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Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth
Introduction: The Many Lanes of Research on Magnesium Sulfate
The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.
Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.
Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.
This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.
Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.
Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth
Without a doubt, magnesium sulfate (MgSO4) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.
Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.
This history also holds lessons for our specialty given the dearth of drugs approved for use in pregnancy and the recent withdrawal from the market of Makena — one of only nine drugs to ever be approved by the Food and Drug Administration for use in pregnancy — after a second trial showed lack of benefit in preventing recurrent preterm birth. The story of MgSO4 tells us it’s acceptable to have major stumbling blocks: At one point, MgSO4 was considered to be not only not helpful, but harmful, causing neonatal death. Further research disproved this initial finding.
Moreover, the MgSO4 story is one that remains unfinished, as my laboratory and other researchers work to better understand its biologic plausibility and to discover additional neuroprotective agents for anticipated preterm birth that may further reduce the risk of cerebral palsy. This leading cause of chronic childhood disability is estimated by the United Cerebral Palsy Foundation to affect approximately 800,000 people in the United States.
Origins and Biologic Plausibility
The MgSO4 story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.1 MgSO4 was first used for eclampsia in 1906,2 and was first reported in the American literature for eclampsia in 1925.3 In 1959, its effect as a tocolytic agent was reported.4
More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).5 The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.
The precise molecular mechanisms of action of MgSO4 for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.
Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO4 may ameliorate both.6,7
Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO4 sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).
In vitro research in our laboratory has also shown that MgSO4 may dampen inflammatory reactions driven by intrauterine infections, which, like preterm birth, increase the risk of cerebral palsy and adverse neurodevelopmental outcomes.8 MgSO4 appears to do so by blocking the voltage-gated P2X7 receptor in umbilical vein endothelial cells, thus blocking endothelial secretion of the proinflammatory cytokine interleukin (IL)–1beta. Much more research is needed to determine whether MgSO4 could help prevent cerebral palsy through this mechanism.
The Long Route of Research
The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO4 to prevent seizures in preeclampsia or as a tocolytic agent.5 In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO4 was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.
This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO4 had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”9
In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.
The six published randomized controlled trials looking at MgSO4 and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO4 administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO4 for preventing preeclampsia.
Again, none of the randomized controlled trials demonstrated statistical significance for their primary outcomes or concluded that there was a significant neuroprotective effect for cerebral palsy. Rather, most suggested benefit through secondary analyses. Moreover, as mentioned earlier, research that proceeded after the first published randomized controlled trial — the Magnesium and Neurologic Endpoints (MAGnet) trial — was suspended early when an interim analysis showed a significantly increased risk of mortality in MgSO4-exposed fetuses. All told, it wasn’t until researchers obtained unpublished data and conducted meta-analyses and systematic reviews that a significant effect of MgSO4 on cerebral palsy could be seen.
The three systematic reviews and the Cochrane review, each of which used slightly different methodologies, were published in rapid succession in 2009. One review calculated a relative risk of cerebral palsy of 0.71 (95% CI, 0.55-0.91) — and a relative risk for the combined outcome of death and cerebral palsy at 0.85 (95% CI, 0.74-0.98) — when women at risk of preterm birth were given MgSO4.15 The number needed to treat (NNT) to prevent one case of cerebral palsy was 63, investigators determined, and the NNT to prevent one case of cerebral palsy or infant death was 44.
Another review estimated the NNT for prevention of one case of cerebral palsy at 52 when MgSO4 is given at less than 34 weeks’ gestation, and similarly concluded that MgSO4 is associated with a significantly “reduced risk of moderate/severe CP and substantial gross motor dysfunction without any statistically significant effect on the risk of total pediatric mortality.”16
A third review, from the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU), estimated an NNT of 46 to prevent one case of cerebral palsy in infants exposed to MgSO4 before 30 weeks, and an NNT of 56 when exposure occurs before 32-34 weeks.17
The Cochrane Review, meanwhile, reported a relative reduction in the risk of cerebral palsy of 0.68 (95% CI, 0.54-0.87) when antenatal MgSO4 is given at less than 37 weeks’ gestation, as well as a significant reduction in the rate of substantial gross motor dysfunction (RR, 0.61; 95% CI, 0.44-0.85).18 The NNT to avoid one case of cerebral palsy, researchers reported, was 63.
Moving Forward
The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.19 For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.19
In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”20
Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO4 administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).
The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.21
N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.21 Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.
Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.
References
1. Clio Med. 1984;19(1-2):1-21.
2. Medicinsk Rev. (Bergen) 1906;32:264-272.
3. Am J Obstet Gynecol. 1996;174(4):1390-1391.
4. Am J Obstet Gynecol. 1959;78(1):27-32.
5. Pediatrics. 1995;95(2):263-269.
6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.
7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.
8. Pediatr Res. 2020;87(3):463-471.
9. J Child Neurol. 1992;7(1):70-76.
10. Lancet. 1997;350:1517-1518.
11. JAMA. 2003;290:2669-2676.
12. BJOG. 2007;114(3):310-318.
13. Lancet. 2002;359(9321):1877-1890.
14. N Engl J Med. 2008;359:895-905.
15. Obstet Gynecol. 2009;113(6):1327-1333.
16. Am J Obstet Gynecol. 2009;200(6):595-609.
17. Obstet Gynecol 2009;114:354-364.
18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.
19. www.thennt.com.
20. Obstet Gynecol. 2010;115:669-671.
21. Front Synaptic Neurosci. 2012;13:680899.
*This story was corrected on June 10, 2024.
