Objective
Brain death (BD) during pregnancy might justify in select cases maternal somatic support to obtain fetal viability and maximize perinatal outcome. This study is a systematic review of the literature on cases of brain death in pregnancy with attempt to prolong pregnancy to assess perinatal outcomes.
Data Sources
We performed a systematic review of the literature using Ovid MEDLINE, Scopus, PubMed (including Cochrane database), and CINHAIL from inception to April 2020.
Study Eligibility Criteria
Relevant articles describing any case report of maternal brain death were identified from the aforementioned databases without any time, language, or study limitations. Studies were deemed eligible for inclusion if they described at least 1 case of maternal brain death.
Methods
Only cases of brain death in pregnancy with maternal somatic support aimed at maximizing perinatal outcome were included. Maternal management strategy, diagnosis, clinical course, fetal monitoring, delivery, and fetal and neonatal outcome data were collected. Mean, range, standard deviation, and percentage calculations were used as applicable.
Results
After exclusion, 35 cases of brain death in pregnancy were analyzed. The mean gestational age at diagnosis of brain death was at 20.2±5.3 weeks, and most cases (68%) were associated with maternal intracranial hemorrhage, subarachnoid hemorrhage, and hematoma. The most common maternal complications during the study were infections (69%) (eg, pneumonia, urinary tract infection, sepsis), circulatory instability (63%), diabetes insipidus (56%), thermal variability (41%), and panhypopituitarism (34%). The most common indications for delivery were maternal cardiocirculatory instability (38%) and nonreassuring fetal testing (35%). The mean gestational age at delivery was 27.2±4.7 weeks and differed depending on the gestational age at diagnosis of brain death. Most deliveries (89%) were via cesarean delivery. There were 8 cases (23%) of intrauterine fetal demise in the second trimester of pregnancy (14–25 weeks), and 27 neonates (77%) were born alive. Of the 35 cases of brain in pregnancy, 8 neonates (23%) were described as “healthy” at birth, 15 neonates (43%) had normal longer-term follow-up (>1 month to 8 years; mean, 20.3 months), 2 neonates (6%) had neurologic sequelae (born at 23 and 24 weeks of gestation), and 2 neonates (6%) died (born at 25 and 27 weeks of gestation). Mean birth weight was 1,229 grams, and small for gestational age was present in 17% of neonates. The rate of live birth differed by gestational age at diagnosis of brain death: 50% at <14 weeks, 54.5% at 14 to 19 6/7 weeks, 91.7% at 20 to 23 6/7 weeks, 100% at 24 to 27 6/7 weeks, and 100% at 28 to 31 6/7 weeks.
Conclusion
In 35 cases of brain death in pregnancy at a mean gestation age of 20 weeks, maternal somatic support aimed at maximizing perinatal outcome lasted for about 7 weeks, with 77% of neonates being born alive and 85% of these infants having a normal outcome at 20 months of life. The data of this study will be helpful in counseling families and practitioners faced with such rare and complex cases.
Introduction
The concept of brain death (BD) was first introduced by Mollaret and Goulon in 1959 ; however, their hypothesis was not supported by scientific data. After the first human heart transplantation, performed by Christiaan Barnard in 1967, when a beating human heart was harvested from a donor diagnosed as brain dead, the need of scientific criteria was strongly perceived. The following year, 1968, a Harvard ad hoc committee in the United States defined the neurologic criteria for the diagnosis of BD. BD was described as irreversible cessation of all functions of the entire brain defined by the persistence of 4 signs: complete abolition of consciousness and of any movements, abolition of cranial nerves reactivity, abolition of spontaneous respiration (absence of respiratory movements in the presence of hypercapnia), and flat electroencephalogram (EEG). After 1968, most countries of the world adopted these criteria mainly to allow the withdrawal of unnecessary vital support (ie, ventilator support) after a diagnosis of BD and, in selected cases, organ donation for transplantation. In fact, it is considered unethical and futile to continue to support vital organ functions after the diagnosis of BD; however, during pregnancy, prolonged maternal somatic support might be justified to obtain fetal viability and good perinatal outcome. , The complexity of BD in pregnancy requires a multidisciplinary approach, involving cooperation among obstetricians, neurosurgery or neurology, intensive care medicine, neonatology, anesthesiology, transplantation surgery, and ethics committee. To the best of our knowledge, there are limited data for prognosis and clinical guidance in maternal patients with BD. In this article, we reviewed the available cases of somatic support in pregnant women with BD, focusing on perinatal outcomes.
