Cerebral palsy and its medicolegal implications in low- resource settings - the need to establish causality and revise criteria to implicate intrapartum hypoxia: A narrative review.

The objective of this study was to establish scientific causality and to devise criteria to implicate intrapartum hypoxia in cerebral palsy (CP) in low-resource settings, where there is potential for an increase in damaging medicolegal claims against obstetric caregivers, as is currently the situation in South Africa. For the purposes of this narrative review, an extensive literature search was performed, including any research articles, randomised controlled trials, observational studies, case reports or expert or consensus statements pertaining to CP in low-resource settings, medicolegal implications, causality, and criteria implicating intrapartum hypoxia. In terms of causation, there are differences between high-income countries (HICs) and low-resource settings. While intrapartum hypoxia accounts for 10 - 14% of CP in HICs, the figure is higher in low-resource settings (20 - 46%), indicating a need for improved intrapartum care. Criteria implicating intrapartum hypoxia presented for HICs may not apply to low-resource settings, as cord blood pH testing, neonatal brain magnetic resonance imaging (MRI) and placental histology are frequently not available, compounded by incomplete clinical notes and missing cardiotocography tracings. Revised criteria in an algorithm for low-resource settings to implicate intrapartum hypoxia in neonatal encephalopathy (NE)/ CP are presented. The algorithm relies first on specialist neurological assessment of the child, determination of the occurrence of neonatal encephalopathy (by documented or verbal accounts) and findings on childhood MRI, and second on evidence of antepartum and intrapartum contributors to the apparent hypoxia-related CP. The review explores differences between low-resource settings and HICs in trying to establish causation in NE/CP and presents a revised scientific approach to causality in the context of low-resource settings for reaching appropriate legal judgments.

Clinical practice.

Basal ganglia and thalamus (BGT) hypoxic-ischaemic brain injury is currently the most contentious issue in cerebral palsy (CP) litigation in South Africa (SA), and merits a consensus response based on the current available international literature. BGT pattern injury is strongly associated with a preceding perinatal sentinel event (PSE), which has a sudden onset and is typically unforeseen and unpreventable. Antepartum pathologies may result in fetal priming, leading to vulnerability to BGT injury by relatively mild hypoxic insults. BGT injury may uncommonly follow a gradual-onset fetal heart rate deterioration pattern, of duration ≥1 hour. To prevent BGT injury in a clinical setting, the interval from onset of PSE to delivery must be short, as little as 10 - 20 minutes. This is difficult to achieve in any circumstances in SA. Each case needs holistic, multidisciplinary, unbiased review of all available antepartum, intrapartum and postpartum and childhood information, aiming at fair resolution without waste of time and resources.

Right of Reply.

To the Editor: The article by Bhorat et al. [1] in the SAMJ, entitled 'Cerebral palsy and criteria implicating intrapartum hypoxia in neonatal encephalopathy - an obstetric perspective for the South African setting', starts off by raising concerns about 'steep rises in insurance premiums, placing service delivery under serious threat'. It does not acknowledge any service delivery issues that already exist in the public sector obstetric services in South Africa (SA). According to Whittaker,[2] in 2019, there were 303 obstetricians and gynaecologists employed in the SA public sector and 579 in the private sector, and of those employed in the public sector, 190 were performing private sector work. That a large number of the children with cerebral palsy (CP) were delivered in the public sector service was not noted by Bhorat et al.,[1] nor was the fact that the overwhelming majority of court cases are against the state (not against individual doctors) in provinces and hospitals with significant medical staffing and resource issues. For example, the liabilities for Eastern Cape Province in the 2019/20 period were ZAR36 751 207 v. only ZAR33 155 in Western Cape Province for the same period.[2].

Cerebral Palsy and Criteria Implicating Intrapartum Hypoxia in Neonatal Encephalopathy - An Obstetric Perspective for the South African Setting.