Introduction: The Many Lanes of Research on Magnesium Sulfate
The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.
Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.
Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.
This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.
Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.
Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth
Without a doubt, magnesium sulfate (MgSO4) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.
Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.
This history also holds lessons for our specialty given the dearth of drugs approved for use in pregnancy and the recent withdrawal from the market of Makena — one of only nine drugs to ever be approved by the Food and Drug Administration for use in pregnancy — after a second trial showed lack of benefit in preventing recurrent preterm birth. The story of MgSO4 tells us it’s acceptable to have major stumbling blocks: At one point, MgSO4 was considered to be not only not helpful, but harmful, causing neonatal death. Further research disproved this initial finding.
Moreover, the MgSO4 story is one that remains unfinished, as my laboratory and other researchers work to better understand its biologic plausibility and to discover additional neuroprotective agents for anticipated preterm birth that may further reduce the risk of cerebral palsy. This leading cause of chronic childhood disability is estimated by the United Cerebral Palsy Foundation to affect approximately 800,000 people in the United States.
Origins and Biologic Plausibility
The MgSO4 story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.1 MgSO4 was first used for eclampsia in 1906,2 and was first reported in the American literature for eclampsia in 1925.3 In 1959, its effect as a tocolytic agent was reported.4
More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).5 The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.
The precise molecular mechanisms of action of MgSO4 for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.
Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO4 may ameliorate both.6,7
Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO4 sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).
In vitro research in our laboratory has also shown that MgSO4 may dampen inflammatory reactions driven by intrauterine infections, which, like preterm birth, increase the risk of cerebral palsy and adverse neurodevelopmental outcomes.8 MgSO4 appears to do so by blocking the voltage-gated P2X7 receptor in umbilical vein endothelial cells, thus blocking endothelial secretion of the proinflammatory cytokine interleukin (IL)–1beta. Much more research is needed to determine whether MgSO4 could help prevent cerebral palsy through this mechanism.
The Long Route of Research
The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO4 to prevent seizures in preeclampsia or as a tocolytic agent.5 In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO4 was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.
This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO4 had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”9
In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.
The six published randomized controlled trials looking at MgSO4 and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO4 administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO4 for preventing preeclampsia.
Again, none of the randomized controlled trials demonstrated statistical significance for their primary outcomes or concluded that there was a significant neuroprotective effect for cerebral palsy. Rather, most suggested benefit through secondary analyses. Moreover, as mentioned earlier, research that proceeded after the first published randomized controlled trial — the Magnesium and Neurologic Endpoints (MAGnet) trial — was suspended early when an interim analysis showed a significantly increased risk of mortality in MgSO4-exposed fetuses. All told, it wasn’t until researchers obtained unpublished data and conducted meta-analyses and systematic reviews that a significant effect of MgSO4 on cerebral palsy could be seen.
The three systematic reviews and the Cochrane review, each of which used slightly different methodologies, were published in rapid succession in 2009. One review calculated a relative risk of cerebral palsy of 0.71 (95% CI, 0.55-0.91) — and a relative risk for the combined outcome of death and cerebral palsy at 0.85 (95% CI, 0.74-0.98) — when women at risk of preterm birth were given MgSO4.15 The number needed to treat (NNT) to prevent one case of cerebral palsy was 63, investigators determined, and the NNT to prevent one case of cerebral palsy or infant death was 44.
Another review estimated the NNT for prevention of one case of cerebral palsy at 52 when MgSO4 is given at less than 34 weeks’ gestation, and similarly concluded that MgSO4 is associated with a significantly “reduced risk of moderate/severe CP and substantial gross motor dysfunction without any statistically significant effect on the risk of total pediatric mortality.”16
A third review, from the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU), estimated an NNT of 46 to prevent one case of cerebral palsy in infants exposed to MgSO4 before 30 weeks, and an NNT of 56 when exposure occurs before 32-34 weeks.17
The Cochrane Review, meanwhile, reported a relative reduction in the risk of cerebral palsy of 0.68 (95% CI, 0.54-0.87) when antenatal MgSO4 is given at less than 37 weeks’ gestation, as well as a significant reduction in the rate of substantial gross motor dysfunction (RR, 0.61; 95% CI, 0.44-0.85).18 The NNT to avoid one case of cerebral palsy, researchers reported, was 63.
Moving Forward
The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.19 For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.19
In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”20
Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO4 administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).
The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.21
N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.21 Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.
Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.
References
1. Clio Med. 1984;19(1-2):1-21.
2. Medicinsk Rev. (Bergen) 1906;32:264-272.
3. Am J Obstet Gynecol. 1996;174(4):1390-1391.
4. Am J Obstet Gynecol. 1959;78(1):27-32.
5. Pediatrics. 1995;95(2):263-269.
6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.
7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.
8. Pediatr Res. 2020;87(3):463-471.
9. J Child Neurol. 1992;7(1):70-76.
10. Lancet. 1997;350:1517-1518.
11. JAMA. 2003;290:2669-2676.
12. BJOG. 2007;114(3):310-318.
13. Lancet. 2002;359(9321):1877-1890.
14. N Engl J Med. 2008;359:895-905.
15. Obstet Gynecol. 2009;113(6):1327-1333.
16. Am J Obstet Gynecol. 2009;200(6):595-609.
17. Obstet Gynecol 2009;114:354-364.
18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.
19. www.thennt.com.