Why was this study conducted?
There are limited data on perinatal outcomes after brain death (BD) in pregnancy with maternal somatic support aimed at maximizing perinatal outcomes.
Key findings
In this systematic review of literature, the mean gestational age of 35 cases of BD in pregnancy was 20 weeks; maternal somatic support lasted for 7 weeks, with 77% of neonates being born alive and 85% of these infants having a normal outcome at 20 months of life. The rate of live birth differed by gestational age at diagnosis of BD: 50% at <14 weeks of gestation, 54.5% at 14 to 19 6/7 weeks of gestation, 91.7% at 20 to 23 6/7 weeks of gestation, 100% at 24 to 27 6/7 weeks of gestation, and 100% at 28 to 31 6/7 weeks of gestation.
What does this add to what is known?
As there is no systematic review on perinatal outcomes after BD in pregnancy with maternal somatic support, the data in this study will be helpful in counseling families and practitioners faced with such rare and complex cases.
Objective
This study aimed to evaluate by systematic review of literature all cases of BD during pregnancy with attempt at prolonging pregnancy with the aim of assessing perinatal outcomes.
Methods
Search strategy
This review was performed according to a protocol recommended for systematic review. The review protocol was designed a priori defining methods for collecting, extracting, and analyzing data. The search was conducted using Ovid MEDLINE, Scopus, PubMed, CINHAIL, and the Cochrane Library as electronic databases from inception to April 2020. Key words used in electronic searching included “maternal OR pregnancy AND brain death,” “maternal OR pregnancy” AND “brain death,” and “maternal OR pregnancy” AND “brain death” OR “brain death” (MeSH terms). No restriction for language or geographic location was applied. Reference lists of retrieved relevant articles were screened for finding additional studies.
Study selection and outcomes
All studies that reported at least 1 case of maternal BD during pregnancy with an attempt at prolonging pregnancy after BD were eligible for inclusion. We excluded studies dealing with pregnancy in a persistent vegetative state. Furthermore, we excluded studies that only discussed ethical and legal issues or with no maternal and perinatal outcome data. The primary outcome was neonatal live birth, assessed by trimester of pregnancy in which diagnosis of BD was made. Secondary outcomes included latency from gestational age at diagnosis of BD to delivery (days), assessed by gestational age in which diagnosis of BD was made; the evaluation of fetal monitoring methods (eg, cardiotocography [CTG], biophysical profile [BPP], ultrasound, fetal growth monitoring, and Doppler assessment), medical treatments (eg, steroids for fetal maturity), maternal medical complications and somatic support procedures (eg, nutrition and ventilatory support, drugs infusion, organ procurement), pregnancy-specific issues (eg, tocolytic use, indication for delivery, delivery mode), and fetal and neonatal outcomes.
Data extraction and analysis
All nonduplicate identified articles were independently reviewed by 2 authors (M.G.D. and A.S.), and relevant articles were selected by mutual agreement. Disagreement was resolved by discussion with a third reviewer (F.B. or V.B.). All articles were case reports or small series. Articles were deemed eligible for inclusion in our review if they described at least 1 case of maternal BD. There was no patient or public involvement in the study selection. There was no funding source involved in this study. For each case, we extracted maternal age, parity, cause of BD, diagnosis of BD, gestational age at diagnosis of BD, comorbidity before diagnosis of BD, maternal medical complications probably related and subsequent to BD, nutrition, and ventilatory support technique. In addition, we assessed fetal monitoring methods (CTG, BPP, ultrasound, biometry, and Doppler evaluation), use of steroids for fetal maturity and tocolytic use, medications used during life support, pregnancy outcomes (indication for delivery, gestational age of delivery, mode of delivery, organ procurement for transplantation), neonatal outcome (sex, weight, birthweight percentile, neonatal Apgar scores at 5 minutes, neonatal complications, and long-term outcomes). In our analysis, we particularly focused on the latency from diagnosis of BD to delivery, fetal monitoring, and pregnancy complications. We contacted available authors for additional information to try to get long-term neonatal outcomes. Means, standard deviations, ranges, and percentages were calculated using reported data points. Any data points that were not reported in case reports are explicitly stated in the tables below as NA (not available). This systematic review has been submitted to PROSPERO (identification number 218078).