The science surrounding cerebral palsy indicates  that it is a complex medical condition with multiple contributing variables and factors, and causal pathways are often extremely difficult to delineate. The pathophysiological processes are often juxtaposed on antenatal factors, genetics, toxins, fetal priming, failure of neuroscientific autoregulatory mechanisms, abnormal biochemistry and abnormal metabolic pathways. Placing this primed compromised compensated brain through the stresses of an intrapartum process could be the final straw in the pathway  to brain injury and later CP.  It is thus simplistic to base causation of cerebral palsy on only an intrapartum perspective with radiological 'confirmation', as is often the practice in medicolegal cases in South African courts. The present modalities (MRI and CTG when available) that retrospectively attempt to determine causation in courts are inadequate when used in isolation. Unless a holistic scientific review of the case including all contributing clinical factors (antepartum, intrapartum and neonatal), fetal heart rate monitoring, neonatal MRI if possible (and preferred) or late MRI, and histology (placental histology if performed) are taken into account, success for plaintiff or defendant currently in a court of law will depend on eloquent legal argument rather than true scientific causality. The 10 criteria set out in this document to implicate acute intrapartum hypoxia in hypoxic ischaemic encephalopathy/neonatal encephalopathy serve as a guideline in the medicolegal setting.

Maternal intravenous immunoglobulin: a non-invasive treatment option for Rhesus D-sensitised women with previous adverse pregnancy outcomes

Background. Maternal intravenous immunoglobulin (IVIG) may delay the onset and severity of fetal anaemia in Rhesus D (RhD)- sensitised pregnancies, thereby minimising the need for intrauterine transfusion and its associated complications. Objective. To compare the pregnancy outcomes of RhD-sensitised women who received antenatal IVIG with those who did not receive antenatal IVIG. Methods. This was a retrospective cross-sectional analysis of RhD-sensitised women who attended the Wits Fetal Medicine Centre (Johannesburg) from 1 January 2008 to 31 May 2018. Criteria for maternal IVIG administration were: (i) previous adverse pregnancy outcome (early neonatal death, intrauterine fetal death or miscarriage related to RhD sensitisation), (ii) women with high antibody titre levels (≥1:64) in the absence of fetal anaemia; and (iii) rising antibody titre levels. Maternal antibody titre levels, pregnancy and neonatal outcomes were compared in women who received IVIG v. those who did not receive IVIG. Results. Of the 42 RhD-sensitised women, 14 received IVIG. A greater proportion of women experienced a decrease in antibody titres in the IVIG v. no-IVIG group (43% v. 11%, respectively; p=0.04). Nine of the 10 women in the IVIG group with a previous adverse pregnancy outcome had a successful pregnancy outcome following IVIG treatment. Conclusion. Maternal IVIG may provide a successful pregnancy outcome in RhD-sensitised women with previous adverse pregnancy outcomes related to Rh disease, or women with raised or increasing maternal antibody titre levels who present in the first or early second trimester

Changes in verbal and visuospatial working memory from Grade 1 to Grade 3 of primary school: Population longitudinal study.

BACKGROUND: Adaptive working memory training is being implemented without an adequate understanding of developmental trajectories of working memory. We aimed to quantify from Grade 1 to Grade 3 of primary school (1) changes in verbal and visuospatial working memory and (2) whether low verbal and visuospatial working memory in Grade 1 predicts low working memory in Grade 3. METHOD: The study design includes a population-based longitudinal study of 1,802 children (66% uptake from all 2,747 Grade 1 students) at 44 randomly selected primary schools in Melbourne, Australia. Backwards Digit Recall (verbal working memory) and Mister X (visuospatial working memory) screening measures from the Automated Working Memory Assessment (M = 100; SD = 15) were used to assess Grades 1 and 3 (ages 6-7 and 8-9 years) students. Low working memory was defined as ≥1 standard deviation below the standard score mean. Descriptive statistics addressed Aim 1, and predictive parameters addressed Aim 2. RESULTS: One thousand seventy (59%) of 1802 Grade 1 participants were reassessed in Grade 3. As expected for typically developing children, group mean standard scores were similar in Grades 1 and 3 for verbal, visuospatial, and overall working memory, but group mean raw scores increased markedly. Compared to "not low" children, those classified as having low working memory in Grade 1 showed much larger increases in both standard and raw scores across verbal, visuospatial, and overall working memory. Sensitivity was very low for Grade 1 low working memory predicting Grade 3 low classifications. CONCLUSION: Although mean changes in working memory standard scores between Grades 1 and 3 were minimal, we found that individual development varied widely, with marked natural resolution by Grade 3 in children who initially had low working memory. This may render brain-training interventions ineffective in the early school year ages, particularly if (as population-based programmes usually mandate) selection occurs within a screening paradigm.