20. Obstet Gynecol. 2010;115:669-671.
21. Front Synaptic Neurosci. 2012;13:680899.
*This story was corrected on June 10, 2024.
Introduction: The Many Lanes of Research on Magnesium Sulfate
The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.
Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.
Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.
This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.
Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.
Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.
E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth
Without a doubt, magnesium sulfate (MgSO4) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.
Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.
This history also holds lessons for our specialty given the dearth of drugs approved for use in pregnancy and the recent withdrawal from the market of Makena — one of only nine drugs to ever be approved by the Food and Drug Administration for use in pregnancy — after a second trial showed lack of benefit in preventing recurrent preterm birth. The story of MgSO4 tells us it’s acceptable to have major stumbling blocks: At one point, MgSO4 was considered to be not only not helpful, but harmful, causing neonatal death. Further research disproved this initial finding.
Moreover, the MgSO4 story is one that remains unfinished, as my laboratory and other researchers work to better understand its biologic plausibility and to discover additional neuroprotective agents for anticipated preterm birth that may further reduce the risk of cerebral palsy. This leading cause of chronic childhood disability is estimated by the United Cerebral Palsy Foundation to affect approximately 800,000 people in the United States.
Origins and Biologic Plausibility
The MgSO4 story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.1 MgSO4 was first used for eclampsia in 1906,2 and was first reported in the American literature for eclampsia in 1925.3 In 1959, its effect as a tocolytic agent was reported.4
More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).5 The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.
The precise molecular mechanisms of action of MgSO4 for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.
Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO4 may ameliorate both.6,7
Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO4 sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).
In vitro research in our laboratory has also shown that MgSO4 may dampen inflammatory reactions driven by intrauterine infections, which, like preterm birth, increase the risk of cerebral palsy and adverse neurodevelopmental outcomes.8 MgSO4 appears to do so by blocking the voltage-gated P2X7 receptor in umbilical vein endothelial cells, thus blocking endothelial secretion of the proinflammatory cytokine interleukin (IL)–1beta. Much more research is needed to determine whether MgSO4 could help prevent cerebral palsy through this mechanism.
The Long Route of Research
The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO4 to prevent seizures in preeclampsia or as a tocolytic agent.5 In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO4 was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.
This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO4 had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”9
In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.
The six published randomized controlled trials looking at MgSO4 and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO4 administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO4 for preventing preeclampsia.
Again, none of the randomized controlled trials demonstrated statistical significance for their primary outcomes or concluded that there was a significant neuroprotective effect for cerebral palsy. Rather, most suggested benefit through secondary analyses. Moreover, as mentioned earlier, research that proceeded after the first published randomized controlled trial — the Magnesium and Neurologic Endpoints (MAGnet) trial — was suspended early when an interim analysis showed a significantly increased risk of mortality in MgSO4-exposed fetuses. All told, it wasn’t until researchers obtained unpublished data and conducted meta-analyses and systematic reviews that a significant effect of MgSO4 on cerebral palsy could be seen.
The three systematic reviews and the Cochrane review, each of which used slightly different methodologies, were published in rapid succession in 2009. One review calculated a relative risk of cerebral palsy of 0.71 (95% CI, 0.55-0.91) — and a relative risk for the combined outcome of death and cerebral palsy at 0.85 (95% CI, 0.74-0.98) — when women at risk of preterm birth were given MgSO4.15 The number needed to treat (NNT) to prevent one case of cerebral palsy was 63, investigators determined, and the NNT to prevent one case of cerebral palsy or infant death was 44.
Another review estimated the NNT for prevention of one case of cerebral palsy at 52 when MgSO4 is given at less than 34 weeks’ gestation, and similarly concluded that MgSO4 is associated with a significantly “reduced risk of moderate/severe CP and substantial gross motor dysfunction without any statistically significant effect on the risk of total pediatric mortality.”16
A third review, from the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU), estimated an NNT of 46 to prevent one case of cerebral palsy in infants exposed to MgSO4 before 30 weeks, and an NNT of 56 when exposure occurs before 32-34 weeks.17
The Cochrane Review, meanwhile, reported a relative reduction in the risk of cerebral palsy of 0.68 (95% CI, 0.54-0.87) when antenatal MgSO4 is given at less than 37 weeks’ gestation, as well as a significant reduction in the rate of substantial gross motor dysfunction (RR, 0.61; 95% CI, 0.44-0.85).18 The NNT to avoid one case of cerebral palsy, researchers reported, was 63.
Moving Forward
The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.19 For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.19
In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”20
Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO4 administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).
The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.21
N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.21 Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.
Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.
References
1. Clio Med. 1984;19(1-2):1-21.
2. Medicinsk Rev. (Bergen) 1906;32:264-272.
3. Am J Obstet Gynecol. 1996;174(4):1390-1391.
4. Am J Obstet Gynecol. 1959;78(1):27-32.
5. Pediatrics. 1995;95(2):263-269.
6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.
7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.
8. Pediatr Res. 2020;87(3):463-471.
9. J Child Neurol. 1992;7(1):70-76.
10. Lancet. 1997;350:1517-1518.
11. JAMA. 2003;290:2669-2676.
12. BJOG. 2007;114(3):310-318.
13. Lancet. 2002;359(9321):1877-1890.
14. N Engl J Med. 2008;359:895-905.
15. Obstet Gynecol. 2009;113(6):1327-1333.
16. Am J Obstet Gynecol. 2009;200(6):595-609.
17. Obstet Gynecol 2009;114:354-364.
18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.
19. www.thennt.com.