Results
Initially, 1045 manuscripts were identified; after exclusion, 35 cases of BD in pregnancy from 35 manuscripts were included ( Figure 1 ). The mean age of the mothers was 27.8±5.8 years, and 55% of the patients were multiparous ( Table 1 ). When reported (n=34), the main causes for the BD were intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), or hematoma (68%); trauma (12%); suicide attempt (9%); and cerebral tumor or mass (6%) ( Table 1 ). Details on the diagnosis of BD were not reported in 66% of cases, with most cases (65%) reporting criteria for the diagnosis of BD listing EEG and clinical examination as criteria ( Table 1 ). The diagnosis of BD was made at a mean gestational age of 20.2 ±5.3 weeks; among the cases, 11% were in the first trimester of pregnancy, 83% were in the second trimester of pregnancy, and 6% were in the third trimester of pregnancy ( Table 1 ).
| Study, year | Country | Age of mother (y) | Parity | Cause of BD | Diagnosis of BD | Gestational age at BD (wk) |
|---|---|---|---|---|---|---|
| Dillon et al, 1982 | United States | 24 | 0 | Meningitis | Two EEG, 24 h apart, demonstrated no cerebral activity. Evoked brainstem showed no activity. | 23 |
| Friedman et al, 1983 | Israel | 25 | NA | ICH; SAH | “A clinical state of brain death was diagnosed on basis of deep coma, generalized flaccidity, no reflexes, frozen eyes with maximally dilated pupils and no response to light or ice water introduced into the external meatus of the ear.” | 33 |
| Heikkinen et al, 1985 | Finland | 31 | 3 | ICH and SAH | All brainstem reflexes were absent. | 21 |
| EEG was performed. | ||||||
| Apnea test was not performed. | ||||||
| Shrader, 1986 | United States | 27 | NA | NA | “Neurological examination shows no brain activity.” | 22 |
| Field et al, 1988 | United States | 27 | 0 | CNS mass | EEG was performed. | 22 |
| “Diagnosis of brain death was made using Harvard criteria.” | ||||||
| Bernstein et al, 1989 | United States | 30 | 3 | Traumatic brain injury | EEG was performed. Maternal temperature=35.9°C. | 15 |
| Auditory and visual evoked responses were absent. | ||||||
| Antonini et al, 1992 | Italy | 25 | 0 | ICH | EEG was performed. | 15 |
| Anstötz, 1993 | Germany | 18 | NA | Car accident | NA | 13 |
| Nettina et al, 1993 | United States | 31 | NA | ICH | NA | 27 |
| Béguin, 1993 | Switzerland | 20 | NA | ICH | NA | 20 |
| Wuermeling, 1994 | Germany | 18 | NA | Car accident | EEG was performed. Doppler-sonography of the arteries supplying the brain was performed. | 14 |
| Iriye et al, 1995 | United States | 35 | 2 | ICH after cocaine | EEG was performed. | 30 |
| Vives et al, 1995 | Spain | 25 | 1 | Meningitis | EEG was performed. | 27 |
| Catanzarite et al, 1997 | United States | 25 | 1 | ICH | NA | 25 |
| Lewis and Vidovich, 1997 | United States | 20 | NA | ICH; SAH | “The patient was pronounced brain dead based on two clinical examinations done 6 hours apart.” | 25 |
| Spike, 1999 | United States | 20 | NA | ICH | EEG was performed. Blood flow scan showed no cerebral blood flow. | 16 |
| Beca et al, 1999 | Chile | 26 | 0 | ICH | EEG was performed. | 18 |
| Apnea test was not performed. | ||||||
| Lane et al, 2004 | Ireland | 26 | NA | Cerebral venous sinus thrombosis | Brainstem tests were performed. | 13 |
| Hussein et al, 2006 | United Kingdom | 33 | 0 | ICH | NA | 26 |
