Generally speaking it has been the understanding that preeclampsia has a beneficial influence on fetal lung maturation. This, however, has been questioned by recent studies suggesting no positive effect of preeclampsia on fetal lung maturation, which form the basis of this paper. From the multiple studies analyzed in this paper a big disagreement is found towards this subject with a time correlated connection to what is concluded. Recent studies find either no or a negative influence of preeclampsia on fetal lung maturation while older studies find a positive influence. Several aspects may contribute to this difference, among these, more advanced medical care and earlier termination of preeclampsia pregnancies in the recent studies can covers the physiologic effect preeclampsia may has on fetal lung maturation. In addition the current treatment regime to prevent respiratory distress syndrome in infants of preeclampsia women is reassessed, and considered to be the best treatment since it almost reduces the incidence of respiratory distress syndrome by half. However more studies is required to determine the effect of preeclampsia on fetal lung maturation as well as the mechanisms behind it, among these 11ßHSD1 and 11ßHSD2 is suggested to be possible mechanisms to induce fetal lung maturation. Based on the studies in this paper I draw the conclusion that it cannot be determined wherever preeclampsia benefits fetal lung maturation or not, which require the need of additionally studies.
Problem statement
Does preeclampsia in pregnancies lead to increased maturation of the lung function in preterm delivered infants and should the current treatment be considered?
Introduction
Preeclampsia is a major health concern to both mother and fetus and is the leading cause of maternal morbidity. Preeclampsia is estimated to affect 2% of the Danish population but is believed to complicate an even higher population in undeveloped countries.1 Preeclampsia is a multi organ disorder with onset after 20th week of gestation. The diagnostic criteria include a blood pressure that exceeds 140 mmHg (systolic) and 90 mmHg (diastolic) and simultaneous detection of proteinuria measured to be more than 0.3 g/day. Often preeclampsia is also accompanied with edema. Without medical intervention preeclampsia can lead to kidney failure, liver rupture, stroke, eclampsia with seizures and HELLP syndrome. 2
The definitive reason for preeclampsia is yet to be found but may be associated with oxidative stress, angiogenic factors, immune response between mother and placenta and superficial placentation.3 The incidence is higher among primipare than multipara and diabetes, kidney and autoimmune disorders, high age and family history of preeclampsia appear to be predisposing to preeclampsia.2
In preeclampsia pregnancies the life of the mother is at first priority. Mild preeclampsia can be monitored frequently while serve preeclampsia often requires hospitalization. Patients will be treated with antihypertensive medications and magnesium sulphate to prevent seizures.1 The only intervention to cure preeclampsia is birth, which explains that almost every preeclampsia pregnancy leads to preterm birth. Induced preterm birth can be necessary to save the mother’s life but is also crucial to the child. Whether and when to provoke delivery is a decision based on both the conditions of mother and child, but with the mother as first priority.2 Many complications seen after preeclampsia are due to preterm birth. One of the biggest issues is respiratory distress syndrome. Respiratory distress syndrome occurs in the absence of surfactant in the lungs at birth, resulting in collapse of the lungs. 4 It has been generally believed that the fetal lung maturation and overall fetal maturation is increased in pregnancies complicated by preeclampsia, which is thought to be a natural adaptation to the stressful environment in uterus. 5 Also, back in the 1970’s and 1980’s a low incidence of RDS was shown among complicated pregnancies with increased L/S ratio in consequence supporting the on going perception.6. However recent studies 5,7-9 have questioned the relationship between increased FLM and preeclampsia. Consequently the need to shed light on this matter is emphasized.
In this paper I will examine the theory that preeclampsia leads to increased maturation of the lung function in preterm infants and based on the outcome discuss whether the infants should be treated otherwise
Methods
This paper is based on articles found on PubMed database with access through Aarhus university library. The articles are chosen in regard to their ability to enlighten the correlation between preeclampsia and fetal lung maturation as well as the mechanisms and treatment of preeclampsia. I have been using different combination of Mesh terms, some of which I made up myself and others found in previous articles, among these; Preeclampsia, respiratory distress syndrome, fetal lung maturation/function, L/S-ratio, LBC, corticosteroids, 11ßHSD etc. In addition, studies have also been found by searching the reference list found in previous studies. When choosing the articles, I have tried to be critic towards old studies since they may be obsolesced. Since very few studies have been searching this specific topic, I have critically implicated some of these articles in this paper.
