M. Sean Esplin

PATERNAL AND MATERNAL COMPONENTS OF THE PREDISPOSITION TO PREECLAMPSIA

BACKGROUND There is an inherited maternal predisposition to preeclampsia. Whether there is a paternal component, however, is not known. METHODS We used records of the Utah Population Database to identify 298 men and 237 women born in Utah between 1947 and 1957 whose mothers had had preeclampsia during their pregnancy. For each man and woman in the study group, we identified two matched, unrelated control subjects who were not the products of pregnancies complicated by preeclampsia. We then identified 947 children of the 298 male study subjects and 830 children of the 237 female study subjects who had been born between 1970 and 1992. These children were matched to offspring of the control subjects (1950 offspring of the male control group and 1658 offspring of the female control group). Factors associated with preeclampsia were identified, and odds ratios were calculated with the use of stepwise logistic-regression analysis. RESULTS In the group whose mothers had had preeclampsia (the male study group), 2.7 percent of the offspring (26 of 947) were born of pregnancies complicated by preeclampsia, as compared with 1.3 percent of the offspring (26 of 1973) in the male control group. In the female study group, 4.7 percent of the pregnancies (39 of 830) were complicated by preeclampsia, as compared with 1.9 percent (32 of 1658) in the female control group. After adjustment for the offsprings year of birth, maternal parity, and the offsprings gestational age at delivery, the odds ratio for an adult whose mother had had preeclampsia having a child who was the product of a pregnancy complicated by preeclampsia was 2.1 (95 percent confidence interval, 1.0 to 4.3; P=0.04) in the male study group and 3.3 (95 percent confidence interval, 1.5 to 7.5; P=0.004) in the female study group. CONCLUSIONS Both men and women who were the product of a pregnancy complicated by preeclampsia were significantly more likely than control men and women to have a child who was the product of a pregnancy complicated by preeclampsia.

Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection

Objective. Pro-inflammatory chemokines have been associated with preterm parturition. Monocyte chemotactic protein-1 (MCP-1) is a chemokine capable of recruiting monocytes/macrophages into sites of inflammation, as well as stimulating the respiratory burst required for macrophage activation. MCP-1 transcripts and immuno-reactivity are expressed by uterine tissues (i.e., decidual cells and myometrium) and, thus, may participate in the process of labor. This study was conducted to determine if preterm labor leading to preterm delivery and intra-amniotic infection (IAI) are associated with changes in the amniotic fluid concentrations of MCP-1. Study design. A cross-sectional study was designed to examine the amniotic fluid concentrations of MCP-1 in women in two groups: 1) those presenting with preterm labor with intact membranes; and 2) those with preterm prelabor rupture of membranes (PROM). Amniotic fluid was obtained by transabdominal amniocentesis from 131 women in preterm labor with intact membranes and 105 women with preterm PROM. IAI was defined by a positive amniotic fluid culture for microorganisms. Group 1 included women with preterm labor and intact membranes (n = 131), and was subdivided into the following groups: a) delivery at term in the absence of IAI (n = 42); b) preterm delivery ( < 37 weeks) in the absence of IAI (n = 58); and c) preterm delivery in the presence of IAI (n = 31). Group 2 consisted of women with PROM (n = 105), and was subdivided into women with (n = 51) and without (n = 54) IAI. Non-parametric statistics were used for data analysis. Results. 1) Immuno-reactive MCP-1 was detected in all amniotic fluid samples; 2) IAI, regardless of the membrane status, was associated with a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those without IAI (p < 0.001 for both comparisons); 3) women in preterm labor who delivered preterm without IAI had a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those who delivered at term (p < 0.001); 4) histological chorioamnionitis was associated with increased amniotic fluid concentrations of immuno-reactive MCP-1; and 5) a significant relationship existed between the amniotic fluid concentrations of immuno-reactive MCP-1 and the interval from amniocentesis to delivery. Conclusions. Amniotic fluid concentrations of immuno-reactive MCP-1 were increased in women in preterm labor with IAI, those without IAI who delivered preterm, and those who displayed acute inflammatory lesions in the extra-placental membranes. These findings suggest that MCP-1 may play a role in preterm labor regardless of the presence of IAI.

