Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study

Background:People whose singleton pregnancy is affected by hypertensive disorders of pregnancy (HDP) are at risk of future cardiovascular disease. It is unclear, however, whether this association can be extrapolated to twin pregnancies. We aimed to compare the association between HDP and future cardiovascular disease after twin and singleton pregnancies.Methods:We conducted a population-based retrospective cohort study that included nulliparous people in Ontario, Canada, 1992–2017. We compared the future risk of cardiovascular disease among pregnant people from the following 4 groups: those who delivered a singleton without HDP (referent) and with HDP, and those who delivered twins either with or without HDP.Results:The populations of the 4 groups were as follows: 1 431 651 pregnant people in the singleton birth without HDP group; 98 631 singleton birth with HDP; 21 046 twin birth without HDP; and 4283 twin birth with HDP. The median duration of follow-up was 13 (interquartile range 7–20) years. The incidence rate of cardiovascular disease was lowest among those with a singleton or twin birth without HDP (0.72 and 0.74 per 1000 person-years, respectively). Compared with people with a singleton birth without HDP, the risk of cardiovascular disease was highest among those with a singleton birth and HDP (1.47 per 1000 person-years; adjusted hazard ratio [HR] 1.81 [95% confidence interval (CI) 1.72–1.90]), followed by people with a twin pregnancy and HDP (1.07 per 1000 person-years; adjusted HR 1.36 [95% CI 1.04–1.77]). The risk of the primary outcome after a twin pregnancy with HDP was lower than that after a singleton pregnancy with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]), when compared directly.Interpretation:In a twin pregnancy, HDP are weaker risk factors for postpartum cardiovascular disease than in a singleton pregnancy.

Cardiovascular disease has been shown to be the leading cause of death among women.^1–3 Classic risk factors for cardiovascular disease include obesity, diabetes mellitus, hypertension and family history of cardiovascular disease. ³ More recently, an association has been established between a history of hypertensive disorders of pregnancy (HDP) — gestational hypertension and pre-eclampsia — and future risk of cardiovascular disease.^1,4–11 Consequently, some recommend using a history of HDP for cardiovascular disease risk stratification in women.^3,12The leading hypothesis for the pathogenesis of HDP is that it results from abnormal placentation due to impaired trophoblast invasion,^13–16 resulting in reduced placental perfusion.^17–19 This, in turn, leads to abnormal secretion of the angiogenic factors soluble FMS-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng),²⁰ which induce endothelial dysfunction and the clinical manifestations of HDP.^19,21–24 The mechanisms underlying the association between HDP and future cardiovascular disease are under debate.²⁵ One hypothesis is that HDP are merely a marker of underlying subclinical or clinical vascular risk factors that predispose a person to both HDP and future cardiovascular disease.A person who is pregnant with twins is at about 3–4 times higher risk of HDP than a person with a singleton pregnancy,^26–33 with rates of 14% and 5%, respectively.³⁴ The higher risk of HDP in twin pregnancies may be due to higher circulating sFlt1 and sEng owing to greater placental mass in twin pregnancies, ^35–37 and less related to the classic vascular risk factors for HDP in a singleton pregnancy. Therefore, a logical question is whether the established higher risk of future cardiovascular disease after singleton pregnancies with HDP also occurs in twin pregnancies with HDP. Limited data are available to answer this question.³⁸ In the current study, we aimed to test the hypothesis that the association between HDP and future cardiovascular disease is less pronounced in twin versus singleton pregnancies.     

Fetal prostaglandin levels in twin pregnancies

Umbilical venous plasma and amniotic fluid concentrations of prostaglandins E₂ (PGE), F_2α (PGF) and 13,14 dihydro-15-keto-F_2α (PGFM) were measured in 31 twin pregnancies by specific radioirmnunoassays. There was no significant difference between twins I and II in the same pregnancy but PGE and PGFM were significantly increased during labour in fetal blood. This rise was not manifest in the latent phase. PG concentration in amniotic fluid rose with advancing gestational age but was more pronounced in the case of PGE than for PGF and PGFM. No significant differences between amniotic sac concentrations of PGs of twin I and II were found during the prelabour period, but in all four patients in labour with intact membranes, the PG levels were increased in twin I. The fetal plasma and amniotic fluid levels of PGE and PGFM were significantly correlated in the prelabour group.     