Fetal lung maturity in preeclampsia
Preeclampsia can lead to placental insufficiency a condition with ongoing degradation of placenta functions leading to further lack of oxygen and nutrients.10 The resulting hypoxia activates the fetal hypothalamic pituitary adrenal axis leading to cortisol release. 11
The combined knowledge about cortisol levels increases under preeclampsia and that medical corticosteroids have lowered the incidence of respiratory stress syndrome may have resulted in the preceding perception of preeclampsia as an inducer of FLM. 7 Over decades multiple studies have investigated whether preeclampsia results in increased fetal lung maturation with different conclusions as will be elucidated in the following.
Lecithin/sphingomyelin ratio and lamellar body count
The lecithin/sphinomyelin(L/S) ratio and lamellar body count(LBC) are two out of several test for fetal lung maturity. Both test are invasive which is associated with a small risk of miscarriage or preterm labor. The test consists in injecting a long needle through the stomach and into the uterus where amniotic fluid is collected. The procedure is called amniocentesis.12
The L/S ratio is constant until week 30 after which lecithin increases but sphingomyelin stay persistent. This results in an increased ratio. The higher the ratio, the better the lung maturity. In general the L/S ratio needs to be more than 2.0 to exceed the accepted ratio in which is associated with a low risk of respiratory distress syndrome.
LBC express the form surfactant takes when stored in type 2 pneumocyts and is increased during pregnancy why it is also a way of predicting FLM. 13
A study by Stimac, T. et al. (2012) examined the correlation between preeclampsia and FLM by using LBC.8 The study is based on a cohort of 306 pregnant women who were categorized in to four groups. The women were divided into three groups; 25 women were included in the group of preeclampsia, 74 women were included in the group of IUGR, 63 in the group of both IUGR and preeclampsia and 144 were included as controls. As seen in the figure below, the different groups have about the same LBC before week 31 of gestation. The levels subsequently begin to increase, LCB levels in preeclampsia pregnancies a little slower than the other groups. But at term (week 37-39) the levels suddenly increase in the group of preeclampsia, which can be contributed to the fact that the groups are very small, and very few preeclampsia women reaches full term.
Figure 1:
The lamellar body counts in the different groups as a function of gestational age.
Original figure from T. Stimac et al. (2012)8
This study provides no information that substantiates the thesis that preeclampsia have a beneficial effect on fetal lung maturity.
Winn, H. N. et al. (2000) also examined the influence on fetal lung maturity in preeclampsia.9 In this study the FLM was determined by the L/S ratio. The study population consisted of 90 patients who had been subjected to amniocentesis to test for fetal lung maturity. Out of 90 patients 59 were classified as patients with preterm labor without preeclampsia and 31 were classified as patients with preeclampsia. The two groups were matched in fetal age, parity and race. The results showed a significant increased FLM in the group of preterm patients compared to the preeclampsia patients.
Despite the very small study population this study also shows no evidence that preeclampsia should have any beneficial effects on the FLM, as a matter of fact it actually indicates a delayed FLM.
The L/S ratio and LBC are often used to measure FLM. However the L/S ratio only takes lecithin and sphingomyelin into account leaving several other phospholipids out. Because of it the concept of microviscosity will be introduced below.
Fetal lung maturity based on the microviscosity of amniotic fluid
The microviscosity of the amniotic fluid includes all phospholipids why it also is a relevant measure of FLM.14 The microviscosity is influenced by the phospholipid by decreasing at higher concentrations.
The microviscosity is measured by fluorescence polarization of amniotic fluid taken via amniocentesis. A fluorescent hydrocarbon probe is added to the amniotic fluid and lit by polarized light. At high phospholipid concentration a larger amount of probe will be bound and less fluorescent polarized response will appear.15
Simon, N. V. et al. (1982) conducted a study by using microviscosity to predict fetal lung maturity in complicated pregnancies.15 The study included 252 women without complications, beside preterm labor, as controls and 172 women with different kinds of complications among these diabetes, chronic hypertension and pregnancy-induced hypertension. From the control group a reference variable for FLM where made to correlate with gestational age found to be 4.8. A significant lower value of microviscosity where found when looking at the group of hypertensive. When separation chronic and pregnancy-induced hypertension a lower value where found for chronic hypertensive emphazing the effect of the stress duration.
