Causes and circumstances of maternal death: a secondary analysis of the Community-Level Interventions for Pre-eclampsia (CLIP) trials cohort.

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation).

Associations Between Migraine and Adverse Pregnancy Outcomes: Systematic Review and Meta-analysis.

IMPORTANCE: Migraine is a highly prevalent disorder associated with cardiovascular diseases. Cardiovascular diseases are also associated with preeclampsia (PE). The adverse pregnancy outcomes PE, preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) and placental abruption share aspects in their pathophysiology, which are also found in patients with migraine, such as inflammatory stress and hypercoagulability. OBJECTIVE: To determine the association of adverse pregnancy outcomes including PE, PTB, LBW, SGA, and placental abruption with a history of migraine through a systematic review and meta-analysis. EVIDENCE ACQUISITION: MEDLINE (PubMed), the Cochrane Library, and EMBASE, were searched from inception to November 11, 2018. Cohort studies and case-control studies evaluating migraine history and pregnancy complications were eligible. RESULTS: Of 1388 screened references, 14 studies were included in the systematic review. There were higher risks of PE (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.51-2.85; I2 = 76%) and LBW (OR, 1.18; 95% CI, 1.03-1.34; I2 = 9%) in women with migraine compared with women without migraine. We observed no significant association between history of migraine and PTB (OR, 1.23; 95% CI, 0.97-1.55; I2 = 61%) or SGA (OR, 1.06; 95% CI, 0.98-1.15; I2 = 0%). CONCLUSIONS: A history of migraine is significantly associated with an increased risk of adverse pregnancy outcomes including PE and LBW. We hypothesize that shared pathophysiology due to underlying preclinical cardiovascular risk in women with migraine might play a role during pregnancy. RELEVANCE: Pregnant women with a history of migraine should be considered at higher risk of adverse pregnancy outcomes and should be informed, monitored, and treated preventively accordingly.

Cerebral white matter lesions, subjective cognitive failures, and objective neurocognitive functioning: A follow-up study in women after hypertensive disorders of pregnancy.

OBJECTIVE: Hypertensive disorders of pregnancy, like preeclampsia, are a leading cause of maternal and fetal morbidity/mortality worldwide. Preeclampsia can be complicated by the occurrence of convulsions (eclampsia). Women who experienced (pre)eclampsia more frequently report daily cognitive failures and showed increased emotional dysfunction several years later, but are not impaired on objective neurocognitive testing. In addition, women with preterm preeclampsia more often have cerebral white matter lesions (WML) on follow-up. We aimed to determine whether WML presence is related to cognitive dysfunction, anxiety, and depressive symptoms in (pre)eclamptic women. METHOD: Forty-one eclamptic, 49 preeclamptic, and 47 control women who had a normotensive pregnancy completed the Cognitive Failures Questionnaire (CFQ), the Hospital Anxiety and Depression Scale (HADS), and a broad neurocognitive test battery (visual perception and speed of information processing, motor functions, working memory, long-term memory, attention, and executive functioning). All underwent cerebral magnetic resonance imaging (MRI), and WML presence was recorded. Median elapsed time since index pregnancy was 6 years. Average age was 40 years. RESULTS: WML were more prevalent in women who had experienced preterm (pre)eclampsia (<37 weeks; 40%) than in controls (21%, p = .03). In (pre)eclamptic women, CFQ and HADS scores were higher than those in controls (44 ± 16.1 vs. 36 ± 11.0, p < .001, and 11 ± 6.3 vs. 8 ± 5.5, p < .001). There was no difference in objective cognitive performance as measured by neurocognitive tests. Subjective and objective cognitive functioning, anxiety, and depressive symptoms were not related to WML presence. CONCLUSION: Formerly (pre)eclamptic women report cognitive dysfunction, but do not exhibit overt cognitive impairment when objectively tested on average 6 years following their pregnancy. The presence of WML is not related to objective nor to subjective cognitive impairment, anxiety, and depressive symptoms. Longitudinal studies are needed to study whether the presence of WML is a risk factor for developing objective cognitive impairment in the long term.

Hypertensive Disorders of Pregnancy Appear Not to Be Associated with Alzheimer's Disease Later in Life.

