Fetal Gender: Impact on Pregnancy Complications and Neonatal Outcome
Background- Obstetrical complications such as preterm delivery, pre-eclampsia, and placental abruption are more common in pregnancies with male fetuses. - Hyperemesis gravidarum, IUGR, and placenta accreta are more common in pregnancies with female fetuses. - In PPROM, a significantly higher proportion of female fetuses have a histological diagnosis of chorioamnionitis (55%).- Males have higher neonatal mortality rates up to one year of life; 3.44/1000 in males versus 2.18/1000 in females.- Very low birthweight males have a higher risk for neonatal complications and a higher mortality rate. ObjectivesThe overall objective of this study was to determine the extent to which fetal gender impacts on pregnancy complications and subsequent neonatal outcome. Material and Methods- Hospital-based cohort study at St. Josephs Health Care Center, London, ON.- Date extracted from electronic regional perinatal/neonatal databases from January 1st/1996 to December 31st/2005.- Singleton pregnancies of >25 completed weeks, without major congenital anomalies were included- A logistic regression analysis was done for caesarean section and gender at >37 weeks GA and for neonatal outcome at 25-32 weeks and >32 weeks GA - Statistical analyses were done using SASÔ. A p-value of <0.05 was considered significant, and where appropriate, a t-test, Chi-square test , or Wilcoxon two-sample test were used ResultsTotal Cohort: n=16657 male(M) and 15792 female(F) infantsMales have higher incidence of preterm delivery, intrapartum fever and antibiotics and delivery by caesarean section (CS). Males have higher incidence of 5-minute APGAR <7, NICU admission, RDS, mechanical ventilation, sepsis, IVH and have a longer NICU stay. Males have higher birth and placental weights25-28 weeks: No significant differences in maternal or neonatal outcomes except more neonatal sepsis in males (M; 45.7%, vs. F; 32.0%, p<0.01)29-32 weeks: Higher incidence of mild-severe PIH in mothers pregnant with females (M; 19.0% vs. F; 24.9%, p<0.05).33-36 weeks: Pregnant mothers with males have more intrapartum fever; receive more antibiotics without a difference in clinical diagnoses of chorioamnionitis. Males have a lower incidence of placenta previa (M; 2.7% vs. F; 4.5%, p<0.05).Male neonates have higher birth weights, are more likely to be admitted to the NICU, have a longer NICU stay and have more respiratory complications.≥37 weeks: Pregnant mothers with males have more intrapartum fever; receive more antibiotics without a difference in clinical diagnoses of chorioamnionitis. Males are more likely to be delivered by CS (M; 19.1% vs. F; 16.7%, p<0.001), with higher CS rates for failure to progress and/or non-reassuring fetal heart rate. Male neonates have a higher birth weight, higher incidence of 5-minute APGAR<7, more NICU admission and longer NICU stay and more respiratory complications (RDS, mechanical ventilation).