20. Obstet Gynecol. 2010;115:669-671.
21. Front Synaptic Neurosci. 2012;13:680899.
*This story was corrected on June 10, 2024.
Gestational Diabetes Treatment Moves Forward With Uncertainty And Hope
FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
The State Of Knowledge About Oral Hypoglycemics
The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.
Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.
In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.
In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”
A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.
“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”
Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.
Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.
Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
The Challenge of Heterogeneity
In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.
Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.
A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.
Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”
Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.
There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)
“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”
Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.
The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity
Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.
She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.
A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”
Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.
“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”
The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.
In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.
Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”
FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
The State Of Knowledge About Oral Hypoglycemics
The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.
Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.
In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.
In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”
A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.
“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”
Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.
Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.
Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
The Challenge of Heterogeneity
In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.
Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.
A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.
Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”
Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.
There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)
“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”
Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.
The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity
Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.
She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.
A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”
Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.
“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”
The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.
In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.
Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”
FAIRFAX, VIRGINIA — , but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.
Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.
The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.
The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.
“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.
The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.
The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.
The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.
The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
The State Of Knowledge About Oral Hypoglycemics
The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.
Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.
In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.
In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”
A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.
“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”
Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.
Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.
Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
The Challenge of Heterogeneity
In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.
Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.
A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.
Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”
Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.
There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)
“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”
Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.
The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity
Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.
She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.
A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”
Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.
“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”
The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.
In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.
Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”
FROM DPSG-NA 2023
The Knowns and Unknowns About Delivery Timing in Diabetes
FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.
The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.
“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
ACOG Recommendations, Randomized Trials (New And Old)
The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).
In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.
ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.
The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.
The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)
Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).
Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.
What Retrospective Studies Reveal
Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.
Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”
The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.
However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).
In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)
The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.
Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.
In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).
Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”
Dr. Grantz reported no disclosures.
FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.
The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.
“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
ACOG Recommendations, Randomized Trials (New And Old)
The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).
In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.
ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.
The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.
The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)
Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).
Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.
What Retrospective Studies Reveal
Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.
Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”
The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.
However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).
In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)
The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.
Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.
In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).
Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”
Dr. Grantz reported no disclosures.
FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.
“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.
The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.
“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
ACOG Recommendations, Randomized Trials (New And Old)
The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).
In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.
ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.
The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.
The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)
Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).
Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.
What Retrospective Studies Reveal
Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.
Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”
The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.
However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).
In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)
The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.
Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.
In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).
Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”
Dr. Grantz reported no disclosures.
FROM DPSG-NA 2023
A nurse’s view: Blood test for severe preeclampsia will save lives
There is amazing news for the world of obstetrics and for all pregnant women. Severe preeclampsia is a critical obstetrical condition that can have serious outcomes for a mother and baby. It can lead to eclampsia, an obstetrical emergency, which often results in death of the mother and/or baby.
Based on research published in the Journal of the American Heart Association, the incidence of new‐onset hypertensive disorders of pregnancy (gestational hypertension and preeclampsia/eclampsia) have nearly doubled in the United States from 2007 to 2019. And they continue to climb.
According to the Preeclampsia Foundation, 5%-8% of all pregnancies in the United States will result in preeclampsia. Black women are at a 60% higher risk than white women, and according to various sources, other risk groups include those who became pregnant via in vitro fertilization, mothers of multiples (twins and triplets), women with gestational diabetes, women over age 35, women with chronic hypertension, obesity, polycystic ovary syndrome, sickle cell disease, rheumatoid arthritis, lupus, migraines, antiphospholipid syndrome, previous pregnancy with preeclampsia, family history, and scleroderma.
Screening and treatment
Preeclampsia is a multiorgan disease of pregnancy, and can be mild, but may quickly progress to severe, which can be life-threatening for mother and baby. It was previously referred to as toxemia or the high blood pressure disease of pregnancy. It primarily involves the cardiovascular, neurologic and renal systems, and the liver. Patients typically present with elevated blood pressures, but other symptoms may include headache, swelling of hands and feet, blurry/double vision or seeing spots, nausea/vomiting, and epigastric pain. It is diagnosed with elevated blood pressures, blood work, and protein in the urine.
Early screening for preeclampsia is done in the first trimester. Presently, a combination of prenatal blood work, blood pressure monitoring, and recognition of high-risk groups is used to determine a treatment plan going forward. The American Congress of Obstetricians and Gynecologists recommends women that fall into this group for potentially developing preeclampsia take daily aspirin as a preventative measure.
In its milder form, a pregnant woman can be observed as an outpatient – monitored with antepartum testing, lab work, and patient education to report significant symptoms as listed above. Teaching patients about fetal kick counts to monitor their baby’s movements is equally important. Women with mild preeclampsia usually can safely deliver at term, being induced between 37-39 weeks’ gestation.
On the other hand, if mild preeclampsia progresses to severe preeclampsia, delivery may be preterm for the safety of mother and baby. Severe preeclampsia can lead to maternal organ damage, seizures, and even death of mother and/or baby.
About 20% of women with severe preeclampsia will develop HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, a life-threatening disease that often warrants immediate delivery. According to the National Library of Medicine, the mortality rate of women with HELLP syndrome is up to 24% and the perinatal death rate is up as high as 37%. These serious conditions can cause ineffective maternal clotting, liver rupture, placental abruption, and postpartum hemorrhage. It is most prevalent in the third trimester but can occur within 48 hours of delivery.
The only cure for preeclampsia in any form is delivery.