This study did not examine the effect of preeclampsia but did find that hypertensive disorder in pregnancy, including pregnancy-induced hypertension, decreases microviscosity indicating increased fetal lung maturation. It also found microviscosity as a good measurement to predict FLM.
Although all of the above mentioned methods are good ways to predict FLM, respiratory distress syndrome is the direct effect of deficient lung maturation. Consequently the prevalence of RDS in preeclampsia can also be a good way of reflecting preeclampsia’s influence on FLM.
Prevalence of respiratory distress syndrome in preeclampsia pregnancies
Respiratory distress syndrome is defined by insufficient levels of surfactant leading to increased surface tension that may further leads to pulmonary collapse. In some litterateur it is also referred to as hyaline membrane disease, which is contributed to the large amount of hyaline membranes found at pulmonary autopsy of deceased infants. It is diagnosed by dyspnea and oxygen requirement within the first 24 hours after birth. 4
A study by Friedman, S. A. et al. (1995) sought to find a beneficial correlation between preeclampsia and the effects on infants born before week 35.5 Included in the study population were 223 infants born to mothers with preeclampsia. In the control group 223 infants from normotensive mothers matched for gestational age, gender, race and birth method were included. The study ought to clarify multiple parameters including RDS, neonatal death and the duration of invasive care and ventilation. According to this study there was found no difference in the incidence of RDS and neonatal death. Only the duration of medical care differed significantly. That been said, no adjustment was made towards the use of corticosteroids that ought to enhance lung maturity. A greater proportion of women with preeclampsia where under glucocorticoid therapy in which should be expected to advantageous towards a better outcome. Lacks of such improvement leads to the conclusion that infants from preeclampsia have an increased risk of developing RDS and consequently have a lower FLM.
Another study by Chang, E. Y. et al. (2004), found a similar trend.7 The study population was based on 814 women diagnosed with preeclampsia and the control group was obtained from women without preeclampsia. Both groups had preterm delivery in gestation week 24 to 37. The findings were as shown in figure 2. Before gestation week 32 preeclampsia women had a significantly increased risk of delivering an infant with RDS compared to the control group when controlled for multiple confounding. After gestation week 32 no significant difference could be found in between the two groups.
This study also failed to find a beneficial effect from preeclampsia, rather the reverse as it appeared to aggravate the risks of RDS.
Figure 2:
The HMD/RDS incidence in percent in women with preeclampsia compared to control group as a function of weeks of gestation.
Original figure from Chang, E. Y. et al. (2004) 7
The two studies above compare infants born to preeclampsia women with infants born to normotensive or non-preeclampsia women. A study by Yoon, J. (1980) tried to investigate the different outcome when comparing women with various degrees of preeclampsia.16 The study included 2105 infants in gestational week 28 to 36. They were divided into two groups: Hypertension disease of pregnancy (HDOP) and non-hypertension disease of pregnancy (non-HDOP). HDOP were further divided into mild preeclampsia, serve preeclampsia, eclampsia and hypertension with and without toxemia. The study found that FLM was increased in the HDOP group as shown by the lower incidence of idiopathic respiratory distress syndrome (IRDS). Further more it was found that the higher the toxicity the lower the incidence of IRDS, e.g. the incidence of IRDS were 20% at mild preeclampsia, 13% at serve preeclampsia and 7,1% at eclampsia. But a higher toxicity also showed to increase the fetal mortality.
This study did emphases the theory of preeclampsia as a protective mechanism of RDS and that the more serve the preeclampsia the lower IRDS incidence. However the study also did find that the mortality in the two groups was not significantly different.
Discussion
A disagreement towards the problem statement appears to prevail among the studies analyzed in this paper. However some differences among the studies do leap out and may explain why different conclusions occur.
