Michael J. Peek

The detection, investigation and management of hypertension in pregnancy: full consensus statement

Hypertension in pregnancy is associated with increased maternal and fetal morbidity and mortality I t is a common sign, reflecting a number of underlying disorders that may have different clinical outcomes. It is important that a woman with hypertension be diagnosed accurately so that the cause of the hypertension can be identified. She can then be informed about her likely clinical course and be managed appropriately. Hypertensive disorders in pregnancy are best managed with a multidisciplinary approach; the obstetrician should remain the doctor in charge and seek advice from other appropriate specialists (eg anaesthetists. neonatologists, physicians) where indicated. This document offers a framework for a team approach to the diagnosis, investigation and management of women with hypertension in pregnancy The recommendations are those of a multidisciplinary working party set up by the Australasian Society for the Study of Hypertension in Pregnancy to review and revise its previous guidelines for the detection, investigation and management of hypertension in pregnancy They are based on definitions and a classification system that reflect current knowledge. It is recommended that each obstetric unit develop its own management protocols.

Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia

Preeclampsia is the leading cause of morbidity and mortality in pregnancy. Although the etiology of preeclampsia is still unclear, it is believed to involve rejection of the fetus, possibly due to an imbalance between regulatory (Treg) and effector T cells. To test this, we compared the frequencies of circulating CD4+ T cells expressing Foxp3, IFN-γ, IL-10, or IL-17 at the end of the third trimester of healthy and preeclamptic pregnancies. The size of the Treg cell compartment, defined by the frequency of CD4+CD25high, CD4+CD127lowCD25+, and CD4+Foxp3+ cells was significantly higher in normal compared with preeclamptic pregnancies. CD4+CD25high and CD4+CD127lowCD25+ populations in preeclampsia were not significantly different from those in nonpregnant controls, whereas CD4+Foxp3+ cells numbersre slightly lower in preeclampsia. The suppressive activity of ex vivo-sorted CD4+CD127lowCD25+ Treg cells was not significantly different between the three study groups. The percentage of CD4+IL-17-producing T cells decreased significantly in healthy compared with preeclamptic pregnancies and nonpregnant controls, whereas CD4+IL-10- and CD4+IFN-γ-producing cells remained unchanged. Consequently, the ratio of Foxp3+ Treg to IL-17-expressing CD4+ T cells was significantly increased in healthy but not in preeclamptic pregnancies. Thus, preeclampsia is associated with the absence of normal systemic skewing away from IL-17 production toward Foxp3+ expression. Finally, preeclamptic women had significantly higher levels of soluble endoglin, an inhibitor of TGF-β receptor signaling, which may bias toward IL-17 production. These results suggest that homeostasis between regulatory and proinflammatory CD4+ T cells might be pivotal for the semiallogeneic fetus to be tolerated within the maternal environment.

The detection, investigation and management of hypertension in pregnancy: executive summary

These are the recommendations of a multidisciplinary working party set up by the Australasian Society for the Study of Hypertension in Pregnancy to review and revise its previous guidelines for the detection, investigation and management of hypertension in pregnancy. They are based on definitions and a classification system that reflect current knowledge. It is recommended that each obstetric unit develop its own management protocols. The following summarises the contents of the consensus report. This may prove a useful “office guide” for clinicians but should still be interpreted in light of the full discussion within the body of this report.

Altered decidual DC-SIGN+ antigen-presenting cells and impaired regulatory T-cell induction in preeclampsia.

Regulatory T (Treg) cell expansion is required for tolerance of the semi-allogeneic fetus in healthy pregnancy and impaired in preeclampsia in humans. However, the reasons remain unknown. Herein, we show that expansion of CD4(+)Helios(-)Foxp3(+) adaptive Treg (iTreg) cells, rather than CD4(+)Helios(+)Foxp3(+) natural Treg cells, accounts for this expansion in healthy pregnancy. This expansion is even more pronounced in the decidua, where there is an overrepresentation of iTreg cells. In preeclampsia, however, there is impaired systemic iTreg cell expansion, associated with a lack of iTreg cell overrepresentation in the decidua. Because decidual antigen-presenting cells (APCs) may be important for iTreg cell induction, we studied decidual CD14(+) APCs using immunohistochemistry and flow cytometry. We show that decidual CD14(+)DC-SIGN(+) APCs are closely associated with Foxp3(+) Treg cells. Furthermore, CD14(+)DC-SIGN(+) cells display a distinct phenotype compared with their CD14(+)DC-SIGN(-) counterparts. In particular, they have increased expression of tolerogenic molecules, HLA-G, and immunoglobulin-like transcript 4. In vitro, CD14(+)DC-SIGN(+) APCs from healthy pregnant women induced iTreg cells significantly more efficiently than CD14(+)DC-SIGN(-) APCs. Conversely, in preeclampsia, both CD14(+)DC-SIGN(+) and CD14(+)DC-SIGN(-) APCs induced iTreg cells poorly. These results suggest that decidual CD14(+)DC-SIGN(+) APCs may play important roles in iTreg cell induction, a process that is defective in preeclampsia and likely contributes to its pathogenesis.

