In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations.

To examine temporal trends in early-onset compared with late-onset preeclampsia and associated severe maternal morbidity. The study included all singleton deliveries in Washington State between 2000 and 2008 (N=670,120). Preeclampsia onset was determined using hospital records linked to birth certificates. Severe maternal morbidity was defined as any potentially life-threatening condition. Logistic regression was used to obtain adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). The preeclampsia rate was 3.0 per 100 singleton births, and increased slightly from 2.9 to 3.1 between 2000 and 2008. Rates of early-onset and late-onset disease were 0.3% and 2.7%, respectively. The temporal increase was significant only for early-onset disease (4.5%/year; 95% CI 2.3-5.8%) after adjustment for changes in maternal characteristics. Maternal death rates were higher among women with early-onset (42.1/100,000 deliveries) and late-onset preeclampsia (11.2/100,000) compared with women without preeclampsia (4.2/100,000). The rate of severe maternal morbidity (excluding obstetric trauma) was 12.2 per 100 deliveries in the early-onset group (aOR 3.7, 95% CI 3.2-4.3), 5.5 per 100 deliveries in the late-onset group (aOR 1.7, 95% CI 1.6-1.9), and approximately 3 per 100 in women without preeclampsia. Early-onset preeclampsia conferred a substantially higher risk of cardiovascular, respiratory, central nervous system, renal, hepatic, and other morbidity. However, rates of obstetric trauma were significantly lower among women with preeclampsia. Women with early-onset and late-onset preeclampsia have significantly higher rates of specific maternal morbidity compared with women without early-onset and late-onset disease. : II.

One of the United Nations’ Millennium Development Goals of 2000 was to reduce maternal mortality by 75% in 15 y; however, this challenge was not met by many industrialized countries. As average maternal age continues to rise in these countries, associated potentially life-threatening severe maternal morbidity has been understudied. Our primary objective was to examine the associations between maternal age and severe maternal morbidities. The secondary objective was to compare these associations with those for adverse fetal/infant outcomes. This was a population-based retrospective cohort study, including all singleton births to women residing in Washington State, US, 1 January 2003–31 December 2013 (n = 828,269). We compared age-specific rates of maternal mortality/severe morbidity (e.g., obstetric shock) and adverse fetal/infant outcomes (e.g., perinatal death). Logistic regression was used to adjust for parity, body mass index, assisted conception, and other potential confounders. We compared crude odds ratios (ORs) and adjusted ORs (AORs) and risk differences and their 95% CIs. Severe maternal morbidity was significantly higher among teenage mothers than among those 25–29 y (crude OR = 1.5, 95% CI 1.5–1.6) and increased exponentially with maternal age over 39 y, from OR = 1.2 (95% CI 1.2–1.3) among women aged 35–39 y to OR = 5.4 (95% CI 2.4–12.5) among women aged ≥50 y. The elevated risk of severe morbidity among teen mothers disappeared after adjustment for confounders, except for maternal sepsis (AOR = 1.2, 95% CI 1.1–1.4). Adjusted rates of severe morbidity remained increased among mothers ≥35 y, namely, the rates of amniotic fluid embolism (AOR = 8.0, 95% CI 2.7–23.7) and obstetric shock (AOR = 2.9, 95% CI 1.3–6.6) among mothers ≥40 y, and renal failure (AOR = 15.9, 95% CI 4.8–52.0), complications of obstetric interventions (AOR = 4.7, 95% CI 2.3–9.5), and intensive care unit (ICU) admission (AOR = 4.8, 95% CI 2.0–11.9) among those 45–49 y. The adjusted risk difference in severe maternal morbidity compared to mothers 25–29 y was 0.9% (95% CI 0.7%–1.2%) for mothers 40–44 y, 1.6% (95% CI 0.7%–2.8%) for mothers 45–49 y, and 6.4% for mothers ≥50 y (95% CI 1.7%–18.2%). Similar associations were observed for fetal and infant outcomes; neonatal mortality was elevated in teen mothers (AOR = 1.5, 95% CI 1.2–1.7), while mothers over 29 y had higher risk of stillbirth. The rate of severe maternal morbidity among women over 49 y was higher than the rate of mortality/serious morbidity of their offspring. Despite the large sample size, statistical power was insufficient to examine the association between maternal age and maternal death or very rare severe morbidities. Maternal age-specific incidence of severe morbidity varied by outcome. Older women (≥40 y) had significantly elevated rates of some of the most severe, potentially life-threatening morbidities, including renal failure, shock, acute cardiac morbidity, serious complications of obstetric interventions, and ICU admission. These results should improve counselling to women who contemplate delaying childbirth until their forties and provide useful information to their health care providers. This information is also useful for preventive strategies to lower maternal mortality and severe maternal morbidity in developed countries.