Logistic regression: Caesarean Section >37 weeks:
Logistic regression analysis showed that the most frequent factors associated with CS; IUGR(<3rd percentile), LGA(>97th percentile), birth weight >4000g and chorioamnionitis, were all independently associated with an increased risk for CS. A gender effect was demonstrated for CS in male fetuses >4000g, who had a significantly higher odds ratio for CS than female fetuses >4000g (OR(95%CI) for CS and fetal weight >4000g; M 1.91(1.78, 2.04) vs. F 1.44(1.33, 1.56)). Although there were no differences in gestational age, significantly more male fetuses weighed >4000g at birth (M; 16.7% vs. F; 9.7%, p<0.001) and male fetuses >4000g were 27.2g heavier than female fetuses >4000g (M; 4291.8 ± 255.3g vs. F; 4264.6 ± 244.3g, p<0.001). Neonatal outcome 25-32 weeks: 5-minutes APGAR<7, pulmonary complications and sepsis all independently correlated with gestational age, without an association with gender.≥ 33 weeks: 5-minute APGAR<7, pulmonary index, and sepsis independently correlated with GA, male sex associated with higher NICU admission and pulmonary index. DiscussionMale gender is associated with increased incidence of preterm delivery, possibly through the action of androgen precursors, which are involved in the production of estrogens which may facilitate labor.There is a male disadvantage with respect to neonatal morbidity, as described previously for preterm babies. In our cohort, there are no differences in the preterm groups, probably due to small sample size. Alternatively, extreme prematurity is likely to be the overwhelming factor causing neonatal morbidity, diluting a possible effect of gender. Near-term and term males have more NICU admissions and pulmonary complications, likely the result of slower lung development and surfactant production. DHT and testosterone have been shown to delay fetal lung maturation.There is a higher incidence of CS in the term male group, due to a higher incidence of FTP and/or NRFHR. A higher odds ratio persists for male infants in when the birth weight is >4000g. This is potentially the result of a slightly higher birth weight of males in this group. New knowledge, transdisciplinarity and knowledge transferThis study demonstrates that the male disadvantage of higher rates of preterm birth and increased neonatal morbidity and mortality extends past prematurity with a significant increase in morbidity in male neonates born at term. This is suggestive of a true gender effect on pathophysiological processes associated with pregnancy and transition to neonatal life. Alternatively, the differences at term may simply be effects of fetal size: bigger babies tend to have longer labours, longer interval between membrane rupture and delivery and therefore more infections, more dystocia, more fetal heart rate abnormalities with longer labours and more asphyxia, and as a consequence maybe have a less than optimal start in life. A study investigating these labour- and delivery factors is underway. This study has been completed in close collaboration with a neonatologist, statistician and epidemiologist. Results will be presented at SGI this month and a scientific paper is in progress: feel free to comment, all input is welcome. If you would like to have a look at the original stats and numbers, please contact me at bdevrije@uwo.ca. Questions1. Statisticians never fail to remind me that if you look at 20 items, one is bound to be significantly different - based on chance. Although it makes sense that heavier babies have more caesarean sections, can a – statistically significant – difference of 27 grams more in the ‘heavy males’ (males that weigh more than 4000g (8lb8oz)) group account for the increased odds ratio for caesarean sections? And is there a better way to assess this?2. What do you think is the clinical relevance of this project - could you think of ways that clinicians could act on this information and develop algorythms to reduce this male disadvantage?
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Jo Watson RN, MScN,
Jo Watson RN, MScN, ACNP
Director, Obstetrics and Gynaecology
Sunnybrook Health Sciences Centre
I wonder about attributing the morbidity to sex rather than explanations such as larger birth weight. Examination of the physiologic underpinnings of the male sex may hold more insight into these findings.
Hi Jo, Thank you for your
Hi Jo,
Thank you for your comments, and I agree with you, there are gender-associated differences in immunity that are more likely to explain differences in incidence of infectious complications of pregnancy and even pre-eclampsia and IUGR. In adults, these gender-associated differences in survival have been linked to differences in immune responses after challenges such as trauma or sepsis. One of the few researchers actively investigating gender-associated differences in pregnancy is Vicky Clifton in Newcastle, Australia, who assessed 11betaHSD, glucocorticoid receptors, cytokines and placental proteinomics is astmatic pregnancies. My studies in the lab look into gender associated differences in innate and reactive immune system in term placenta, maternal and fetal plasma, and the production of cytokines after an immune challenge.
However, I think size does matter - particularly in the mode of delivery. Although there is an increased rate of caesarean sections in males, the difference in odds ratios is small (>4000g, CS: OR 1.4 vs >4000g, CS and male: OR 1.9) and even in the '>4000g group', males are slightly heavier than females. It would be interesting to look at labour factors (length of labour, forceps, interval between membrane rupture and delivery), because if truly a weight effect, you would expect to see an increase in these other parameters.
Unfortunaltely, assessment of immunological pathways that are important in initiating and maintaining labour is impaired since labour itself is such an overwhelming factor in the immunological changes at delivery, that a possible gender effect will likely be diluted.
I was just wondering if
I was just wondering if similar gender differences are noticed with natural multiple pregnancies. I know there are many complications with multiple births but are there similar disadvantages observed with male twins versus female twins?
Reading the statistics section, it would have been easier to follow and comment had I seen the regression formulas.
