is progressively worse)
  • Management depends on the stage and severity of compromise and may include:

Twin anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types polycythemia Polycythemia An increase in the total red cell mass of the blood. Renal Cell Carcinoma sequence (TAPS):

  • A form of atypical chronic twin-to-twin transfusion syndrome 
  • Due to sparse vascular anastomoses
  • Characterized by: 
    • Large difference in hemoglobin and reticulocyte Reticulocyte Immature erythrocytes. In humans, these are erythroid cells that have just undergone extrusion of their cell nucleus. They still contain some organelles that gradually decrease in number as the cells mature. Ribosomes are last to disappear. Certain staining techniques cause components of the ribosomes to precipitate into characteristic ‘reticulum’ (not the same as the endoplasmic reticulum), hence the name reticulocytes. Erythrocytes: Histology levels between the twins
    • Absence of oligohydramnios Oligohydramnios Oligohydramnios refers to amniotic fluid volume less than expected for the current gestational age. Oligohydramnios is diagnosed by ultrasound and defined as an amniotic fluid index (AFI) of ‰¤ 5 cm or a single deep pocket (SDP) of < 2 cm in the 2nd or 3rd trimester. Oligohydramnios and polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios
  • May occur either: 
    • Spontaneously 
    • Iatrogenically (after laser treatment for twin-to-twin transfusion syndrome) 
  • Management: In the absence of poor prognostic factors, expectant management is appropriate.

Twin reversed arterial perfusion (TRAP):

  • Approximately 1% of  monochorionic twins
  • Occurs when a twin with an absent/rudimentary heart is perfused by the other twin via abnormal placental anastomoses (artery-to-artery shunt) 
  • Donor twin: 
    • Also called the “ pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols twin” 
    • Suffers from high-output heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) (e.g., polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios and cardiomegaly Cardiomegaly Enlargement of the heart, usually indicated by a cardiothoracic ratio above 0. 50. Heart enlargement may involve the right, the left, or both heart ventricles or heart atria. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (heart failure) or several forms of cardiomyopathies. Ebstein’s Anomaly)  
  • Recipient twin: 
    • Also called the “acardiac twin”
    • Normally developed lower body, underdeveloped upper body
  • Management:

Monoamniotic twins

  • Umbilical cord Umbilical cord The flexible rope-like structure that connects a developing fetus to the placenta in mammals. The cord contains blood vessels which carry oxygen and nutrients from the mother to the fetus and waste products away from the fetus. Placenta, Umbilical Cord, and Amniotic Cavity entanglement 
  • Conjoined twins:
    • Very rare: approximately 1 per 50,000–100,000 births
    • Requires expert care during pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care and after delivery 
    • Separation after birth may be feasible but is associated with significant morbidity Morbidity The proportion of patients with a particular disease during a given year per given unit of population. Measures of Health Status and mortality Mortality All deaths reported in a given population. Measures of Health Status.

References

  1. Gabbe, S. G. (2017). Obstetrics: normal and problem pregnancies. (7th ed.). Elsevier. 
  2. Resnik, R., et al. (2019). Creasy and Resnik’s maternal-fetal medicine: Principles and practice. Elsevier.
  3. Cunningham, F. G. (2018). Williams obstetrics. New York: McGraw Hill Medical.
  4. Chasen, S. (2021). Twin pregnancy: Overview. In Barss, V.A. (Ed.), UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/twin-pregnancy-overview
  5. Mandy, G. T. (2020). Neonatal complications, outcome, and management of multiple births. In Kim, M.S. (Ed.), UpToDate. Retrieved August 24, 2021, from https://www.uptodate.com/contents/neonatal-complications-outcome-and-management-of-multiple-births 
  6. Hayes, E. J. (2021). Triplet pregnancy. In Barss, V.A. (Ed.), UpToDate. Retrieved September 15, 2021, from https://www.uptodate.com/contents/triplet-pregnancy
  7. Multifetal Gestations: Twin, Triplet, and Higher-Order Multifetal Pregnancies (2021). Obstetrics & Gynecology, 137(6). Retrieved September 15, 2021, from doi:10.1097/aog.0000000000004397 
  8. Moldenhauer, J. S. (2021). Multifetal pregnancy. MSD Manual Professional Version. Retrieved September 15, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/abnormalities-and-complications-of-labor-and-delivery/multifetal-pregnancy

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