Genetic Disorders and the Fetus. Группа авторов

Chapter 10) including whole‐exome sequencing (see Chapter 14). In circumstances in which parents steadfastly withhold permission for autopsy, radiographs, MRI, computed tomography, and needle liver biopsy for DNA could provide important information when a precise diagnosis has yet to be made.^1017–1019 In most stillbirths, the cause(s) is not determined. In the long QT syndrome, which has rarely been diagnosed in utero,¹⁰²⁰ and which we have diagnosed in the first month of life,¹⁰²¹ affected mothers have an increased risk of fetal death, not only due to an arrhythmia, but also to putative placental or myometrial dysfunction.¹⁰²² Moreover, stillbirth at ≥23 weeks of gestation in these mothers is associated with an increased risk of severe maternal morbidity, especially among those with comorbidities.¹⁰²³ MRI could provide a useful acceptable alternative when fetal anomalies are expected.¹⁰¹⁷ The autopsy is the last opportunity parents will have to determine causation, which may ultimately be critical in their future childbearing plans and also for their previous children. A formal protocol for evaluating the cause of stillbirth or perinatal death is important (Box 1.3) to secure a definitive diagnosis, thereby laying the foundation for providing accurate recurrence risks and future precise prenatal diagnosis. In the emotional chaos that invariably follows stillbirth, necessary actions may be forgotten. An action checklist (Box 1.4) serves to orient the process. In addition, in the face of known or suspected genetic disorders in which mutation analysis now or in the future may be critical, care should be taken to obtain tissue for DNA banking or for establishing a cell line. Later, parents may return and seriously question the failure of the physician to secure tissues or DNA that would have been so meaningful in future planning (e.g. X‐linked intellectual disability).

Box 1.3 Elements of a stillbirth evaluation

Key components	Details	Comments
Patient history	Family history Recurrent spontaneous abortionsStillbirthsMonogenic disorder(s)Congenital malformations or syndromesChromosomal disordersEthnicityConsanguinityNeurodevelopmental delayMaternal history: Previous venous thromboembolismDiabetes mellitusChronic hypertensionThrombophiliaSystemic lupus erythematosusAutoimmune diseaseEpilepsySevere anemiaHeart diseaseTobacco, alcohol, drug or medication useObstetric history: Recurrent miscarriagesPrevious child with congenital malformation, syndrome or genetic disorderPrevious child with intrauterine growth restrictionPrevious gestational hypertension or preeclampsiaPrevious gestational diabetes mellitusPrevious placental abruptionPrevious fetal demiseCurrent pregnancy:Maternal agePaternal ageGestational age at stillbirthMedical conditions complicating pregnancyCholestasisPregnancy weight gain and body mass indexComplications of multifetal gestation, such as twin–twin transfusion syndrome, twin reversed arterial perfusion syndrome, and discordant growthPlacental abruptionAbdominal traumaPreterm labor or rupture of membranesGestational age at onset of prenatal careIntrauterine growth restrictionAbnormalities seen on an ultrasound imageInfections or chorioamnionitis
Fetal autopsy	If patient declines, external evaluation by a trained perinatal pathologist. Other options include photographs, X‐ray imaging, ultrasonography, magnetic resonance imaging, and sampling of tissues, such as blood or skin. Freeze tissue for future DNA study If macerated tissue, request permission for needle biopsy of liver for DNA study	Provides important information in approximately 30% of cases
Placental examination	Includes evaluation for signs of viral or bacterial infection. Discuss available tests with pathologist	Provides additional information in 30% of cases. Infection is more common in preterm stillbirth (19 vs. 2% at term)
Fetal karyotype/microarray	Amniocentesis before delivery provides the greatest yield. Umbilical cord proximal to placenta if amniocentesis declined Whole‐exome or whole‐genome sequencing/from frozen tissue or needle biopsy	Abnormalities found in approximately 8% of cases
Maternal evaluation at time of demise	Fetal–maternal hemorrhage screen: Kleihauer–Betke test or flow cytometry for fetal cells in maternal circulationSyphilisLupus anticoagulantAnticardiolipin antibodiesβ2 glycoprotein antibodies	Routine testing for inherited thrombophilias is not recommended. Consider in cases with a personal or family history of thromboembolic disease
In selected cases	Indirect Coombs	If not performed previously in pregnancy
	Glucose screening (oral glucose tolerance test, hemoglobin A1C)	In the large‐for‐gestational‐age baby
	Toxicology screen	In cases of placental abruption or when drug use is suspected
Source: Modified from American College of Obstetricians and Gynecologists, Society for Maternal‐Fetal Medicine.1010

Box 1.4 Action checklist following stillbirth

      Psychologic support is important for couples who have lost an offspring from any cause – a situation compounded by fetal or congenital abnormality.^{1024, 1025} The birth (or prenatal detection) of twins discordant for a chromosomal disorder is not rare, given the increased frequency of multiple pregnancy associated with advanced maternal age and the use of assisted reproductive techniques. Pregnancy reduction¹⁰²⁶ (see Chapter 32), or the death of one twin, or delivery of both, evokes severely conflicting emotions that may well affect the mother's care for the surviving child.¹⁰²⁷ Considerable psychologic skill must be marshaled by physicians if meaningful care and support are to be provided.¹⁰²⁸

      Supporting telephone calls from doctor and staff, and encouragement to attend appointments every 6 weeks, or more frequently when appropriate, are often appreciated by patients. Review of the autopsy report and discussion with reiterative counseling should be expected of all physicians. Frequently, parents receive an autopsy report by mail without further opportunity for explanation and discussion. In one study, 27 percent failed to receive autopsy results.¹⁰²⁹ Providing contact with support groups whose focus is the disorder in question is also valuable. In the United States, the vast majority of these groups have combined to form the Alliance of Genetic Support Groups, which acts as a central clearinghouse and referral center.

      Family matters

Beyond all the “medical” steps taken in the wake of stillbirth or perinatal death due to fetal defects are critical matters important to the family and its future. Active, mature, and informed management is necessary in these difficult and frequently poignant situations. Regardless of the cause of the child's defect(s), maternal guilt is almost invariable and sometimes profound. Recognition of a definitive cause unrelated to a maternal origin should be explained in early discussions and reiterated later. For autosomal