The value and role of non-invasive prenatal testing in a select South African population.

BACKGROUND: Concerns have been raised about the injudicious use of non-invasive prenatal testing (NIPT) using cell-free DNA (cfDNA), which often leads to inaccuracies in interpretation of the role and value of cfDNA in prenatal screening. OBJECTIVES:  To determine the value and role of NIPT in a select South African (SA) population. METHODS:  A retrospective review of patients who elected to have NIPT between 1 October 2013 and 30 June 2015 at the Morningside Mediclinic Maternal and Fetal Medicine Centre in Johannesburg, SA. Patients had NIPT after either combined first-trimester screening (CFTS) or a second-trimester ultrasound scan. Data were collected on details of the first- and/or second-trimester screening, results of the NIPT, invasive tests done, decisions made in the event of abnormal results, and pregnancy outcomes. RESULTS:  Overall, 3 473 first- and second-trimester fetal assessments were done at the centre during the study period, and 2.3% of patients (n=82) elected to have NIPT. The majority of these individuals elected to have NIPT on the basis of positive findings on CFTS, or markers of aneuploidy detected on a second-trimester ultrasound scan. Of the tests done, 97.6% produced results. Of those with no results, one did not meet quality metrics and the other had a low fetal fraction of cfDNA. There were two abnormal NIPT results, one indicating a high risk of trisomy 13 and the other a triploidy. Patients who screened negative elected not to have an invasive test. CONCLUSION:  The value of NIPT in this study was that it made it possible to avoid a number of invasive tests. NIPT had a role in contingency screening.

Delayed presentation and diagnosis of metastatic hepatocellular carcinoma in pregnancy.

Hepatocellular carcinoma (HCC) is rare in women of reproductive age. If diagnosed, the underlying cirrhosis is associated with infertility in the majority of cases. There is limited literature on HCC in pregnancy, even more so for cases of metastatic disease. We present a case of delayed presentation and diagnosis of metastatic HCC in pregnancy. A 30-year-old pregnant woman presented at 23 weeks' gestation and was diagnosed as HIV-infected, with anaemia. She was initiated on an efavirenz-based fixed-dose combination and oral haematinics. She subsequently presented at 32 weeks' gestation with dyspnoea, and was diagnosed with pre-eclampsia. She was also found to have hepatosplenomegaly and ascites. She went into spontaneous preterm labour at 32 weeks and 4 days. A diagnosis of metastatic HCC was made postpartum, based on the radiological findings and biochemistry. We discuss the challenges of diagnosing metastatic HCC in pregnancy.