Thank you for your
Thank you for your interesting comment; and I agree that twins would be the perfect comparison - if outcomes would be similar for each twin. However, twins have increased rates of growth restriction, congenital anomalies, gestational diabetes, pre-eclampsia, as well as an increase in preterm birth which - as suggested in the singletons, may obscure any gender effect that is there. Additionally, twin A, the firstborn, seems to do better than twin B, regardless of the mode of delivery!
I have not found any references regarding twin gender studies, and have eliminated them from my study for the reasons above - and I fear that my numbers of opposite sex twins are too low.
With regards to the stats: A two page limit does not leave space for a table:
Table 2A Reason for C-Sections by sex
# C-Sections
Male (n=2838)
Female (n=2388)
p value
Failure to Progress (FTP/CPD)
2131/5227 (40.8%)
1235 (43.5%)
896 (37.5%)
<0.001
Non-reassuring fetal heart rate
1040/5227 (19.9%)
622 (21.9%)
418 (17.5%)
<0.001
Malpresentation
1114/5227 (21.3%)
512 (18.0%)
602 (25.2%)
<0.001
Previous c-section
1189/5227 (22.8%)
613 (21.6%)
575 (24.1%)
0.033
Table 2B. Logistic Regression Analyses for infants ≥37 Weeks GA with gender & c-section
Dependent Variable
C-section
Sex - Male
OR (95% CI)
p value
OR (95% CI)
p value
c
IUGR (<3%)
1.42 (1.15, 1.75)
0.001
1.05 (0.88, 1.26)
0.566
0.537
LGA (>97%)
2.21 (1.96, 2.49)
<0.001
1.01 (0.91, 1.13)
0.867
0.571
Birth Weight > 4000 g
1.44 (1.33, 1.56)
<0.001
1.91 (1.78, 2.04)
<0.001
0.594
Chorioamnionitis
5.92 (4.45, 7.88)
<0.001
1.02 (0.76, 1.35)
0.921
0.691
The odds ratios and p values are ‘adjusted’ for the other factor. For example, adjusting for c-section, there is a difference between males and females in the proportion with a birth weight > 4000 g(p<.001, OR=1.91, 95% CI 1.78-2.04).
The c statistic represents the area under the curve. A value of .50 would have no discriminating capacity while a value of 1.0 would do so perfectly.
Interesting research - I
Interesting research - I appreciated your discussion section at the end that tied your research findings together and hinted at possible explanations for gender differences.
When reading your research, I found myself questioning what the possible mechanisms for these gender differences might be. You noted that androgens may be playing a role - do you have any other thoughts or speculations about what might be driving these differences?
Thanks,
Alex.
I think that the mechanism
I think that the mechanism lays mainly in the immune system - which is affected by sex hormones, but also in innate immunity. If you look at the (reproductive, societal) roles man and women traditionally play, women may have to be more tolerant immunologically than male (look at the size of the conceptus and imagine it being 50% foreign body: there is no infection that large you would easily survive), while an injured but surviving male may be more detrimental to the tribe than of use, hence the fight-until-you-die response. (sorry...)
I am working on a literature review and here is a small summary of what immuological factors have been studied:
Hints regarding immunity of maternal-fetal system come from adult human and animal studies of trauma and sepsis. Male gender has been shown to be a risk factor for the development of severe sepsis and recent trauma literature demonstrate that men have a higher incidence of mortality than women. One of the explanations proposed for this gender difference is the influence of sex hormones on the host immune response. Animal studies have further suggested that mitogen-activated protein kinase differences are involved in the mechanism of these gender differences.
When examining the immunity of the maternal-fetal system, some authors have discovered gender differences among the immune components of the amniotic fluid compartment. In particular, two groups have looked at the levels of interleukin-1 receptor antagonist (IL-1ra) in the maternal-fetal system. IL-1ra is a cytokine present in amniotic fluid and acts by blocking the effect of the cytokine interleukin-1 (IL-1). IL-1 has been shown to be increased in women with preterm labour and intrauterine infection (Bry, 1995- 17). It acts by stimulating production of prostaglandins in the amnion and decidua, which induces uterine contractions. Furthermore, administration of IL-1 to mice induced preterm labour. For these reasons, IL-1 is thought to mediate inflammation related to chorioamnionitis and preterm labour in the feto-placental compartment.