Current understanding of genetic factors in preterm birth

Several lines of evidence support a genetic predisposition to spontaneous preterm labour and preterm birth. Firstly, a leading risk factor for spontaneous preterm labour and preterm birth is a personal or family history. If a woman previously delivered preterm, her subsequent babies are also more likely to be born preterm. Women who experienced an early preterm birth (<32 completed weeks) in their first pregnancy have the highest rate of recurrent preterm birth in subsequent pregnancies. Spontaneous preterm labour and preterm birth in subsequent pregnancies tend to recur at equivalent gestational ages. If a woman herself was born preterm, she is also at an increased risk of spontaneous preterm labour and preterm birth, with the risks being highest for those women who themselves were born most preterm. This predisposition does not apply to men who were born preterm. Racial predispositions to preterm birth have also been observed. Black women suffer twice the rate of preterm birth compared with Caucasians, even when confounding social and economic variables are controlled. It is well established that upper genital tract infection and/or inflammation is seen in association with spontaneous preterm labour and preterm birth. Previous investigations have focussed primarily on an infectious aetiology for this finding. However, an alternative hypothesis has emerged, which suggests that this finding may represent an abnormal inflammatory response. The frequent association of spontaneous preterm labour and preterm birth with histological infection/inflammation and elevated body fluid concentrations of inflammatory cytokines has focussed investigations on single gene polymorphisms of these cytokines in both mother and fetus. The polymorphisms tumour necrosis factor‐α‐308 (TNF‐α‐308), interleukin‐1β (IL‐1β) + 3953/3954 and IL‐6–174 have been most consistently associated with spontaneous preterm labour and preterm birth. Toll‐like receptors (TLRs) are important components of the innate immune systems, which have also been linked to spontaneous preterm labour and preterm birth. Both maternal and fetal polymorphisms of the TLR‐4 gene have been associated with spontaneous preterm labour and preterm birth in certain populations, but in others no apparent link has been observed. These findings confirm a clear genetic predisposition to spontaneous preterm labour and preterm birth and raise hopes that patient‐specific therapies may be developed in the future.

17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm

OBJECTIVE We sought to evaluate whether 17 alpha-hydroxyprogesterone caproate (17-OHP) reduces preterm birth (PTB) in nulliparous women with a midtrimester cervical length (CL) <30 mm. STUDY DESIGN In this multicenter randomized controlled trial, nulliparous women with a singleton gestation between 16 and 22 3/7 weeks with an endovaginal CL <30 mm (<10th percentile in this population) were randomized to weekly intramuscular 17-OHP (250 mg) or placebo through 36 weeks. The primary outcome was PTB <37 weeks. RESULTS The frequency of PTB did not differ between the 17-OHP (n = 327) and placebo (n = 330) groups (25.1% vs 24.2%; relative risk, 1.03; 95% confidence interval, 0.79-1.35). There also was no difference in the composite adverse neonatal outcome (7.0% vs 9.1%; relative risk, 0.77; 95% confidence interval, 0.46-1.30). CONCLUSION Weekly 17-OHP does not reduce the frequency of PTB in nulliparous women with a midtrimester CL <30 mm.

Proteomic identification of serum peptides predicting subsequent spontaneous preterm birth

OBJECTIVE We sought to identify serum markers of subsequent spontaneous preterm birth (SPTB) in asymptomatic women prior to labor. STUDY DESIGN Serum proteomics was applied to sera from 80 pregnant women sampled at 24 weeks and an additional 80 pregnant women sampled at 28 weeks. Half had uncomplicated pregnancies and half had SPTB. RESULTS Three specific peptides arising from inter-alpha-trypsin inhibitor heavy chain 4 protein were significantly reduced in women at 24 and 28 weeks having subsequent SPTB. The most discriminating peptide had a sensitivity of 65.0% and specificity of 82.5%; odds ratio, 8.8; and 95% confidence interval, 3.1-24.8. A combination of the 3 new biomarkers and 6 previously studied biomarkers increased sensitivity to 86.5%, with a specificity of 80.6% at 28 weeks. CONCLUSION Three novel serum markers of SPTB have been identified using serum proteomics. Using a combination of these new markers with additional markers, women at risk of SPTB can be identified weeks prior to SPTB.

Progression of Pulmonary Arteriovenous Malformation During Pregnancy: Case Report and Review of the Literature

Pulmonary arteriovenous malformations (PAVM) expand during pregnancy because of increases in blood volume, cardiac output, and venous distensibility. More than half of the cases reported during pregnancy are associated with hereditary telangiectasia. In this case a 36-year-old primigravida presented at 24 weeks of gestation with new onset hemoptysis and dyspnea. A PAVM was noted in the right lower lobe during angiography and was successfully treated with embolization. Recurrence of symptoms occurred at 36 weeks of gestation after recanalization of the PAVM. Cesarean delivery was performed because of both this recurrence and breech presentation. The patients symptoms subsequently resolved after delivery. The patient underwent a segmentectomy without complication 6 months after delivery. Thus, women with known PAVM or a history of hereditary telangiectasia should be followed with serial chest roentgenograms and arterial blood gases to detect acute progression of the PAVM. Embolization can be used during pregnancy if the PAVM is symptomatic.