Nuchal Translucency as a Method of First-Trimester Screening for Aneuploidy

Objective. To determine the effectiveness of nuchal translucency (NT) screening in predicting aneuploidy and structural abnormalities in a South African population. Study design. Descriptive study. Setting. Chris Hani Baragwanath Hospital fetal medicine unit. Outcome measures. An adjusted risk was derived from the combination of maternal age-related risk and the risk derived from NT screening. A positive screen was denoted by an adjusted risk of more than 1/300 and a negative screen by an adjusted risk of less than 1/300. In order to determine the number of undiagnosed abnormalities in the group; all babies were examined by a paediatrician at birth to detect and describe dysmorphic features. Results. A total of 428 patients underwent first-trimester screening between July 2003 and July 2005. Three per cent were lost to follow-up. Of the 415 patients analysed; 59 screened positive and 356 screened negative. The mean age for both groups of patients was 30.1 years. Of the 57 patients who screened positive; 24 elected to have chorionic villus sampling (CVS). This resulted in the detection of 6 chromosomal abnormalities and 2 structural abnormalities. Among the remaining 356 patients; who had screened negative; 2 had an increase in the adjusted risk when the risk was compared with the background risk; and 1 chromosomal abnormality was detected in this group; 8 elected to have CVS because of a previous history of a chromosomal abnormality; and there were no abnormalities among them. Conclusions. The use of these screening methods has enabled prenatal karyotyping to become cost effective; and allows concentration on pregnancies at highest risk for chromosomal abnormalities; regardless of age

Cervical length at 23 weeks' gestation--relation to demographic characteristics and previous obstetric history in South African women.

OBJECTIVES: To determine the distribution of cervical length in a routine population of singleton pregnancies; to examine the relationship between cervical length, demographic characteristics, and previous obstetric history; and to compare these data with data from a similar study undertaken in the UK. PATIENTS AND METHODS: The study was conducted among women attending routine antenatal clinics at Coronation, Johannesburg General and Chris Hani Baragwanath hospitals. Cervical length was measured by means of transvaginal ultrasound at 23 weeks' gestation in women with singleton pregnancies attending these clinics, as part of a multicentre randomised trial investigating the value of cerclage in a short cervix. The distribution of cervical length was determined and the significance of differences in median cervical lengths between subgroups was calculated according to maternal age, ethnic origin, maternal body mass index (BMI), cigarette smoking, alcohol intake, and previous obstetric history. RESULTS: Cervical screening was offered to women (N = 2 173) attending clinics for a 23-week scan during the study period (July 1999-September 2002). Most women (N = 1 920) accepted, while 253 declined. Complete outcomes (date and mode of delivery, gestation at delivery, birth weight, Apgar scores, maternal blood loss, whether the patient was cerclaged or not, and any complications) were obtained for 1 603 women who accepted screening. Cervical length was measured successfully in all cases. Median cervical length was 33.7 mm and in 64 cases (3.3%) the length was 15 mm or less. Significantly shorter cervical lengths were found in those with a history of previous miscarriage, preterm delivery, those aged less than 20 years and those with an abnormal BMI. Cervical length was not significantly shorter in black women than in coloured and white women. CONCLUSIONS: At 23 weeks' gestation the median cervical length in a South African population was 33.2 mm. In 3.3% of the population the length was < or = 15 mm. There was an association between cervical length, demographic characteristics and previous obstetric history.

Reduction of cesium concentration in ovine tissues following treatment with Prussian Blue labeled with 59Fe.

The effectiveness of Prussian Blue in reducing the radiocesium contamination in ovine tissues was investigated. Five ewes were fed 137Cs-contaminated wheat for 30 d. When the 137Cs concentration in milk had reached equilibrium, one animal, serving as the control, was slaughtered and the activity in its tissues was measured. Two ewes were offered daily 1 g of Prussian Blue labeled with 59Fe in the Fe(III) position, outside the complex anion. One week after the administration of Prussian Blue, these animals were slaughtered, 1 wk apart, and the level of 137Cs in their tissues was measured. Comparing the concentration of 137Cs in the blood and tissues of the Prussian Blue treated animals to the corresponding concentrations measured in the control, a considerable reduction in the radiocesium activity concentration is observed. However, 137Cs concentrations are maintained at non-zero (about 20%) values in the first 2 wk after the administration of Prussian Blue. This observation can be attributed to the fact that most of 137Cs binds to Prussian Blue in the animals' digestive tracts and the measured activity concentrations follow the elimination of cesium from tissues. Using a two-compartment mathematical model, we can predict the level of 137Cs in tissue, following the administration of Prussian Blue. Labeling Prussian Blue in the Fe(III)-position resulted in the measurement of a (2.4 +/- 0.02) % retention of Fe(III) in sheep.