| Souza et al, 2006 | Brazil | 40 | 0 | ICH | Transcranial Doppler scan of the cerebral arteries was performed. | 25 |
| Hurtado et al, 2007 | Mexico | 19 | 0 | Attempting suicide (gunshot) | NA | 19 |
| Mejía et al, 2008 | Argentina | 29 | 0 | ICH | EEG was performed. Auditory and somatosensitive evoked responses were absent. | 17 |
| Yeung et al, 2008 | United States | 26 | NA | Metastatic melanoma—hematoma in the right cerebellum | Evoked potentials were negative. | 15 |
| Woderska et al, 2012 | Poland | 40 | 4 | ICH | NA | 22 |
| Said et al, 2013 | United Arab Emirates | 35 | 2 | ICH | NA | 16 |
| Burkle et al, 2015 | United States | 32 | NA | ICH | NA | 22 |
| Kinoshita et al, 2014 | Japan | 32 | NA | Attempted suicide; cardiac arrest | “Standard brain death criteria of the Japanese Ministry of Health” | 20 |
| Wawrzyniak, 2015 | Poland | 30 | 3 | ICH | Apnea test and instrumental examination were not performed. | 22 |
| Nishimura et al, 2016 | Japan | 30 | 1 | Attempting suicide; cardiac arrest | NA | 23 |
| Gopčević et al, 2017 | Croatia | 34 | 2 | ICH | “Clinical testing to confirm the diagnosis of maternal brain death was performed twice. | 20 |
| Apnea test were not performed. | ||||||
| Confirmation of brain death by multi-slice computerized tomography contrast pan-angiography could only be confirmed after delivery.” | ||||||
| Holliday and Magnuson-Woodward, 2017 | United States | 36 | 4 | Anoxic brain injury secondary to cocaine | “Brain death testing was performed.” | 19 |
| Piskorz and Jakubiec-Wisniewska, 2019 | Poland | 29 | 0 | ICH | NA | 21 |
| Pikto-Pietkiewicz et al, 2019 | Poland | 27 | NA | ICH | NA | 13 |
| Reinhold et al, 2019 | German | 28 | NA | Traffic accident; ICH | Clinical examination was performed. | 9 |
| EEG was performed. | ||||||
| Boran et al, 2019 | Turkey | 21 | NA | Intracranial mass; ICH | Apnea test. | 19 |
| Transcranial Doppler ultrasonography. | ||||||
| Total | 27.8±5.8 y (25.0–31.5) | NA=15/35 (43%) | NA: 1/35 (3%) | NA: 12/35 (34%) | 20.2±5.3 wk (16–23) | |
| Multiparous=11/20 (55%) | ICH, SAH, or hematoma: 23/34 (68%) | Clinical examination: 8/23 (35%) | First trimester of pregnancy: 12.0±2.0 (4/35 [11%]) | |||
| Nulliparous=9/20 (45%) | Trauma: 4/34 (12%) | EEG+clinical examination: 7/23 (30%) | Second trimester of pregnancy: 20.6±3.8 (29 /35 [83%]) | |||
| Attempted suicide: 3/34 (9%) | EEG: 4/23 (17%) | Third trimester of pregnancy: 31.5±2.2 (2/35 [6%]) | ||||
| Cerebral tumor or mass: 2/34 (6%) | EEG+cerebral blood flow scan: 2/23 (9%) | |||||
| Cocaine: 2/34 (6%) | Transcranial Doppler scan of the cerebral arteries: 1/23 (4%) | |||||
| Meningitis: 2/34 (6%) | Apnea test+transcranial Doppler ultrasonography: 1/23 (4%). | |||||
| Cardiac arrest: 2/34 (6%) | ||||||
| Cerebral venous sinus thrombosis: 1/34 (3%) |
Comorbidities were reported in 14 of 22 cases (64%) reporting this variable. The most common complications possibly related to the BD in pregnancy were infections (69%) (eg pneumonia, urinary tract infection [UTI], sepsis), circulatory instability (63%), diabetes insipidus (DI) (56%), thermal variability (41%), and panhypopituitarism (34%) ( Table 2 ). Nutrition was enteral (43%), parenteral (33%), or a combination of these 2 methods (24%). When reported in the papers, 80% of the cohort of patients with BD was ventilated via a tracheostomy, whereas 20% of the cohort of patients with BD was ventilated via orotracheal intubation ( Table 2 ).
