Journal Club Papers
Paper 1: Nationwide, Couple-Based Genetic Carrier Screening.
Kirk et al. for the Mackenzie’s Mission Investigators.
NEJM. 11 November 2024. D01: 10.1056/NEJMoa2314768
1 in 40 Australians are genetic carriers for spinal muscular atrophy (SMA); an autosomal recessive condition where the most severe phenotype is associated with neonatal death. In 2011, Mackenzie Casella was diagnosed with SMA without any previously known family history; she passed away at 7 months old. Her family vowed to improve access to education about SMA and reproductive carrier screening. The Australian Reproductive Genetic Carrier Screening Project (Mackenzie’s Mission) was launched in 2018 to do just this.
This study was designed to examine the feasibility, acceptability and outcomes for nation-wide, couple-based genetic carrier screening. Adult couples planning pregnancy or those pregnant <10 weeks’ gestation across Australia were eligible for funded screening for a panel of 1300 genes associated with 750 severe, child-onset conditions.
In addition to the uptake of screening, and the prevalence of couples identified with an increased chance of having a child with a relevant genetic condition, psychosocial outcomes were also examined, including self-reported decisional regret, health-related quality of life and anxiety.
Findings:
- Over 19,000 couples were offered inclusion in the study; 45.9% (10,244) underwent genetic carrier screening, with 9,107 (90.7%) of those completing screening.
- The study cohort was generally representative of the Australian population. However, couples were less likely to undergo genetic carrier screening if they already had two or more children, if they were from socioeconomically disadvantaged areas, or had no post-school education.
- Genetic carrier screening newly identified 175 (1.9%) couples at high risk of conceiving a child with an autosomal recessive or X linked condition. Most of these affected couples (n=134; 76.7%) planned to change their pregnancy management as a result, for example, through IVF with preimplantation genetic testing.
Follow-up:
- Half of screened couples (48.0%; n=4,449) responded to a survey within 3 months of disclosure of results. 98.9% felt screening was acceptable, reporting low overall decisional regret and no change to self-perceived health-related quality of life across all groups.
- Couples with an increased chance of having a child with a genetic condition reported significant anxiety, with a median State-Trait Anxiety Inventory score of 40 (IQR 30–50) within 3 months of disclosure of results (scores ≥40 are consistent with clinically significant anxiety).
Currently, parental carrier screening for Fragile X, spinal muscular atrophy and cystic fibrosis are covered by Medicare in Australia. The McKenzie’s Mission project has identified that extended panel screening of couples is feasible and acceptable to those planning a pregnancy or are in early pregnancy.
The study findings demonstrate that screening changes pregnancy planning among couples identified with a high chance of having a clinically important genetic condition. However, the high prevalence of anxiety in this group emphasises the need for appropriate counselling of couples prior to carrier screening and post disclosure support.
Paper 2: Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.
Moise et al.,
NEJM, 7 August 2024. DOI: 10.1056/NEJMoa2314466.
Haemolytic disease of the fetus and newborn (HDFN) occurs when there is incompatibility between maternal and fetal blood types – the mother’s immune system produces (allo)antibodies which can cross the placenta and attack fetal red blood cells, causing haemolytic anaemia. Current standard of care for HDFN consists of close monitoring and, when fetal anaemia arises preterm, repeated intrauterine transfusions. Such procedures carry a significant risk of preterm birth, preterm rupture of membranes, and fetal loss.
The current study proposes a novel solution. Nipocalimab is a monoclonal antibody that inhibits the transfer of alloantibodies from mother to fetus. It binds to FcRn, a molecule in placental cells that transports IgG (including alloantibodies) from the maternal, through the placenta and into the fetal compartment. Hence, Nipocalimab reduces maternal-fetal transfer of alloantibodies. This could protect fetal red blood cells and prevent (or delay) the need for transfusion.
This study was a phase II, open-label, single-group study designed to evaluate the safety and efficacy of nipocalimab among 13 women with previous, severe early-onset (<24 weeks’ gestation) HDFN.