The temporal aspect
When looking at the studies examined above a time-based correlation is seen among the studies supporting increased fetal lung maturation in preeclampsia and the studies that disagree. The studies found to show increased FLM are from the 1980’s15,16 while newer studies suggest that preeclampsia either decrease FLM or do not affect it at all5,7-9. This may propose that studies are getting better but several other factors may also cause it. The reason why the incidence of RDS in preeclampsia was lower in the 1980’s than seen in the newer studies could be contributed to the fact that more advanced medical science than in the 1980’s out do the positive biological effect preeclampsia may has on fetal lung maturation, consequently concealing the additive changes.5 At the same time the progress of neonatal medicine and technology lets younger and smaller infants survive17 which may contribute to more and worse cases of RDS since the incidence of RDS depends very much on the gestational age when delivered.
As a part of the better neonatal technology and monitoring, most preeclampsia pregnancies get terminated preterm.18 When labor is indicated the adaptive mechanism may not attain levels to affect fetal lung maturation. As an example a study by Lee, J. found that RDS occurred in 50,1% of the indicated labors and only in 38,4% of the spontaneous labors.18
Figure 3:
The predicted probability of RDS according to gestational age at delivery, spontaneous and indicated labors respectively.
Original figure from Lee, J. (2009)
Based on this study it could be interesting to investigate if infants of women with preeclampsia have a lower incidence of RDS when delivered spontaneous compared to indicated delivered infants.
Confounding problems
Confounding problems may also serve to the disagreement seen in the studies. Even though the studies do take several relevant confounders into account, such as gestational age, infant gender and parity, all of the studies, besides Yoon, J. et al., compare the infants from preeclampsia women with preterm infants from non-preeclampsia women. This may contribute to confounding since preterm labor intrinsically is a pathologic event.5 Consequently preterm labor is induced by another pathologic cause that may, just like preeclampsia, lead to stress induced fetal lung maturation. The only way to avoid this problem would be to terminate completely healthy pregnancies so they matched the infants’ gestational age of the preeclampsia women. Since this will be very much an ethical wrong practice it will be difficult to make a better control group.
Another suggestion to a control group could be to compare different severities of preeclampsia to each other like, Yoon, J. et al. did in his study in 1980. This study showed a big difference in the incidence of RDS among different severities of preeclampsia.16 Because of that a separation could be made in future studies to better clarify wherever a given effect on fetal lung maturation is seen in preeclampsia. Also it could be interesting to make “an up to date” version of the study made by Yoon, J. et al. in 1980 to exclude the temporal aspect that is suggested above.
Overall, no final conclusions about the effects of preeclampsia on FLM can be made based on the studies in this paper. When considering that preeclampsia may increase, decrease or has no effect on FLM, the treatment to prevent infants born to preeclampsia women from developing RDS, will be discussed in the following based on the current regimen.
Reassessment of the current treatment regimen to prevent RDS in preeclampsia
In general the incidence of RDS in preeclampsia has been lowered by the use of corticosteroids. When delivering an infant before week 34 of gestation corticosteroid therapy is needed. The treatment consists in 12 mg betamethasone given intramuscularly to subsequently dose after 24 hours and then once a week until delivery. 19 Full betamethasone effect will first be seen after 48 hours of administration. Serve preeclampsia can quickly intensify why corticosteroid therapy must be initiated instantly. 20
While conducting a study of women with serve preeclampsia given either betamethasone or placebo, Amorin, M.M. et al. found that corticosteroids almost reduced the incidence of RDS by half.19 Also, the only complication corresponding to this treatment was maternal diabetes when treating after the regime above. However maternal diabetes may not stop a woman from being treated with corticosteroid since the pregnancy often is terminated before the diabetes get hold.
Still you can get around the fact that increased gestational age decreases the incidence of RDS why monitoring the pregnant women to keep her from delivering as long as possible is the best way to prevent RDS. 21 As seen on figure 4 the incidence of RDS decreases considerably with gestational age.
Figure 4:
The incidence of RDS with increasing gestational age.