On the other hand, IL-1ra has been shown to block the effects of IL-1, including the stimulation of prostaglandin production by amnion cells (Bry 1995 – 6,7,20, 21). Romero et al. added to previous findings by showing that administration of systemic IL-1ra prevented preterm delivery induced in mice by IL-1. Given that IL-1ra plays such an integral role in preterm delivery and inflammation related to intrauterine infection, the presence of gender differences in IL-1ra could explain improved outcomes in pregnancies bearing female fetuses in complications of chorioamnionitis and preterm labour. Alternatively, this could mean that there is relatively more IL-1 activity in males, compared to females, which would permit the induction of labour (Romero).
In a small observational study of 42 women at midtrimester, 30 women undergoing cordocentesis for diagnostic purposes, 126 women with preterm labour, 105 women at term and eight women who were healthy and non-pregnant, Romero et al. (1994) measured the concentration of IL-1ra in maternal plasma, fetal plasma, amniotic fluid and neonatal urine. They found that the concentration of IL-1ra in amniotic fluid was significantly higher in female fetuses than male fetuses both at pre-term and term gestation (p<0.001 and p<0.001). The same trend was observed in the concentration of IL-1ra in neonatal urine (p<0.005).
More recent work has explored the possibility of gender differences in other cytokines involved in the immune system of the maternal-fetal system. Poggi et al. (2004) analyzed 74 samples of amniotic fluid taken from mid-trimester amniocenteses for levels of angiogenin, interleukin-6 (IL-6), and interleukin-10 (IL-10). Past literature has demonstrated that all three of these markers are elevated at midtrimester in pregnancies that are later complicated by preterm delivery. Angiogenin levels were found to be significantly lower in pregnancies with male fetuses compared to those with female pregnancies (p=0.007). However, there were no significant differences found between genders in levels of IL-6 (p=0.4) and IL-10 (p=0.1).
Gender differences have also been found in immune markers produced by the fetal lung. Clara cell protein 16 (CC16) is an immunomodulatory protein produced by the fetal lung with anti-inflammatory properties. CC16 inhibits the inflammatory production and activity of IL-1B, tumor necrosis factor-alpha, interferon-gamma (Perni 2005 – Dierynck) and phospholipase A2. Perni et al. (2005) found that CC16 levels at mid-trimester were elevated in pregnancies that were later complicated by preterm premature rupture of membranes (PPROM). They also found that in the 233 samples of mid-trimester amniotic fluid samples, male-bearing pregnancies had significantly higher median CC16 levels than female-bearing pregnancies (p=0.0005).
Other researchers have focused their efforts on describing the effect of sex hormones on the various components of the immune system. Roberts et al. (2001) point out several examples of this relationship in the human system. For example, the reactivity of the immune system in the reproductive organs of a woman varies according to her menstrual cycle. These changes promote an infection-free environment in the uterus just prior to ovulation, and then a relatively permissive environment that allows implantation without recognition of the sperm as a foreign antigen.
Further evidence for the immunomodulatory properties of sex hormones can be seen during pregnancy, when estrogen and progesterone, which are produced by the uterus and placenta, control the function of macrophages, natural killer (NK) cells, mast cells, eosinophils, neutrophils and T cells. As above, the tight regulation of immune cells prevents the maternal system from recognizing the developing trophoblast as foreign.
Additional immune factors I am currently investigating include the NFkB pathway and beta defensins, a protein important in the innate immunity
Thanks for your comments,
Barbra
Really interesting response
Really interesting response and way to frame it - I had not thought of it in that way. Thanks for that.
Alex.
Dear Barbra, this is an
Dear Barbra,
this is an exciting, inspiring piece of clinical research. I enjoyed reading it.