Outcomes of expectantly managed preterm premature rupture of membranes occurring before 24 weeks of gestation

OBJECTIVE: To assess contemporary outcomes in expectantly managed preterm premature rupture of membranes (PROM) before 24 weeks of gestation. METHODS: We analyzed all patients with singleton pregnancies and preterm PROM before 24 weeks of gestation from 2001 to 2007. Patients immediately electing delivery, delivering within 12 hours of preterm PROM, carrying anomalous fetus(es), or multiple gestations were excluded. Neonatal survival without major morbidities was the primary outcome. Data were analyzed with multivariable logistic regression and Cox regression models. Week-specific probability estimates for neonatal morbidity and mortality were calculated based on gestational age at the time of preterm PROM. RESULTS: One hundred fifty-nine women fulfilled study criteria. Median gestational age at preterm PROM for all patients was 21.4 (range 14.0–23.9) weeks of gestation. Median delivery gestational age was 24.7 (range 15.4–34.1) weeks. Forty-seven patients experienced either an intrauterine fetal demise, elected delivery after initial expectant management, or delivered before planned resuscitation. Of 112 newborns admitted to neonatal intensive care, 89 (56.0% of all neonates) survived; 43 (48.3% of survivors, 27.0% of all neonates) had no major neonatal morbidities. Morbidity probabilities decreased with increasing gestational age at the time of preterm PROM. Delivery gestational age was predictive of both neonatal morbidity and mortality. CONCLUSION: More than one half of women who achieved at least 12 hours of latency and elected expectant management had a surviving infant; nearly 50% of survivors had no major neonatal morbidity. These contemporary outcomes are valuable in counseling women with early preterm PROM. LEVEL OF EVIDENCE: III

All-Cause and Cause-Specific Mortality after Hypertensive Disease of Pregnancy

OBJECTIVE: To assess whether women with a history of hypertensive disease of pregnancy have increased risk for early adult mortality. METHODS: In this retrospective cohort study, women with one or more singleton pregnancies (1939–2012) with birth certificate information in the Utah Population Database were included. Diagnoses were categorized into gestational hypertension; preeclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; and eclampsia. Women with more than one pregnancy with hypertensive disease (exposed) were included only once, assigned to the most severe category. Exposed women were matched one to two to unexposed women by age, year of childbirth, and parity at the time of the index pregnancy. The causes of death were ascertained using Utah death certificates and the fact of death was supplemented with the Social Security Death Index. Hazard ratios for cause-specific mortality among exposed women compared with unexposed women were estimated using Cox regressions adjusting for neonatal sex, parental education, preterm delivery, race–ethnicity, and maternal marital status. RESULTS: A total of 60,580 exposed women were matched to 123,140 unexposed women; 4,520 (7.46%) exposed and 6,776 (5.50%) unexposed women had died by 2012. All-cause mortality was significantly higher among women with hypertensive disease of pregnancy (adjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.57–1.73). Exposed womens greatest excess mortality risks were from Alzheimer disease (adjusted HR 3.44, 95% CI 1.00–11.82), diabetes (adjusted HR 2.80, 95% CI 2.20–3.55), ischemic heart disease (adjusted HR 2.23, 95% CI 1.90–2.63), and stroke (adjusted HR 1.88, 95% CI 1.53–2.32). CONCLUSION: Women with hypertensive disease of pregnancy have increased mortality risk, particularly for Alzheimer disease, diabetes, ischemic heart disease, and stroke.

Frequency of fetal heart rate categories and short-term neonatal outcome.

OBJECTIVE: To estimate the time spent in each fetal heart rate category during labor and during the last 2 hours before delivery in term singleton pregnancy and to estimate the relationship between the time spent in each category and short-term neonatal outcomes. METHODS: This study reviewed fetal heart rate data and newborn outcomes of women in term labor in 10 hospitals over 28 months. Fetal heart rate characteristics were assessed by labor and delivery nurses, and categories were assigned by computer using definitions from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The duration of time in each category was calculated and correlated with newborn outcome. RESULTS: Forty-eight thousand four hundred forty-four patients were identified. Considering all of labor, category I was present 77.9% of the time, category II was present 22.1% of the time, and category III was present 0.004% of the time. In the last 2 hours before delivery, category I decreased to 60.9% of the duration, category II increased to 39.1%, and category III increased to 0.006%. Newborns of women whose last 2 hours were exclusively category I did well; only 0.6% had 5-minute Apgar scores less than 7, and 0.2% had low Apgar scores with neonatal intensive care unit (NICU) admission. When more than 75% of the last 2 hours was category II, low 5-minute Apgar score increased to 1.3% of patients, and low 5-minute Apgar score with NICU admission increased to 0.7% (both P<.001). CONCLUSION: Category I and category II fetal heart rate patterns are common in labor, and category III patterns are rare. Increasing time in category II in the last 2 hours of labor is associated with increased short-term newborn morbidity. LEVEL OF EVIDENCE: III

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

BackgroundBecause of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB.ResultsWe reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity.ConclusionsIL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.Population structure is an important confounding factor that should be controlled for in studies of PTB.