Original figure from Ruth, C. A. et al. (2012).21
The treatment provided to women with preeclampsia to prevent RDS is identical to what is provided to pregnant women with threatened preterm labor. Regardless if preeclampsia leads to increased FLM or not, it cannot be ignored that corticosteroid have a critically impact on reducing the incidence of RDS in preeclampsia when given before week 34 of gestation. Besides the use of corticosteroids in pregnancies have shown to be very safe. 19
However, recent studies have tried to find alternatives to the use of corticosteroids, among these ambroxol and thyroidea-releasing hormone. 22,23 Ambroxol is an active metabolite of Bromhexin that cleaves mucopolysaccarides in mucus to reduce the viscosity, while TRH stimulate the secretion of T3 and T4 to induce growth and act as agonist to catecholamines. 22
Ambroxol has in animal studies shown to activate type II penumocytes and promote surfactant release and the formation of more stable surfactant. In the case of TRH, animal studies have shown that TRH increases the production of phospholipid as well as having a synergistic influence on corticosteroid receptors. 22
Yet not enough evidence has been made towards any of these alternatives, while corticosteroids must still be considered the best option in preventing RDS.
Further perspectives
To assess the impact of preeclampsia on fetal lung maturation it would be beneficial to know the mechanisms. However, I have not been able to find any studies that have described the direct mechanisms which preeclampsia affect fetal lung maturation why I have sought to find possible mechanisms to describe the correlation.
Enzymes found to be extremely important for fetal lung maturation are 11ß-HSD enzymes.24 The enzymes exit in to forms: 11ß-HSD1 found in lungs and 11-HSD2 found in placenta and fetus among others. 11ß-HSD1 converts glucocorticoids into active metabolites and 11ß-HSD1 converts glucocorticoids into inactive metabolites.25
Figure 5:
11ß-HSD1 and 11ß-HSD2 enzymatic functions respectively.
Original figure from Mukherjee, S. (2011).26
In normal pregnancies 11ß-HSD2 in placenta increases in amount trough out pregnancy to inactivate cortisol to cortisone. At term concentrations fall abruptly to let glucocorticoids stimulate fetal lung maturation.27 In preeclampsia pregnancies 11ß-HSD is decreased two- to threefold, letting more cortisol affect the child.28 Even though this study does not come to any conclusions about fetal lung maturity, I do think that an early exposure to cortisol could be a mechanism to increased lung maturation even though it requires further examination.
But 11ß-HSD1 may also be affected during preeclampsia leading to increased converting of cortisone to cortisol in lungs. Increased levels of interleukin-1ß may cause increased expression of 11ß-HSD1 during preeclampsia. A study by Yang, Z. et al., showed that higher levels of IL-1ß during pregnancies led to increased expression of 11ß-HSD1 in human fetal lung fibroblasts.25 This study was made on pregnancies affected by chorioamnioitits, but increased IL-1ß was also confirmed in preeclampsia pregnancies by a study conducted by Amash, A. et al.29 This study showed increased concentrations of IL-1ß in both maternal and fetal circulation, but only the concentrations in maternal circulation were found significantly increased. Since 11ß-HSD1 has shown to be critically to fetal lung maturation an increased expression may lead to fetal lung maturation. This has however not been studied towards preeclampsia why it does require further investigation.
Since I have not been able to find relevant studies concerning mechanism in preeclampsia that leads to increased FLM, it could indicate that there is no such mechanism. However it could also be lack of investigation and I do propose to investigate the association between 11ß-HSD1/11ß-HSD2 and preeclampsia induced FLM, since 11ß-HSD has shown to be critically in the lung maturation and to be influenced in other diseases in pregnancies. 24,29
Conclusion
In general too few studies have been studying the thesis that preeclampsia induces fetal lung maturation, especially in the last few decades. Combined with the great controversy about the thesis, the evidence towards preeclampsia as an inducer for fetal lung maturation is very week, however it cannot be declined either. From this analyze I can conclude that additionally studies should be made to clarify the influence preeclampsia may has on fetal lung maturation, by excluding both the temporal aspect and confounding problems that may exist in the previous studies. Also, mechanisms in which preeclampsia affects the fetal lungs should be examined, to get an understanding on how preeclampsia can influence fetal lung maturation. However based on the studies in this paper it must be assumed that when delivering infants of preeclampsia women, infants must be treated as other preterm infants until a better acquaintance is attained.
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