I would like to ask regarding your comment that 'Near-term and term males have more NICU admissions and pulmonary complications, likely the result of slower lung development and surfactant production. DHT and testosterone have been shown to delay fetal lung maturation.':
Did you consider gender-dependent effects of antenatal betamethasone (BM) treatment in logistic regression analysis? If not, do you think it would be a good idea to add this dimension? Is it known whether BM induces lung maturation to a lesser degree in male fetuses/neonates? That could account for higher RDS prevalence in males (and other complications related to lung immaturity). BM seems to protect against IVH. Higher incidence of IVH in males, again, could be due to a (hypothesized) attenuated BM effect on cerebrovascular tone in this gender group.
Another line of thought: Could it be that female fetuses have - on average - a better developed innate immune response which at one hand, , as you noted, manifests itself in higher incidence of histological diagnosis of chorioamnionitis in PPROM patients, and on the other hand (I speculate) gives them advantage that female fetuses can actually mount an (better) immune response to begin with while the male fetuses do not or at least less so which puts them at higher risk of infections, esp. with their lungs being less developed than in female neonates. This would fit into the higher NICU stays of male neonates.
Yet another thought: in fetal sheep it seems to me that body weight may be a better indicator of the individual developmental trajectory than the gestational age per se. In this vein, do you think it could be interesting to do logistic regression analysis for all fetuses >33 weeks looking at the factors you looked at plus umbilical cord (art./vein) pH, lactate, blood gases. I wonder in this context if males being more likely to show non-reassuring FHR patterns over > 37 w are also more likely to be born with signs of acidemia than female fetuses? As we know that non-reassuring FHR patterns are not helpful in identifying fetuses with acidemia, might that be different if one accounts for the gender? That would be immediately clinically relevant, I think.
Thank you and all the best,
Martin
Thanks, Martin, Yes,
Thanks, Martin,
Yes, bethamethasone was added in the logistic regression analysis and more males received steroids, with no significant improvement in outcome - and no gender differences. Again, the groups that would benefit most - the extreme preterms, are only represented in low numbers in this study and gender-associated differences in outcome as overwhelmingly present in the literature were not found in my study - we think because of the sample size. Additionally, males received more steroids and still had more complications.
With regards to your line of thought: this was my original hypothesis as well and we'll see whether I can demonstrate that with my molbio studies. Does the male immune system sit back and only get in action when it's too late? Maybe, who knows. There is an interesting tolerance of the female immune system however, and if your hypothesis is true, how come that the female - more aggressive - immune system tolerates pregnancy so well?
I disagree with your next statement - as in human, term fetal weight is not an accurate predictor of development in sheep due to huge variation - bigger mums have bigger babies, bigger dads have bigger babies, and in my sheep experience - with accurate dating - birthweight in control animals could vary anywhere between 2800 and 5000g. Generally, in the first trimester babies grow all at the same speed and dating based on weight is fairly accurate. In the second and third trimester - for sheep the second half of gestation - other factors play a role, amongst others genetic factors and nutrient supply.
But it will be interesting to look at all factors associated with the increased rate of caesarean sections in males, which includes labour data (length of labour, forceps, vacuum etc) as well as correlation of descriptive markers of fetal distress (type of decelerations, tachycardias, meconium) with pH and APGAR. That is a next study in the making.
Barbra
Dear Barbra, This is an
Dear Barbra,
This is an interesting research.
In your introduction, you said that pre-eclampsia is more common in pregnancies with male fetuses. Can you give more details?
I am wondering if you compare male and female with the same weigh, do you observe diferences?
Thanks
Frederique
Hi Frederique, See another
Hi Frederique,
See another abstract from the (unfinished) review: I do not think the evidence so far is very strong though and maybe I should remove the statement from my introduction. We found higher incidences of pre-eclampsia in females but only in one gestational age group - which I think is more likely to be coincidence rather than a true effect.