BACKGROUND: After hypertensive disorders of pregnancy, more subjective cognitive complaints and white matter lesions are reported compared to women after normal pregnancies. Both have a causal relationship with Alzheimer's disease (AD). AIM: To investigate if women whose pregnancy was complicated by hypertensive disorders have an increased risk of AD. METHODS: A case-control study in women with AD from the Alzheimer Center of the VU University Medical Center Amsterdam and women without AD. Paper and telephone surveys were performed. RESULTS: The response rate was 85.2%. No relation between women with (n = 104) and without AD (n = 129) reporting pregnancies complicated by hypertensive disorders (p = 0.11) was found. Women with early-onset AD reported hypertensive disorders of pregnancy more often (p = 0.02) compared to women with late-onset AD. CONCLUSION: A reported history of hypertensive disorders of pregnancy appears not to be associated with AD later in life.

Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia.

OBJECTIVE: To assess the distribution of cerebral white matter lesions in women who had eclampsia, preeclampsia, or normotensive pregnancies. The pathophysiology of these lesions, more often seen in formerly eclamptic and preeclamptic women, is unclear but may be related to a predisposition for vascular disease, the occurrence of the posterior reversible encephalopathy syndrome, or both while pregnant. Assessing the distribution of such lesions may give insight into their pathophysiology and possible consequences. METHODS: This retrospective cohort study determined the presence, severity, and location of white matter lesions on cerebral magnetic resonance imaging scans of 64 formerly eclamptic, 74 formerly preeclamptic, and 75 parous control women. RESULTS: Formerly preeclamptic and eclamptic women have white matter lesions more often (34.4% [n=47] compared with 21.3% [n=16]; P<.05) and more severely (0.07 compared with 0.02 mL; P<.05) than parous women in a control group. In all women, the majority of lesions was located in the frontal lobes followed by the parietal, insular, and temporal lobes. CONCLUSION: White matter lesions are more common in women with prior pregnancies complicated by preeclampsia or eclampsia compared with parous women in a control group. In no group does regional white matter lesion distribution correspond to the occipitoparietal edema distribution seen in posterior reversible encephalopathy syndrome.

Cerebral white matter lesions and perceived cognitive dysfunction: the role of pregnancy.

OBJECTIVE: Women who suffered eclampsia or preterm preeclampsia are twice as likely to demonstrate cerebral white matter lesions (WML) on magnetic resonance imaging compared with age-matched women who had normotensive pregnancies, and they report more cognitive dysfunctions in everyday life. We aimed to determine whether pregnancy in and of itself has a relationship with the presence of WML and subjective cognitive dysfunction. STUDY DESIGN: Eighty-one parous women who had a normotensive pregnancy were matched for age with 65 nulliparous women and all underwent cerebral magnetic resonance imaging. Presence of cerebral WML was rated and blood pressure was measured. Subjective cognitive functioning was assessed using the Cognitive Failures Questionnaire. RESULTS: There was no difference in the presence (22% vs 19%) of WML between parous and nulliparous women. Age was a predictor for the presence of WML, whereas the presence of current hypertension was not. Average score on the Cognitive Failures Questionnaire was not different between both groups, nor related to WML. CONCLUSION: A history of pregnancy in and of itself is not related to the presence of cerebral WML and the perception of cognitive dysfunction. Because of the relationship with preterm preeclampsia and eclampsia, future research should focus on the clinical importance and development throughout the years of such cerebral WML in young women and focus on risk factors for cardiovascular disease.

Brain lesions several years after eclampsia.

OBJECTIVE: Eclampsia is thought to have no long-term neurological consequences. We aimed to delineate the neurostructural sequelae of eclampsia, in particular brain white matter lesions, utilizing high-resolution 3-Tesla magnetic resonance imaging (MRI). STUDY DESIGN: Formerly eclamptic women were matched for age and year of index pregnancy with normotensive parous controls. The presence and volume of brain white matter lesions were compared between the groups. RESULTS: MRI scans of 39 women who formerly had eclampsia and 29 control women were performed on average 6.4 +/- 5.6 years following the index pregnancy at a mean age of 38 years. Women with eclampsia demonstrated subcortical white matter lesions more than twice as often as compared with controls (41% vs 17 %; odds ratio, 3.3; 95% confidence interval, 1.05-10.61; P = .04). CONCLUSION: Cerebral white matter lesions occur more often in women who formerly had eclampsia compared with women with normotensive pregnancies. The exact pathophysiology underlying these imaging changes and their clinical relevance remain to be elucidated.