The outcome of twin pregnancies in mares

Brood-farm veterinarians were surveyed and theriogenology records were examined to obtain information on the natural outcome of rectally-diagnosed twin pregnancies. Four of the veterinarians estimated that 50% of mares with twin embryos had single foals. In the analyses of palpation records, 31 53 (58%) of the diagnosed twin pregnancies terminated in birth of one foal. However, the loss of one embryo without the loss of the other occurred significantly more often before day 40-42 (30 53 ; 57%) than after day 40-42 (1 16 ; 6%). Of the remaining 15 mares with diagnosed twins at day 40-42, 5 had two foals and 10 had no foals. The methods used for intervention when twins were diagnosed were unsatisfactory. Complete termination of pregnancy with a prostaglandin or an intrauterine flushing resulted in failure to reestablish a singleton pregnancy during the operational breeding season in 10 11 mares. Attempts to eliminate one embryo resulted in loss of both in 6 7 mares. The results indicated that, at the present time, nonintervention should be given more consideration as a method of handling twin pregnancies.     

Maternal antioxidant concentrations after uncomplicated pregnancies

Background: To analyse the post-partum concentrations of intra- and extra-cellular blood antioxidants in women with uncomplicated pregnancies.

Methods: Whole blood and plasma thiols, plasma vitamin E and C, serum cholesterol and triglyceride, ferric reducing ability of plasma (FRAP) concentrations were compared between women delivered by caesarean section (n=17) or spontaneous delivery (n=10). A repeated mixed model was used for statistical analysis.

Results: The majority of whole blood thiols increased significantly in both groups the first days post-partum. However, within the caesarean group free cysteine, oxidised cysteine, homocysteine and glutathione and plasma cysteine and homocysteine levels dropped significantly after 24?h, while FRAP levels peaked significantly in this group. Plasma vitamin E levels decreased significantly in both groups within 24 to 48?h after delivery. Independent of the way of delivery whole blood and plasma thiols were significantly increased and vitamin E levels were significantly decreased 3?months post-partum while plasma vitamin C levels and FRAP were unchanged compared to ante-partum levels.

Discussion: Decreased plasma vitamin E levels shortly post-partum are associated with decreased lipid peroxidation. The 24?h post-partum drop of some plasma and whole blood thiols in the caesarean group may be due to prolonged fasting.     

Maternal antioxidant concentrations after uncomplicated pregnancies

Background: To analyse the post-partum concentrations of intra- and extra-cellular blood antioxidants in women with uncomplicated pregnancies.

Methods: Whole blood and plasma thiols, plasma vitamin E and C, serum cholesterol and triglyceride, ferric reducing ability of plasma (FRAP) concentrations were compared between women delivered by caesarean section (n=17) or spontaneous delivery (n=10). A repeated mixed model was used for statistical analysis.

Results: The majority of whole blood thiols increased significantly in both groups the first days post-partum. However, within the caesarean group free cysteine, oxidised cysteine, homocysteine and glutathione and plasma cysteine and homocysteine levels dropped significantly after 24 h, while FRAP levels peaked significantly in this group. Plasma vitamin E levels decreased significantly in both groups within 24 to 48 h after delivery. Independent of the way of delivery whole blood and plasma thiols were significantly increased and vitamin E levels were significantly decreased 3 months post-partum while plasma vitamin C levels and FRAP were unchanged compared to ante-partum levels.

Discussion: Decreased plasma vitamin E levels shortly post-partum are associated with decreased lipid peroxidation. The 24 h post-partum drop of some plasma and whole blood thiols in the caesarean group may be due to prolonged fasting.     

Hypertensive disease in twin pregnancies: a review.

Reports over the past seventy years show that twin gestations lead to an increased risk of hypertensive disorders. Numerous studies discuss the incidence of hypertensive disease in twin versus singleton gestations, as well as effects of parity, race, age, income level, smoking, zygosity and heritability on this condition. The range of relative risk of gestational hypertension, preeclampsia and eclampsia for twin compared to singleton gestations is 1.2 to 2.7, 2.8 to 4.4 and 3.4 to 5.1 respectively. Parity, African-American ethnicity, and young maternal age are all factors that increase the relative risk of acquiring hypertensive disease to 4.0, 1.8 and 1.5 in mothers of twin gestations. Factors such as maternal smoking, income level and zygosity have a negligible effect on the relative risk of acquiring hypertensive disease in twin gestations. In addition to twin mothers exhibiting a higher incidence of hypertensive disease compared to their singleton counterparts, they also exhibit an earlier onset of hypertensive disease at both 35 and 37 weeks of gestation comparatively. Uric acid levels measured at 30-31 weeks of gestation in twin mothers predicted the onset of preeclampsia with a sensitivity of 73% and a specificity of 74%. The range of risks presented in the literature is wide and the therapies avocated are diverse. We therefore decided to summarize the risks in a comparative fashion and to review current therapeutic strategies for the convenience of clinicians who confront increasing numbers of multiple pregnancies. The tables bring all recent published risks together in the first comparative analysis in which the data has been converted to relative risks and confidence intervals. Because the literature is relatively silent on specific management of hypertensive disease in twin pregnancies, general management recommendations for singleton gestations should be used by practitioners caring over twin gestations.     