The etiology of pre-eclampsia is unknown and multiple theories regarding pathogenesis exist. Among the various theories, an immunologic mechanism has been proposed. It has been suggested that during the period of mutual immunologic tolerance between the maternal fetal systems during the first trimester, a Y chromosome dependent antigen causes histo-incompatability. This immunologic theory draws support from an observation of male gender effect in pregnancies affected by preeclampsia. Toivanen (1970, Science) reported a high male/female ratio among pregnancies affected by pre-eclampsia. This gender effect was not observed in a more recent retrospective study of 10 439 pregnancies in Kuwait (Mahkseed et al., 1998), of which 183 pregnancies were affected by pre-eclampsia. Although sample size was small, this study population was racially homogeneous and distinct from other populations studied, therefore it is possible that there are confounding genetic factors. Basso and Olsen (2000) used retrospective data from the Danish National Board of Health, the Danish National Birth Registry and Statistic Denmark’s Fertility Database over a 16-year period, from 1980 to 1996. They examined 24 065 births affected by pre-eclampsia in reference to a control population of 76 804 births not affected by pre-eclampsia. The male-to-female sex ratio was 1.10 (95% CI = 1.07 – 1.12) in births affected by pre-eclampsia. Steier et al. (2002) examined 64 women with pre-eclampsia with 73 women without pre-eclampsia in singleton pregnancy, during the third trimester. Interestingly, hCG was found to be significantly higher in male-bearing pregnancies affected by pre-eclampsia, compared to male-bearing pregnancies unaffected by pre-eclampsia (p< 0.001). Furthermore, this increase in hCG was not observed in female-bearing pregnancies. Testosterone was also found to be higher in both male- and female-bearing pregnancies affected by pre-eclampsia, compared to uncomplicated pregnancies (p< 0.001). Furthermore, in contradiction to Toivanen’s study, Hsu et al. reported a high female/male ratio in preterm pre-eclamptic pregnancies.
With regards to the weight: I would be cautious to do such an analysis, since gestational age is such an overwhelming factor in outcome - more so than weight.
Regards, barbra
Hi Barbra Thank you for the
Hi Barbra
Thank you for the presentation and the thorough discussion of the other questions, it helps a lot to clarify your ideas. I was wondering if the betamethasone would have an immunomodulatory side effect on the neonates, and that might the reason why although their lungs mature you don't see a difference in the outcomes regarding the complications specially because you are interested in infections.
It would be interesting to compare the differences in the mother of those males that are healthy and those that have complications, is the mother's nutrition very different? Do the mothers of the males with complication have subclinical infections? I guess the males are more susceptibles so maybe the preventions can be done in the prenatal stage.
Good luck, kind regards, Pia
Hi Pia, good to hear from
Hi Pia, good to hear from you. Congratulations too!
There are many reasons why we don't see differences in outcome with regards to the steroids - remember this is not a prospective study but a restrospective database study and therefore relatively dirty: one of the reasons why I left the steroids out of the discussion.
I have been careful to stay away from any conclusion with regards to steroids, since there are so many confounding factors. Not only the patients with preterm labour, but also the pre-eclamptic patients, the ones with a severe IUGR or abruption receive steroids. These small and potentially sick babies are more likely to have received steroids, and are subsequently more likely to have neonatal complications. There have been better designed and larger prospective and randomized studies that have shown a beneficial effect of steroids, and I think that any immunomodulatory effect is obscured by a strong effect on pulmonary function - especially in the extreme prematures - but my database study is unsuitable for such a conclusion.
I wish I knew what affects the initial selection of fetal gender (maybe it's a good thing I don't) but for now, it's chance (51% chance you'll have a male, 49% for female) - with maybe a minor contribution of timing of coitus long before or right before ovulation (there is a theory that suggests that sperm carrying the X-chromosome is heavier and therefore slower, and would reach the egg later than the 'male' sperm - alternatively, if ovulation occurs a bit later after intercourse male sperm has raced right past the egg or is too tired to react while the slow swimming female sperm has just reached the ampulla).
With fetal gender selected by chance you would assume that with a large database study like ours, confounding factors such as nutrition, social issues, intoxications all are corrected for. We did not find differences in parity, intoxications, previous preterms, miscarriages, age etc between the 2 gender groups, suggesting that these background data are similar between the groups. Although I do not have nutritional information, I am assuming there ar no differences in nutritional status - especcially since many women are in the data more than once and often with opposite sex babies.
No information is recorded in the database with regards to subclinical infection. But there have been studies looking at the placentas of males vs. females (Here is the literature review again.....)