- Women with a known positive fetus commenced weekly IV infusion of nipocalimab between 8–14 weeks’ gestation and continued until 35 weeks’ gestation. Intrauterine transfusion was performed in confirmed cases of fetal anaemia.
- There was no placebo group. Instead, the outcomes of the current pregnancy were compared with each woman’s most recent previous pregnancy complicated by severe, early-onset HDFN (a historical benchmark, with confirmed fetal anemia prior to 24 weeks gestation).
- The primary outcome was livebirth at ≥32 weeks’ gestation without the need for intrauterine transfusion.
When treated with nipocalimab, 54% of women (7/13) achieved the primary outcome (livebirth at ≥32 weeks’ gestation without intrauterine transfusion) – this is compared with a historical benchmark of 0% (i.e., no women in this study had previously had a livebirth ≥32 weeks’ gestation without transfusion).
- Eight (62%) women had previously experienced fetal loss, compared with only 1 woman (8%) following treatment with nipocalimab.
- In their previous pregnancies, 11 women (85%) had at least one intrauterine transfusion, compared with 6 women (46%) treated with nipocalimab.
- Serious or severe adverse events occurred in 6 women (46%) and 8 neonates (33%). Most of these events were related to HDFN.
In this study, nipocalimab was able to delay or prevent fetal anaemia and the need for intrauterine transfusions, showing promise for the treatment of severe, early-onset HDFN. However, this is a phase II trial, consisting of only 13 women and using a historical benchmark as a control group. While larger, studies will be required to confirm these findings, this offers hope to families at highest risk of fetal loss from HDFN.
Paper 3: Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer.
Turriff et al.,
NEJM, 3 January 2025. DOI: 10.1056/NEJMoa2401029
Non-invasive prenatal testing (NIPT) is increasingly used in Australia to screen for aneuploidy during pregnancy by sequencing cell-free fetal DNA circulating in the maternal bloodstream. Some women will receive anomalous NIPT results, unrelated to true fetal aneuploidy or insufficient fetal DNA in the sample. Turriff et al investigated women with unusual or ‘unreportable’ NIPT results to better understand the significance of this finding, with remarkable results.
Study cohort: adult women without known cancer, who were pregnant or <2 years postpartum, who received abnormal or non-reportable NIPT results from one of the 12 commercial labs in the United States between December 2019 – December 2023. These results were not explained by fetal aneuploidy or insufficient fetal fraction.
- Eligible women underwent a medical review, physical examination, full body MRI, cervical cancer screening, faecal occult blood test and serum tumour marker testing (CA-125, CA 15-3, CA 27.29, CA 19-9, CEA). Two independent investigators also visually stratified the NIPT sequencing traces, looking for patterns which were subsequently correlated with clinical outcomes.
246 participants were identified for potential inclusion; 107 completed screening and final analysis.
Of these, 52 (49%) were found to have a diagnosis of cancer, including 32 with a haematological malignancy, and 20 with a solid tumour. Most of these women (56%) were asymptomatic.
- Lymphoma was the most commonly diagnosed malignancy (n=31; 60%), followed by colorectal cancer (n=9; 17%) and breast cancer (n=4; 8%). Among the 20 women diagnosed with a solid tumour, 13 had Stage 4 disease.
Whole body MRI was the most sensitive and specific tool used in this study to identify maternal malignancy.
- In women without cancer (n=55), 15 (27%) had normal cell free DNA sequencing in-lab. Abnormal NIPT results were likely explained by fibroids (n=17; 31%) and confined placental mosaicism (n=8; 15%).
- There were 6 patterns of cell free DNA sequencing identified: normal (n=28), chromosomal gains and losses across at least three chromosomes (n=49), chromosomal gains only (n=11), chromosomal losses only (n=4), maternal copy-number variants (CNVs) (n=2) and borderline abnormal (n=11). The “chromosomal gains and losses” pattern was seen in 47 of the 52 women with cancer.
This paper provides practice-changing insights into the significance of an anomalous NIPT result, demonstrating the potential to identify women with cancer before symptoms occur. Further research may be needed before we begin ordering whole body MRIs for all patients with anomalous NIPT results.