Patients with severe preeclampsia are hospitalized until delivery – sometimes a few days to a couple of weeks. Mother and baby are closely watched for further progression, including signs of organ damage in the mother and changes to the well-being of the baby. If the mother’s health is severely compromised, then the baby will be compromised as well. A preterm delivery may be necessary.
Impact of the new test
The National Institute of Health states that preterm babies born from preeclamptic mothers can suffer many health problems including cerebral palsy, deafness, blindness, epilepsy, and a host of other respiratory, cardiovascular, and endocrine issues. But the biggest issue is preterm birth, defined as birth before 37 weeks gestation. Being born preterm can require a long stay in the intensive care nursery.
This is where the first-of-its-kind prognostic blood test comes into play. The test’s ability to predict severe preeclampsia within 2 weeks can help save lives. The test can offer health care providers the ability to administer steroids for fetal lung maturity before delivery and be more prepared to care for what could be a very compromised newborn.
The blood test, which is recommended between 23-35 weeks gestation, involves analyzing a ratio between two proteins from the placenta, sFlt1 and PIGF. The higher the ratio, the higher the risk that severe preeclampsia will develop. Results can be available within 30 minutes, which is critical when contemplating treatment.
An example of the use of this ratio is illustrated with chronic hypertension in pregnancy, which is defined as elevated blood pressure before 20 weeks or even before conception. Since chronic hypertension can be a primary precursor to preeclampsia, patients with this condition are at higher risk. The FDA-approved blood test would be helpful in determining the plan of care; that is, delivery versus hospitalization versus monitor as an outpatient.
With a positive test result, a pregnant woman can be immediately hospitalized where she can get the care she and baby need as they await delivery. Since health care providers already know the high-risk groups, surveillance can begin early, utilizing this blood test to predict the progression to severe preeclampsia. Conversely, if the test is negative, a treatment plan can be made as an outpatient and the pregnancy continues.
Not all hospitals are equipped to care for premature babies. If delivery is not imminent, providers can use this blood test to identify those that should be transferred to a tertiary center for observation and monitoring. Mother and baby would then not be separated after birth.
We really don’t know who will develop severe preeclampsia and who won’t. This new blood test will be a critical tool as pregnant patients go through their second and third trimesters. It will be especially pivotal for these women, but important for all pregnant women in reducing maternal and fetal mortality and morbidity.
Ms. Barnett is a registered nurse in the department of obstetrics, Mills-Peninsula Medical Center, Burlingame, Calif. She has disclosed no relevant financial relationships.
There is amazing news for the world of obstetrics and for all pregnant women. Severe preeclampsia is a critical obstetrical condition that can have serious outcomes for a mother and baby. It can lead to eclampsia, an obstetrical emergency, which often results in death of the mother and/or baby.
Based on research published in the Journal of the American Heart Association, the incidence of new‐onset hypertensive disorders of pregnancy (gestational hypertension and preeclampsia/eclampsia) have nearly doubled in the United States from 2007 to 2019. And they continue to climb.
According to the Preeclampsia Foundation, 5%-8% of all pregnancies in the United States will result in preeclampsia. Black women are at a 60% higher risk than white women, and according to various sources, other risk groups include those who became pregnant via in vitro fertilization, mothers of multiples (twins and triplets), women with gestational diabetes, women over age 35, women with chronic hypertension, obesity, polycystic ovary syndrome, sickle cell disease, rheumatoid arthritis, lupus, migraines, antiphospholipid syndrome, previous pregnancy with preeclampsia, family history, and scleroderma.
Screening and treatment
Preeclampsia is a multiorgan disease of pregnancy, and can be mild, but may quickly progress to severe, which can be life-threatening for mother and baby. It was previously referred to as toxemia or the high blood pressure disease of pregnancy. It primarily involves the cardiovascular, neurologic and renal systems, and the liver. Patients typically present with elevated blood pressures, but other symptoms may include headache, swelling of hands and feet, blurry/double vision or seeing spots, nausea/vomiting, and epigastric pain. It is diagnosed with elevated blood pressures, blood work, and protein in the urine.
Early screening for preeclampsia is done in the first trimester. Presently, a combination of prenatal blood work, blood pressure monitoring, and recognition of high-risk groups is used to determine a treatment plan going forward. The American Congress of Obstetricians and Gynecologists recommends women that fall into this group for potentially developing preeclampsia take daily aspirin as a preventative measure.
In its milder form, a pregnant woman can be observed as an outpatient – monitored with antepartum testing, lab work, and patient education to report significant symptoms as listed above. Teaching patients about fetal kick counts to monitor their baby’s movements is equally important. Women with mild preeclampsia usually can safely deliver at term, being induced between 37-39 weeks’ gestation.
On the other hand, if mild preeclampsia progresses to severe preeclampsia, delivery may be preterm for the safety of mother and baby. Severe preeclampsia can lead to maternal organ damage, seizures, and even death of mother and/or baby.
About 20% of women with severe preeclampsia will develop HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, a life-threatening disease that often warrants immediate delivery. According to the National Library of Medicine, the mortality rate of women with HELLP syndrome is up to 24% and the perinatal death rate is up as high as 37%. These serious conditions can cause ineffective maternal clotting, liver rupture, placental abruption, and postpartum hemorrhage. It is most prevalent in the third trimester but can occur within 48 hours of delivery.
The only cure for preeclampsia in any form is delivery.
Patients with severe preeclampsia are hospitalized until delivery – sometimes a few days to a couple of weeks. Mother and baby are closely watched for further progression, including signs of organ damage in the mother and changes to the well-being of the baby. If the mother’s health is severely compromised, then the baby will be compromised as well. A preterm delivery may be necessary.