A study by Ghidini and Salafia (2005) suggests an immunologic explanation for male predominance in preterm birth. They compared placental histo-pathologic findings between 232 male and 205 female singleton deliveries between 22 and 32 weeks gestation. They found that male placentas had greater severity of histologic evidence of chronic inflammation than female placentas. Interestingly, the areas of chronic inflammation were concentrated at the implantation site, where interstitial trophoblast invasion into the maternal tissues occurs. Chronic inflammation has been demonstrated in transplant rejection and is thought to be associated with immune response against foreign or antigenic tissue. The findings of increased chronic inflammation in male placentas compared to female placentas are indicative of greater maternal immune response against antigenic fetal tissues and invading interstitial trophoblasts in male placentas.
Take care, Barbra
J’aimerais savoir si vous
J’aimerais savoir si vous avez des naissances multiples de jumeaux non identiques (fille- garçon) et , si c’est le cas, pouvez- vous observer l’influence de sexe sur la condition de prématuré dans ce cas-là ?
I was wondering if you have the data, or simply were you interested in boy-girl twins multiple pregnancies. Is there any difference in child condition in case of preterm birth?
eva
Twins were excluded from the
Twins were excluded from the study. They are an entirely different study group with many confounding factors: birth order, mode of delivery, increased risk of congenital anomalies, increased risk of placental insufficiency. I do not think the database contains enough twins to accurately assess this: >50% of the twins are same-sex (based on chance with fraternal twins and add the identical twins) and you then need to separately analyse them according to birth order: twin A male or twin A female since birth order, regardless of the mode of delivery, affects prognosis. Even though you control for maternal/pregnancy related factors, it is not as clean as you would like since they may share a womb but they do not necessary share complications.
Barbra
Hi Barbra, First, I would
Hi Barbra,
First, I would like to thank Barbra; I thoroughly enjoyed reading her research.
My research project revolves around the sex differences in lung development, so I’d like share my thoughts on some of the questions relating to the BM treatment (Martin and Pia comments).
Concerning Martin’s question: “Is it known whether BM induces lung maturation to a lesser degree in male fetuses/neonates? That could account for higher RDS prevalence in males...” and Barbra folling comment.
As Barbra pointed-out, numerous studies have shown that antenatal corticosteroids reduce the risk of neonatal death, respiratory distress syndrome, other associated morbidity and neonatal intensive care unit admission in both sexes. It is also recognized that males present poorer outcome, regardless of antenatal GCs administration. This is probably explained by the fact that both male and female foetuses respond to GCs by the same mechanism. The male pulmonary maturation delay is thus maintained and so is the poorer outcome of male neonates. To date no sex difference has been shown (animal or clinical) relating to GCs response or lung GCs metabolism.
It is also well documented that only completed GCs treatment received up to 7 days prior to delivery are effective to prevent RDS (and subsequent complications).
Maybe the absence of a negative male outcome in your very premature sub-group could be explained (in part) by sub-optimal treatments in the male cohort?
Concerning Pia’s question: “...betamethasone would have an immunomodulatory side effect on the neonates... you don't see a difference in the outcomes regarding the complications especially because you are interested in infections”.
I agree with Barbra that the effect of GCs on lung maturation and prevention of RDS greatly outweighs their effects on subsequent infections, particularly in the most severely preterm neonates. However, antenatal GCs treatments certainly have an immunomodulatory effect on the neonates. For exemple animal studies have shown that antenatal GC treatment suppress fetal blood monocyte function (as measured by H202 production) below that of normal fetal levels 2 days after the initial treatment, but increases above to that of adult monocyte after 7 days (Kramer 2004, 2005). Chorioamnionitis have both been shown to both induce a phenotype of lung maturation and to play a role in BPD onset and progression (Watterberg 1996, Bry 1997) and so is inflammation. So in theory, inadequate immune response in the part of the male foetuses could exacerbate BPD development in the more RDS susceptible males.
This is only supposition, but in could a sex difference in immune response to chorioamnionitis or neonatal infections explain (partly) the male predisposition to BPD?
Thanks,
Eric