| Study, year | Comorbidity before diagnosis of BD | Maternal medical complications probably related and subsequent to BD | Nutrition | Ventilatory support |
|---|---|---|---|---|
| Dillon et al, 1982 | Seizures | Thermal variability, DI | Total parenteral nutrition | Intubated |
| Friedman et al, 1983 | No | NA | NA | NA |
| Heikkinen et al, 1985 | No | Thermal variability, pneumonia, hypotension, DI, aspiration pneumonia ( Pseudomonas bacteria), panhypopituitarism | E/P nutrition | Intubated |
| Shrader, 1986 | NA | DI | Total parenteral nutrition | NA |
| Field et al, 1988 | No | Thermal variability, panhypopituitarism, DI, ARDS, hypotension, UTI ( Klebsiella infection) | Total parenteral nutrition | NA |
| Bernstein et al, 1989 | NA | Thermal variability, panhypopituitarism, DI, pneumonia ( Pseudomonas , Acinetobacter , Haemophilus ) | Enteral nutrition | Tracheostomy |
| Antonini et al, 1992 | NA | Panhypopituitarism, pneumonia (Pseudomonas), UTI, hemodynamic instability, hyperglycemia, anemia | Total parenteral nutrition | NA |
| Anstötz, 1993 | NA | Severe infection | NA | NA |
| Nettina et al, 1993 | NA | Hypothermia; hypotension | NA | NA |
| Béguin, 1993 | NA | No complication | NA | NA |
| Wuermeling, 1994 | NA | Infection | NA | NA |
| Iriye et al, 1995 | Drugs abuse | Hypotension | NA | NA |
| Vives et al, 1995 | UTI and acute sinusitis 1 week earlier | Hypotension, sepsis, DIC, cardiac arrhythmia | NA | NA |
| Catanzarite et al, 1997 | NA | Hypotension, ARDS, DI, panhypopituitarism, aspiration pneumonia | E/P nutrition | NA |
| Lewis and Vidovich, 1997 | History of trauma 11 mo earlier | Hypotension, DI, sepsis | Total parenteral nutrition | NA |
| Spike, 1999 | NA | Panhypopituitarism, DI, thermal variability, hypotension | NA | NA |
| Beca et al, 1999 | No | Hemodynamic instability | NA | NA |
| Lane et al, 2004 | NA | DI, pneumonia, hyper- and hyponatremia | NA | NA |
| Hussein et al, 2006 | No | Anemia, circulatory instability (hypertension, bradycardia, and hypotension), pneumonia, adrenal insufficiency, hyperglycemia, hypothermia | Total parenteral nutrition | NA |
| Souza et al, 2006 | Metallic mitral valve prosthesis (childhood episode of rheumatic fever) in anticoagulant therapy | Panhypopituitarism, hyperglycemia, DI, hypotension, bradycardia, hypothermia, pneumonia | Enteral nutrition | Pressure-limited mechanical ventilation (first 10 d) Tracheotomy after ventilation-associated pneumonia |
| Hurtado et al, 2007 | NA | NA | E/P nutrition | NA |
| Mejía et al, 2008 | Acute otitis media treated with antibiotics | DI, panhypopituitarism, UTI, pneumonia, hemodynamic, instability | Enteral nutrition | NA |
| Yeung et al, 2008 | Metastatic malignant melanoma | Panhypopituitarism, DI, adrenal insufficiency, hyperparathyroidism | Total parenteral nutrition | Tracheotomy |
| Woderska et al, 2012 | Vascular malformation-related subarachnoid hemorrhage at 27 y | Circulatory failure, respiratory failure, respiratory, and UTI | NA | NA |
| Said et al, 2013 | Gestational diabetes mellitus | Several hypotension, hypertension, DI, hypernatremia, panhypopituitarism, hypothermia, sepsis because of pneumonia, UTI, line infection, meningitis | Enteral nutrition | Pressure-limited mechanical ventilation (first 18 d) Tracheotomy |