Impact of the new test
The National Institute of Health states that preterm babies born from preeclamptic mothers can suffer many health problems including cerebral palsy, deafness, blindness, epilepsy, and a host of other respiratory, cardiovascular, and endocrine issues. But the biggest issue is preterm birth, defined as birth before 37 weeks gestation. Being born preterm can require a long stay in the intensive care nursery.
This is where the first-of-its-kind prognostic blood test comes into play. The test’s ability to predict severe preeclampsia within 2 weeks can help save lives. The test can offer health care providers the ability to administer steroids for fetal lung maturity before delivery and be more prepared to care for what could be a very compromised newborn.
The blood test, which is recommended between 23-35 weeks gestation, involves analyzing a ratio between two proteins from the placenta, sFlt1 and PIGF. The higher the ratio, the higher the risk that severe preeclampsia will develop. Results can be available within 30 minutes, which is critical when contemplating treatment.
An example of the use of this ratio is illustrated with chronic hypertension in pregnancy, which is defined as elevated blood pressure before 20 weeks or even before conception. Since chronic hypertension can be a primary precursor to preeclampsia, patients with this condition are at higher risk. The FDA-approved blood test would be helpful in determining the plan of care; that is, delivery versus hospitalization versus monitor as an outpatient.
With a positive test result, a pregnant woman can be immediately hospitalized where she can get the care she and baby need as they await delivery. Since health care providers already know the high-risk groups, surveillance can begin early, utilizing this blood test to predict the progression to severe preeclampsia. Conversely, if the test is negative, a treatment plan can be made as an outpatient and the pregnancy continues.
Not all hospitals are equipped to care for premature babies. If delivery is not imminent, providers can use this blood test to identify those that should be transferred to a tertiary center for observation and monitoring. Mother and baby would then not be separated after birth.
We really don’t know who will develop severe preeclampsia and who won’t. This new blood test will be a critical tool as pregnant patients go through their second and third trimesters. It will be especially pivotal for these women, but important for all pregnant women in reducing maternal and fetal mortality and morbidity.
Ms. Barnett is a registered nurse in the department of obstetrics, Mills-Peninsula Medical Center, Burlingame, Calif. She has disclosed no relevant financial relationships.
There is amazing news for the world of obstetrics and for all pregnant women. Severe preeclampsia is a critical obstetrical condition that can have serious outcomes for a mother and baby. It can lead to eclampsia, an obstetrical emergency, which often results in death of the mother and/or baby.
Based on research published in the Journal of the American Heart Association, the incidence of new‐onset hypertensive disorders of pregnancy (gestational hypertension and preeclampsia/eclampsia) have nearly doubled in the United States from 2007 to 2019. And they continue to climb.
According to the Preeclampsia Foundation, 5%-8% of all pregnancies in the United States will result in preeclampsia. Black women are at a 60% higher risk than white women, and according to various sources, other risk groups include those who became pregnant via in vitro fertilization, mothers of multiples (twins and triplets), women with gestational diabetes, women over age 35, women with chronic hypertension, obesity, polycystic ovary syndrome, sickle cell disease, rheumatoid arthritis, lupus, migraines, antiphospholipid syndrome, previous pregnancy with preeclampsia, family history, and scleroderma.
Screening and treatment
Preeclampsia is a multiorgan disease of pregnancy, and can be mild, but may quickly progress to severe, which can be life-threatening for mother and baby. It was previously referred to as toxemia or the high blood pressure disease of pregnancy. It primarily involves the cardiovascular, neurologic and renal systems, and the liver. Patients typically present with elevated blood pressures, but other symptoms may include headache, swelling of hands and feet, blurry/double vision or seeing spots, nausea/vomiting, and epigastric pain. It is diagnosed with elevated blood pressures, blood work, and protein in the urine.
Early screening for preeclampsia is done in the first trimester. Presently, a combination of prenatal blood work, blood pressure monitoring, and recognition of high-risk groups is used to determine a treatment plan going forward. The American Congress of Obstetricians and Gynecologists recommends women that fall into this group for potentially developing preeclampsia take daily aspirin as a preventative measure.
In its milder form, a pregnant woman can be observed as an outpatient – monitored with antepartum testing, lab work, and patient education to report significant symptoms as listed above. Teaching patients about fetal kick counts to monitor their baby’s movements is equally important. Women with mild preeclampsia usually can safely deliver at term, being induced between 37-39 weeks’ gestation.
On the other hand, if mild preeclampsia progresses to severe preeclampsia, delivery may be preterm for the safety of mother and baby. Severe preeclampsia can lead to maternal organ damage, seizures, and even death of mother and/or baby.
About 20% of women with severe preeclampsia will develop HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, a life-threatening disease that often warrants immediate delivery. According to the National Library of Medicine, the mortality rate of women with HELLP syndrome is up to 24% and the perinatal death rate is up as high as 37%. These serious conditions can cause ineffective maternal clotting, liver rupture, placental abruption, and postpartum hemorrhage. It is most prevalent in the third trimester but can occur within 48 hours of delivery.
The only cure for preeclampsia in any form is delivery.
Patients with severe preeclampsia are hospitalized until delivery – sometimes a few days to a couple of weeks. Mother and baby are closely watched for further progression, including signs of organ damage in the mother and changes to the well-being of the baby. If the mother’s health is severely compromised, then the baby will be compromised as well. A preterm delivery may be necessary.