Paper 4: Determining optimal timing of birth for women with chronic or gestational hypertension at term: The WILL (When to Induce Labour to Limit risk in pregnancy hypertension) randomised trial.
Magee et al.,
PLOS Medicine, 26 November 2024. DOI: 10.1371/journal.pmed.1004481
Chronic (arising prior to 20 weeks’ gestation) and gestational hypertension (arising at or beyond 20 weeks’ gestation) affect 7% of pregnancies, around half of which will reach term. There is currently no clinical consensus about the best time to deliver these pregnancies, although early term birth (37-38 weeks’ gestation) may reduce the risk of maternal complications and healthcare costs. The 2009 landmark HYPITAT trial showed that planned birth at 37 weeks was safer than expectant management for women with mild pre-eclampsia and gestational hypertension. The WILL (When to Induce Labour to Limit risk in pregnancy hypertension) study sought to determine the optimal timing of birth for women with chronic or gestational hypertension at term.
The WILL study was an open-label randomised controlled trial conducted across 50 centres in the UK.
- Women were eligible if they were ≥16 years old; had chronic or gestational hypertension (systolic BP≥140mmHg or diastolic BP≥90mmHg); and had a live singleton fetus at 36+0 to 37+6 weeks’ gestation. Exclusions – preeclampsia, severe hypertension (until resolved), or major fetal anomaly.
Women were assigned in a 1:1 ratio to:
- planned early term birth (either by induction of labour or elective caesarean section) at 38+0-3 weeks’ gestation (intervention) or
- usual care (based on national or local guidance) at term (controls)
The maternal coprimary outcome was a composite of poor maternal outcome (severe hypertension, maternal death, or maternal morbidity such as acute kidney injury, abruption, post-partum haemorrhage, ICU admission etc). The neonatal co-primary outcome was NICU admission for ≥4 hours.
Findings:
The trial aimed to recruit 1,080 participants (540/group) to detect a risk difference in poor maternal outcome of 8% but only 403 women were recruited and funding was withdrawn early due to COVID-19. As such, it was likely underpowered to examine its primary endpoint.
Women in the intervention group (N=201) were more likely than control women (n=202) to be taking an antihypertensive (93.6 vs 92.7%), but there were no other significant differences between groups.
Primary outcomes: there was no difference between groups in the maternal co-primary outcome (13.4% vs 11.9%; aRR 1.16 [95% CI 0.72, 1.87], p=0.538) nor the neonatal co-primary outcome (7.0% vs 6.9%; aRR 1.03 [95% CI 0.52, 2.08], p=0.912).
- There were increased rates of neonatal infection (71.4% vs 57.1%), hypoglycaemia (14.3% vs 7.1%), and poor condition at birth (35.7% vs 21.4%) among the intervention group – however, this was among only 14 infants admitted to the NICU.
- Women in the intervention group birthed an average of 6 days earlier (38.1 weeks vs 39.0 weeks). Only 22.2% of women in the usual care group went into spontaneous labour, and most ultimately required induction.
Secondary outcomes: there was no difference in caesarean delivery rates, however, there was a reduced risk of preeclampsia (27.9% vs 37.6%; aRR 0.74 [95% CI 0.56, 0.98], p=0.039) and requirement for antihypertensives postpartum (73.6% vs 86.1%; aRR 0.86 [95% CI 0.79, 0.95], p=0.002) among the intervention group.
Overall cost of pregnancy did not differ between groups, though there was a reduction in the amount spent on outpatient visits and tests for maternal or fetal wellbeing in the intervention group.
Among women with chronic or gestational hypertension, this trial found no significant difference in major maternal or neonatal adverse outcomes following planned birth at 38+0-3 weeks’. However, it was stopped early and was likely underpowered.
The trial found those induced earlier had reduced rates of preeclampsia or the requirement for anti-hypertensive medications. While statistically significant, it should be noted these were secondary outcomes. However, these findings seem plausible, given it aligns with findings from prior trials such as Hypitat.