Rigorous studies carried out by the National Center for Health Statistics show that previously reported increases in maternal mortality rates in the United States were an artifact of changes in surveillance. The pregnancy checkbox, introduced in the revised 2003 death certificate and implemented by the states in a staggered manner, resulted in increased identification of maternal deaths and in reported maternal mortality rates. This Commentary summarizes the findings of the National Center for Health Statistics reports, describes temporal trends and the current status of maternal mortality in the United States, and discusses future concerns. Although the National Center for Health Statistics studies, based on recoding of death certificate information (after excluding information from the pregnancy checkbox), showed that crude maternal mortality rates did not change significantly between 2002 and 2018, age-adjusted analyses show a temporal reduction in the maternal mortality rate (21% decline, 95% CI 13–28). Specific causes of maternal death, which were not affected by the pregnancy checkbox, such as preeclampsia, showed substantial temporal declines. However, large racial disparities continue to exist: Non-Hispanic Black women had a 2.5-fold higher maternal mortality rate compared with non-Hispanic White women in 2018. This overview of maternal mortality underscores the need for better surveillance and more accurate identification of maternal deaths, improved clinical care, and expanded public health initiatives to address social determinants of health. Challenges with ascertaining maternal deaths notwithstanding, several causes of maternal death (unaffected by surveillance artifacts) show significant temporal declines, even though there remains substantial scope for preventing avoidable maternal death and reducing disparities.

Pre-gestational diabetes mellitus is associated with increased risk of maternal and perinatal adverse outcomes. This systematic review was conducted to evaluate the effectiveness and safety of pre-conception care (PCC) in improving maternal and perinatal outcomes. Databases from MEDLINE, EMBASE, WEB OF SCIENCE, and Cochrane Library were searched, including the CENTRAL register of controlled trials, and CINHAL up until March 2019, without any language restrictions, for any pre-pregnancy care aiming at health promotion, glycemic control, and screening and treatment of diabetes complications in women with type I or type II pre-gestational diabetes. Trials and observational studies were included in the review. Newcastle-Ottawa scale and the Cochrane collaboration methodology for data synthesis and analysis were used, along with the GRADE tool to evaluate the body of evidence. The search identified 8500 potentially relevant citations of which 40 reports of 36 studies were included. The meta-analysis results show that PCC reduced congenital malformations risk by 71%, (Risk ratio (RR) 0.29; 95% CI: 0.21–0.40, 25 studies; 5903 women; high-certainty evidence). The results also show that PCC may lower HbA1c in the first trimester of pregnancy by an average of 1.27% (Mean difference (MD) 1.27; 95% CI: 1.33–1.22; 4927 women; 24 studies, moderate-certainty evidence). Furthermore, the results suggest that PCC may lead to a slight reduction in the risk of preterm delivery of 15%, (RR 0.85; 95% CI: 0.73–0.99; nine studies, 2414 women; moderate-certainty evidence). Moreover, PCC may result in risk reduction of perinatal mortality by 54%, (RR 0.46; 95% CI: 0.30–0.73; ten studies; 3071 women; moderate-certainty evidence). There is uncertainty about the effects of PCC on the early booking for antenatal care (MD 1.31; 95% CI: 1.40–1.23; five studies, 1081 women; very low-certainty evidence) and maternal hypoglycemia in the first trimester, (RR 1.38; 95% CI: 1.07–1.79; three studies; 686 women; very low- certainty evidence). In addition, results of the meta-analysis indicate that PCC may lead to 48% reduction in the risk of small for gestational age (SGA) (RR 0.52; 95% CI: 0.37–0.75; six studies, 2261 women; moderate-certainty evidence). PCC may reduce the risk of neonatal admission to intensive care unit (NICU) by 25% (RR 0.75; 95% CI: 0.67–0.84; four studies; 1322 women; moderate-certainty evidence). However, PCC may have little or no effect in reducing the cesarean section rate (RR 1.02; 95% CI: 0.96–1.07; 14 studies; 3641 women; low-certainty evidence); miscarriage rate (RR 0.86; 95% CI: 0.70–1.06; 11 studies; 2698 women; low-certainty evidence); macrosomia rate (RR 1.06; 95% CI: 0.97–1.15; nine studies; 2787 women, low-certainty evidence); neonatal hypoglycemia (RR 0.93; 95% CI: 0.74–1.18; five studies; 880 women; low-certainty evidence); respiratory distress syndrome (RR 0.78; 95% CI: 0.47–1.29; four studies; 466 women; very low-certainty evidence); or shoulder dystocia (RR 0.28; 95% CI: 0.07–1.12; 2 studies; 530 women; very low-certainty evidence). PCC for women with pre-gestational type 1 or type 2 diabetes mellitus is effective in improving rates of congenital malformations. In addition, it may improve the risk of preterm delivery and admission to NICU. PCC probably reduces maternal HbA1C in the first trimester of pregnancy, perinatal mortality and SGA. There is uncertainty regarding the effects of PCC on early booking for antenatal care or maternal hypoglycemia during the first trimester of pregnancy. PCC has little or no effect on other maternal and perinatal outcomes.