Impact of the new test
The National Institute of Health states that preterm babies born from preeclamptic mothers can suffer many health problems including cerebral palsy, deafness, blindness, epilepsy, and a host of other respiratory, cardiovascular, and endocrine issues. But the biggest issue is preterm birth, defined as birth before 37 weeks gestation. Being born preterm can require a long stay in the intensive care nursery.
This is where the first-of-its-kind prognostic blood test comes into play. The test’s ability to predict severe preeclampsia within 2 weeks can help save lives. The test can offer health care providers the ability to administer steroids for fetal lung maturity before delivery and be more prepared to care for what could be a very compromised newborn.
The blood test, which is recommended between 23-35 weeks gestation, involves analyzing a ratio between two proteins from the placenta, sFlt1 and PIGF. The higher the ratio, the higher the risk that severe preeclampsia will develop. Results can be available within 30 minutes, which is critical when contemplating treatment.
An example of the use of this ratio is illustrated with chronic hypertension in pregnancy, which is defined as elevated blood pressure before 20 weeks or even before conception. Since chronic hypertension can be a primary precursor to preeclampsia, patients with this condition are at higher risk. The FDA-approved blood test would be helpful in determining the plan of care; that is, delivery versus hospitalization versus monitor as an outpatient.
With a positive test result, a pregnant woman can be immediately hospitalized where she can get the care she and baby need as they await delivery. Since health care providers already know the high-risk groups, surveillance can begin early, utilizing this blood test to predict the progression to severe preeclampsia. Conversely, if the test is negative, a treatment plan can be made as an outpatient and the pregnancy continues.
Not all hospitals are equipped to care for premature babies. If delivery is not imminent, providers can use this blood test to identify those that should be transferred to a tertiary center for observation and monitoring. Mother and baby would then not be separated after birth.
We really don’t know who will develop severe preeclampsia and who won’t. This new blood test will be a critical tool as pregnant patients go through their second and third trimesters. It will be especially pivotal for these women, but important for all pregnant women in reducing maternal and fetal mortality and morbidity.
Ms. Barnett is a registered nurse in the department of obstetrics, Mills-Peninsula Medical Center, Burlingame, Calif. She has disclosed no relevant financial relationships.
Atopic dermatitis may be a risk factor for GBS colonization in pregnancy
suggest.
“The rate of GBS colonization among pregnant females with a history of AD has not been previously reported, but AD could be a risk factor for maternal carriage of GBS,” corresponding author David J. Margolis, MD, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and colleagues wrote in the study, which was published as a letter to the editor online in the Journal of Investigative Dermatology. “GBS reporting in a large administrative database represents a unique opportunity to conduct a population-based evaluation of GBS carriage with AD. Understanding this association could expand our understanding of microbial changes associated with AD,” they noted.
To determine if an association between GBS and AD in pregnant women exists, the researchers performed a cross-sectional study using a random sample from an Optum administrative database of pregnant women who had vaginal deliveries between May of 2007 and September 2021. The primary outcome of interest was the presence of GBS based on American College of Obstetricians and Gynecologists–recommended codes for GBS during 36 0/7 to 37 6/7 weeks of pregnancy. They used descriptive statistics to summarize categorical and continuous variables as proportions and means, and logistic regression to examine the association between AD and GBS status.
The cohort included 566,467 pregnant women with an average age of 38.8 years. Of these, 2.9% had a diagnosis of AD or a history of AD, and 24.9% had diagnoses of asthma, seasonal allergies, or both. Women with AD had an increased odds ratio of asthma (OR, 2.55), seasonal allergies (OR, 3.39), or both (OR, 5.35), compared with those without AD.
GBS was reported in 20.6% of the cohort. The median time of follow-up for those with and without GBS was 494 days and 468 days, respectively (P = .134). Among the women with AD, 24.1% had GBS, compared with 20.51% of the women without AD (P <.0001), which translated into an OR of 1.23 (95% confidence interval, 1.18-1.27).
Among the women with GBS, the OR of asthma was 1.08 (95% CI, 1.06-1.10) and was 1.07 (95% CI, 1.05-1.09) among those with seasonal allergies. When adjusted for potential confounders, these findings did not change substantively.
“It is not apparent why pregnant females with AD are more likely to specifically carry GBS,” the authors wrote. “However, several studies have shown that individuals with AD are more likely to carry [Staphylococcus] aureus and that individuals with AD might be deficient in host defenses against S. aureus and other pathogens,” they added.
“Individuals with AD frequently receive antibiotics as part of their AD treatment and this might alter their resident microbiome. Carriage rates may be enhanced by the inhibition of an important barrier protein called filaggrin (FLG) and FLG loss of function genetic variation is known to decrease barrier proteins thought to inhibit the colonization of S. aureus and other pathogens,” the researchers wrote.
They acknowledged certain limitations of their study, including its reliance on an administrative database that does not contain information on past disease.
Asked to comment on the results, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the study, characterized AD as “the poster child for cutaneous dysbiosis – an altered petri dish, so to speak, [that] facilitates survival of the few, leading to decreased microbial diversity that can both enable potential pathogen invasion and immune dysregulation.”
Though it’s not surprising that pregnant AD patients have dysbiosis, the focus on GBS, “which can be a bad actor in the perinatal period, is an interesting connection,” he said. “Will this change practices? Pregnant women should be screened for GBS regardless, but maybe more attention or counseling can be offered to AD patients about the importance of screening. Would decolonization regimens be employed early in pregnancy? This study can’t answer that but certainly raises good questions.”