Quantitative characteristics of components of the placental barrier of women with uncomplicated full-term pregnancies]

Placentas from four healthy women have been studied electron microscopically after urgent spontaneous deliveries. In every placenta 130-200 resorptive villi of the chorion were photographed. The results on morphometric analysis of 1,205 electronograms of the placental barrier are presented. At full-term uncomplicated pregnancies all components of the placental barrier (syncytium, cytotrophoblast, basal membrane of the trophoblast, stromal connective-tissue layer, basal membrane and endothelium of fetal capillaries) have been stated to demonstrate rather stable quantitative characteristics (see Table in the text). The quantitative data obtained can serve for electron microscopic investigation of placenta at different pathologic states of the mother and the fetus, make it possible to differentiate more precisely physiological and pathological changes in placental ultrastructure.     

Maternal blood pressure and fetal ultrasonography in normal baboon pregnancies

Pregnancy in baboons is characterized by lower systolic, diastolic, and mean blood pressures than in the nonpregnant state. As pregnancy progresses, diastolic and mean pressures tend to increase whereas systolic pressure remains low. Sonographic measurements of fetal growth follow a sigmoid pattern, but their increase in relation to length of gestation approximates a straight line between 6 and 21 weeks of gestation (23 to 84% of term).     

Total protein concentrations in human amniotic fluid from normal and twin pregnancies

Total protein concentrations (TPC) in the human amniotic fluid, during 19 to 40 weeks of gestation, from normal and twins pregnancies were compared. In the normal pregnancies the protein concentrations were found to increase with progressing gestation, but to decrease gradually to the term. TPC fluctuations also showed a similar pattern in the twin pregnancies. There was no significant difference in the total protein contents between the normal and twin pregnancies, which probably indicates that the majority of the proteins originate from maternal source.     

Multi-fetal pregnancy reduction does not influence perinatal results in twin pregnancies.

The objective of this study was to compare perinatal results in multifetal pregnancies where the reduction to twins was performed with non-reduced twin pregnancies. Perinatal results in 99 sets of twins after transabdominal multifetal pregnancy reduction of triple and higher-order multiple pregnancies performed in a single center were compared with a control group consisting of 151 twin pregnancies conceived in the same time period after infertility treatment, which were not a result of reduction. The main outcome measures were length of pregnancies, weight of the newborns, percentage of miscarriages and the mode of the delivery were analyzed. No significant difference could be found at a 5% level of significance regarding the average duration of pregnancy or average weight of the twins. Fisher test on 5% significance level did not ascertain any significant difference in the probability of miscarriage between the group with reduction (5.26%) and the group without reduction (12.84%). At a 5% level of statistical significance, no significant difference in probability of perinatal death of the fetus or delivery of a stillborn fetus was found. The percentage of cesarean sections did not differ significantly in both groups. The analysis of both groups demonstrated that reduction of multifetal pregnancies to twins may not influence perinatal results in comparison to twin pregnancies where reduction was not performed.     

Maternal and neonatal outcome in pregnancies with no risk factors.

Between November 1979 and April 1984, 790 consecutive pregnant women who considered themselves as having a "normal" pregnancy were followed in private practice from 9 weeks'' gestation until 6 weeks post partum. The women had no pre-existing disease or problem classified as a risk to the pregnancy at the time of their first visit, had a singleton pregnancy and gave birth at Notre-Dame Hospital, Montreal. Maternal complications occurred during the course of pregnancy in 181 women (23%). Complications were mostly related to obstetric conditions (10%), such as preterm labour, intrauterine growth retardation (IUGR) and antepartum hemorrhage, or to medical conditions (12%), the most prevalent of which was hypertension (77% of medical conditions). Neonatal complications occurred in 183 infants (23%). The corrected perinatal death rate was 2.5 per 1000. Prematurity, IUGR and dysmaturity/postmaturity accounted for nearly half of the complications. Hyperbilirubinemia occurred in 7% of the cases. Among women without any maternal complications during pregnancy, the frequency rate of neonatal complications was 19%, compared with 23% among the entire group of 790 women. Our results suggest that the absence of maternal complications does not protect the infant from a neonatal complication. Further refinement is needed to identify markers of obstetric, medical and neonatal complications in pregnancies with no risk factors.     