Sexual origins of placental dysfunction

Severe placental dysfunction is much more common in pregnancies with a male than with a female fetus. Furthermore, the birthweight/placental weight ratio is increased in these pregnancies, consistent with fetal growth restriction, and is higher with a male fetus than with a female fetus. These observations of placental insufficiency may underlie the increased in-utero loss rate of male fetuses.

Is there an increased maternal–infant prevalence of Factor V Leiden in association with severe pre‐eclampsia?

Objective To compare the prevalence of the Factor V Leiden mutation in children and maternal–infant pairs in pregnancies affected by severe pre‐eclampsia with unmatched normal controls.

Medical amnioreduction with sulindac to reduce cord complications in monoamniotic twins

OBJECTIVE Cord entanglement is a common complication of monoamniotic twins and it is associated with high perinatal mortality. Apart from preterm delivery, no treatment has previously been used to reduce the risks of this complication. We postulated that reducing amniotic fluid volume would stabilize fetal lie and reduce the risk of cord compression. STUDY DESIGN Cord entanglement was documented in three cases of monoamniotic twins in the midtrimester. Sulindac was administered to the mother. Amniotic fluid index, fetal urine output, and umbilical artery and ductus arteriosus Doppler waveforms were investigated before and during treatment by use of real-time and pulsed Doppler techniques. RESULTS Sulindac was associated with a dose-related reduction in amniotic fluid index and fetal urine production without alteration in fetal flow velocity waveforms. Fetal lie stabilized after commencement of treatment. All six twins were delivered with no complications. CONCLUSION Medical amnioreduction with sulindac is a new management option in monoamniotic twins to reduce cord complications.

A Longitudinal Study Using Ultrasound to Assess Flow-Mediated Dilatation in Normal Human Pregnancy

Objective: To develop normal ranges of endothelial function in normal human pregnancy to use as a screening test for preeclampsia. Methods: In this longitudinal study, women were studied five times during pregnancy and once postpartum using flow-mediated dilatation (FMD). FMD is a noninvasive ultrasound technique used to assess endothelial function. Healthy nonpregnant women were controls. Results: FMD increased non-significantly in pregnancy until 32 weeks, when it decreased significantly at 36+ weeks (n = 47). Conclusion: The fall in FMD in the third trimester has not been previously reported. This indicates the importance of gestational age when assessing FMD as a screening test for preeclampsia.

Reverse end-diastolic flow in the middle cerebral artery: An agonal pattern in the human fetus

Serial Doppler ultrasonography in a severely growth-restricted fetus revealed progressive reduction in pulsatility index of the middle cerebral artery, consistent with brain-sparing effect. At 29 weeks, 1 week before fetal death, the pulsatility index in the middle cerebral artery returned to normal values and became reversed the day before fetal death. This report suggests that reverse flow in the middle cerebral artery is one of the terminal hemodynamic events preceding fetal death.

The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy

This study examined the relationship of cigarette smoking and endothelial function in pregnant women by comparing smokers with nonsmokers. Endothelial function was assessed at 28–32 weeks of gestation by flow‐mediated dilatation (FMD) using ultrasound of the brachial artery. The initial FMD was significantly different between the smoking group (n = 21) at 4.0 ± 2.3, indicating endothelial dysfunction, and the nonsmoking group (n = 20) at 9.7 ± 4.0 (P < 0.001). After smoking, this difference in the groups persisted. Babies who were growth restricted (<10th percentile) had mothers with a significantly lower FMD, that is endothelial dysfunction. This work demonstrates persistent endothelial dysfunction in smoking pregnant women.