| Burkle et al, 2015 | NA | NA | NA | NA |
| Kinoshita et al, 2014 | Hypothyroidism | DI, hypothyroidism, hypotension | Enteral nutrition | NA |
| Wawrzyniak, 2015 | Hypertension, hypothyroidism, surgical intervention for cerebral aneurysm | Hypertensive crisis, hypotension, DI, hypothermia and hyperthermia, adrenal insufficiency, Candida sepsis, UTI, pneumonia | E/P nutrition | Pressure-limited mechanical ventilation (first 7 d) Tracheotomy |
| Nishimura et al, 2016 | Depression | Refractory seizure, circulatory instability, aspiration pneumonia | NA | NA |
| Gopčević et al, 2017 | No | Hypotension, DI, diabetes mellitus, hypothermia, pneumonia twice ( Haemophilus , Pseudomonas ), sepsis on 3 occasions ( Enterococcus , Acinetobacter , Pseudomonas ) | Enteral nutrition | Pressure-limited mechanical ventilation and then tracheotomy |
| Holliday and Magnuson-Woodward, 2017 | Hepatitis C, asthma, sleep apnea, and gestational diabetes mellitus | Hyperglycemia, low potassium, DI, panhypothyroidism, hypothermia, hypotension, hospital-acquired pneumonia | Enteral nutrition | Tracheotomy |
| Percutaneous endoscopic gastrostomy tube | ||||
| Piskorz and Jakubiec-Wisniewska, 2019 | NA | Disruption of the hypothalamic pituitary axis | NA | NA |
| Disorder of water, electrolyte, and acid base balance | ||||
| Pikto-Pietkiewicz et al, 2019 | No | ACTH deficit, hypothyroidism, DI, acute pancreatitis, sepsis, UTI, and pneumonia | E/P nutrition | Pressure-limited mechanical ventilation (first 12 d) Tracheotomy |
| Reinhold et al, 2019 | No | Hypopituitarism, severe DI, hypothyroidism, recurrent bacterial pneumonia, and UTI | Enteral nutrition | NA |
| Boran et al, 2019 | Gestational diabetes | Hypernatremia, pneumonia | Enteral nutrition | NA |
| Total mean value | NA: 13/35 (%) | NA: 3/35 (9%) | NA: 14/35 (40%) | NA: 25/35 (71%) |
| No: 8/22 (%) | Infections: 22/32 (69%) | Enteral: 9/21 (43%) | Tracheotomy: 8/10 (80%) | |
| Gestational diabetes mellitus: 3/22 (14%) | Pneumonia: 8/22 (36%) | Parenteral: 7/21 (33%) | Intubated: 2/10 (20%) | |
| Hypothyroidism: 2/22 (9%) | Pneumonia+UTI: 4/22 (18%) | E/P: 5/21 (24%) | ||
| Infection: 2/22 (9%) | Sepsis: 2/22 (9%) | |||
| Vascular malformation: 2/22 (9%) | UTI: 1/22 (5%) | |||
| History of trauma: 1/22 (5%) | Pneumonia + sepsis: 2/22 (9%) | |||
| Metallic mitral valve prosthesis: 1/22 (5%) | UTI+pneumonia+sepsis+meningitis: 1/22 (5%) | |||
| Metastatic malignant melanoma: 1/22 (5%) | Pneumonia+UTI+sepsis: 2/22 (9%) | |||
| Hypertension: 1/22 (5%) | Circulatory instability: 20/32 (63%) | |||
| Depression: 1/22 (5%) | DI: 18/32 (56%) | |||
| Hepatitis C: 1/22 (5%) | Thermal variability: 13/32 (41%) | |||
| Asthma: 1/22 (5%) | Panhypopituitarism: 11/32 (34%) | |||
| Sleep apnea: 1/22 (5%) | Diabetes mellitus or hyperglycemia: 5/32 (16%) | |||
| Seizure: 1/22 (5%) | Electrolytes disorders: 5/32 (16%) | |||
| Drug abuse: 1/22 (5%) | Adrenal insufficiency: 4/32 (13%) | |||
| Hypothyroidism: 4/32 (13%) | ||||
| ARDS or respiratory failure: 3/32 (9%) | ||||
| Anemia: 2/32 (6%) | ||||
| DIC: 1/32 (3%) | ||||
| Hyperparathyroidism: 1/32 (3%) | ||||
| Seizures: 1/32 (3%) | ||||
| Acute pancreatitis: 1/32 (3%) | ||||
| No complication: 1/32 (3%) |
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