Amniotic fluid and hemodynamic model in monochorionic twin pregnancies and twin-twin transfusion syndrome

We developed a mathematical model of monochorionic twin pregnancies and twin-twin transfusion syndrome (TTTS), combining both fetal fluid dynamics and fetoplacental growth and circulation alterations and assuming that transplacental fluid flow from mother to fetus accounts for normal fetal and amniotic fluid volumes. Ten coupled differential equations, describing fetal total body and amniotic fluid volumes, their osmolalities, and fetal blood colloid osmotic pressure, for both donor and recipient twins, were solved numerically. Amniotic flows are controlled by fetal plasma osmolality and hydrostatic and colloid osmotic pressures. We included varying placental anastomoses and placental sharing of the circulations. Consistent with clinical experience, model predictions are: fetofetal transfusion from unidirectional arteriovenous anastomoses cause oligo-polyhydramnios, a normal size recipient but hypovolemic donor; compensating oppositely directed deep and superficial anastomoses moderate discordant development; and anhydramnios results from mild and severe TTTS, where milder forms may even present earlier in gestation than severe TTTS. Unequal placental circulatory sharing may exacerbate discordant development. In conclusion, our model simulates a wide variety of realistic manifestations of amniotic fluid volume and fetal growth in TTTS related to placental angioarchitecture. The model may allow an assessment of the efficacy of current therapeutic interventions for TTTS.     

孕中期双胎妊娠与单胎妊娠孕妇血清AFP与F-β-Hcg水平的比较

目的：检测双胎妊娠孕中期孕妇血清甲胎蛋白（AFP）和人绒毛膜促性腺激素游离B亚基（F-β-hCG）的水平,探索双胎妊娠时孕妇血清学筛查用于Down＇s胎儿高风险评估的AFP、F-β-hCG界定值。方法：收集双胎妊娠129例,孕中期（15～2l周）采集孕妇静脉血,用时间分辨荧光免疫分析技术测定血清AFP和F-β-hCG的浓度,并于分娩后随访,确定胎儿有无异常。另选2603例胎儿无异常的单胎妊娠作对照组。结果：129例双胎妊娠孕妇血清AFP浓度的中位教为98.98ng／ml,F-β-hCG浓度的中位数为32.20ng／mt;2603例单胎妊娠孕妇血清AFP和F-β-hCG浓度的中位数分别为52.15ng／ml和13.00ng／mt。双胎妊娠孕妇血清AFP和F-β-hCG的水平均明显高于对照组（P均〈0.01）。结论：鉴于双胎妊娠孕妇血清AFP和F-β-hCG水平明显升高,双胎妊娠的产前唐氏筛查风险评估时应引入正常双胎妊娠的AFP、F-β-hCG值。     

Factors affecting pregnancy loss for single and twin pregnancies in a high-producing dairy herd

Our objective was to determine the magnitude of, and factors affecting, pregnancy loss for lactating Holstein cows on a commercial dairy farm when diagnosed with twin (n = 98) or single (n = 518) pregnancies using transrectal ultrasonography. Pregnancy losses were assessed with records of non-viable embryos at first pregnancy examination and embryo losses between the first (25-40 d after AI) and second (48 and 82 d after AI) post-breeding pregnancy examinations. Among cows diagnosed with single pregnancies, 3.7% were diagnosed with a non-viable embryo at first pregnancy examination, and 4.6% of those diagnosed with a viable embryo underwent pregnancy loss by the second examination. A total of 11.2% of cows diagnosed with twins experienced a single embryo reduction, whereas 13.3% lost both embryos. Overall, the total proportion of cows experiencing pregnancy loss or experiencing embryo reduction was greater for cows diagnosed with twin than single pregnancies (odds ratio; OR = 3.6), resulting in an embryo survival rate of 91.9% for cows diagnosed with single compared to 75.5% for cows diagnosed with twin pregnancies. Season of breeding and milk production were associated with pregnancy loss for single pregnancies, whereas CL number was associated negatively with embryo reduction and pregnancy loss for twin pregnancies. The risk of twinning and double ovulation among pregnant cows increased with days in milk (DIM), and the risk of double ovulation was greater for cows diagnosed with ovarian cysts and lacking a CL at initiation of an Ovsynch protocol. We concluded that in this herd, embryo reduction and pregnancy loss during early gestation was greater for lactating Holstein cows diagnosed with twin compared to single pregnancies. In addition, cows diagnosed with ovarian cysts and lacking a CL had an increased risk for double ovulation.