The influence of pregnancy and gender on perivascular innervation of rat posterior cerebral arteries.

The authors investigated the influence of pregnancy and gender on the density of trigeminal and sympathetic perivascular nerves in posterior cerebral arteries (PCA) and the reactivity to norepinephrine and calcitonin gene-related peptide (CGRP). PCAs were isolated from nonpregnant, late-pregnant, postpartum, and male rats, mounted and pressurized on an arteriograph chamber to obtain concentration-response curves to norepinephrine and CGRP. Arteries were immunostained for CGRP-, tyrosine hydroxylase-, and protein gene product 9.5 (PGP 9.5)-containing perivascular nerves, and nerve density was determined morphologically. Pregnancy had a trophic effect on trigeminal perivascular innervation (P < .01 vs male); however, this was not accompanied by a change in reactivity to CGRP. Sympathetic and PGP 9.5 nerve densities were not altered by pregnancy or gender, and there were no differences in reactivity to norepinephrine. Together, these results suggest that the increase in trigeminal innervation during pregnancy is more related to nociception than in controlling resting cerebral blood flow.

Self-reported cognitive functioning in formerly eclamptic women.

OBJECTIVE: Recently, persistent brain white matter lesions were demonstrated in eclamptic women when imaged 6 weeks after delivery. Moreover, many of these women complain about cognitive limitations years after the eclamptic pregnancy. Therefore, in a cohort of such women, we assessed cognitive failures in daily life. STUDY DESIGN: Thirty formerly eclamptic women completed the Cognitive Failures Questionnaire. Scores were compared with scores of formerly preeclamptic (n = 31) and healthy parous control participants (n = 30) with the use of a priori Student t test. Groups were matched in terms of current age and years elapsed since index pregnancy. RESULTS: Women who have had eclampsia scored significantly higher on the Cognitive Failures Questionnaire, compared with healthy parous control subjects (43.5 +/- 14.6 vs 36.1 +/- 13.9, respectively; P < .05). CONCLUSION: Women who have had eclampsia reported significantly more cognitive failures years after the index pregnancy. It is hypothesized that this might be due to some degree of cerebral white matter damage. This subjective assessment of cognitive function must be confirmed with objective neurocognitive testing and related to neuroimaging findings.

Pregnancy prevents hypertensive remodeling and decreases myogenic reactivity in posterior cerebral arteries from Dahl salt-sensitive rats: a role in eclampsia?

Previous studies have demonstrated that pregnancy prevents protective hypertension-induced remodeling of cerebral arteries using nitric oxide synthase (NOS) inhibition to raise mean arterial pressure (MAP). In the present study, we investigated whether this effect of pregnancy was specific to NOS inhibition by using the Dahl salt-sensitive (SS) rat as a model of hypertension. Nonpregnant (n = 16) and late-pregnant (n = 17) Dahl SS rats were fed either a high-salt diet (8% NaCl) to raise blood pressure or a low-salt diet (<0.7% NaCl). Third-order posterior cerebral arteries were isolated and pressurized in an arteriograph chamber to measure active responses to pressure and passive remodeling. Several vessels from each group were stained for protein gene product 9.5 to determine perivascular nerve density. Blood pressure was elevated in both groups on high salt. The elevated MAP was associated with significantly smaller active and passive diameters (P < 0.05) and inward remodeling in the nonpregnant hypertensive group only. Whereas no structural changes were observed in the late-pregnant hypertensive animals, both late-pregnant groups had diminished myogenic reactivity (P < 0.05). Nerve density in both the late-pregnant groups was significantly greater when compared with the nonpregnant groups, suggesting that pregnancy has a trophic influence on perivascular innervation of the posterior cerebral artery. However, hypertension lowered the nerve density in both nonpregnant and late-pregnant animals. It therefore appears that pregnancy has an overall effect to prevent hypertension-induced remodeling regardless of the mode of hypertension. This effect may predispose the brain to autoregulatory breakthrough, hyperperfusion, and eclampsia when MAP is elevated.