Dr. Margolis disclosed that he is or recently has been a consultant for Pfizer, Leo, and Sanofi with respect to studies of atopic dermatitis and served on an advisory board for the National Eczema Association. Another author disclosed receiving grants from companies related to work with AD; other authors had no disclosures. Dr. Friedman reported having no relevant disclosures.
suggest.
“The rate of GBS colonization among pregnant females with a history of AD has not been previously reported, but AD could be a risk factor for maternal carriage of GBS,” corresponding author David J. Margolis, MD, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and colleagues wrote in the study, which was published as a letter to the editor online in the Journal of Investigative Dermatology. “GBS reporting in a large administrative database represents a unique opportunity to conduct a population-based evaluation of GBS carriage with AD. Understanding this association could expand our understanding of microbial changes associated with AD,” they noted.
To determine if an association between GBS and AD in pregnant women exists, the researchers performed a cross-sectional study using a random sample from an Optum administrative database of pregnant women who had vaginal deliveries between May of 2007 and September 2021. The primary outcome of interest was the presence of GBS based on American College of Obstetricians and Gynecologists–recommended codes for GBS during 36 0/7 to 37 6/7 weeks of pregnancy. They used descriptive statistics to summarize categorical and continuous variables as proportions and means, and logistic regression to examine the association between AD and GBS status.
The cohort included 566,467 pregnant women with an average age of 38.8 years. Of these, 2.9% had a diagnosis of AD or a history of AD, and 24.9% had diagnoses of asthma, seasonal allergies, or both. Women with AD had an increased odds ratio of asthma (OR, 2.55), seasonal allergies (OR, 3.39), or both (OR, 5.35), compared with those without AD.
GBS was reported in 20.6% of the cohort. The median time of follow-up for those with and without GBS was 494 days and 468 days, respectively (P = .134). Among the women with AD, 24.1% had GBS, compared with 20.51% of the women without AD (P <.0001), which translated into an OR of 1.23 (95% confidence interval, 1.18-1.27).
Among the women with GBS, the OR of asthma was 1.08 (95% CI, 1.06-1.10) and was 1.07 (95% CI, 1.05-1.09) among those with seasonal allergies. When adjusted for potential confounders, these findings did not change substantively.
“It is not apparent why pregnant females with AD are more likely to specifically carry GBS,” the authors wrote. “However, several studies have shown that individuals with AD are more likely to carry [Staphylococcus] aureus and that individuals with AD might be deficient in host defenses against S. aureus and other pathogens,” they added.
“Individuals with AD frequently receive antibiotics as part of their AD treatment and this might alter their resident microbiome. Carriage rates may be enhanced by the inhibition of an important barrier protein called filaggrin (FLG) and FLG loss of function genetic variation is known to decrease barrier proteins thought to inhibit the colonization of S. aureus and other pathogens,” the researchers wrote.
They acknowledged certain limitations of their study, including its reliance on an administrative database that does not contain information on past disease.
Asked to comment on the results, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the study, characterized AD as “the poster child for cutaneous dysbiosis – an altered petri dish, so to speak, [that] facilitates survival of the few, leading to decreased microbial diversity that can both enable potential pathogen invasion and immune dysregulation.”
Though it’s not surprising that pregnant AD patients have dysbiosis, the focus on GBS, “which can be a bad actor in the perinatal period, is an interesting connection,” he said. “Will this change practices? Pregnant women should be screened for GBS regardless, but maybe more attention or counseling can be offered to AD patients about the importance of screening. Would decolonization regimens be employed early in pregnancy? This study can’t answer that but certainly raises good questions.”
Dr. Margolis disclosed that he is or recently has been a consultant for Pfizer, Leo, and Sanofi with respect to studies of atopic dermatitis and served on an advisory board for the National Eczema Association. Another author disclosed receiving grants from companies related to work with AD; other authors had no disclosures. Dr. Friedman reported having no relevant disclosures.
suggest.
“The rate of GBS colonization among pregnant females with a history of AD has not been previously reported, but AD could be a risk factor for maternal carriage of GBS,” corresponding author David J. Margolis, MD, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and colleagues wrote in the study, which was published as a letter to the editor online in the Journal of Investigative Dermatology. “GBS reporting in a large administrative database represents a unique opportunity to conduct a population-based evaluation of GBS carriage with AD. Understanding this association could expand our understanding of microbial changes associated with AD,” they noted.
To determine if an association between GBS and AD in pregnant women exists, the researchers performed a cross-sectional study using a random sample from an Optum administrative database of pregnant women who had vaginal deliveries between May of 2007 and September 2021. The primary outcome of interest was the presence of GBS based on American College of Obstetricians and Gynecologists–recommended codes for GBS during 36 0/7 to 37 6/7 weeks of pregnancy. They used descriptive statistics to summarize categorical and continuous variables as proportions and means, and logistic regression to examine the association between AD and GBS status.
The cohort included 566,467 pregnant women with an average age of 38.8 years. Of these, 2.9% had a diagnosis of AD or a history of AD, and 24.9% had diagnoses of asthma, seasonal allergies, or both. Women with AD had an increased odds ratio of asthma (OR, 2.55), seasonal allergies (OR, 3.39), or both (OR, 5.35), compared with those without AD.
GBS was reported in 20.6% of the cohort. The median time of follow-up for those with and without GBS was 494 days and 468 days, respectively (P = .134). Among the women with AD, 24.1% had GBS, compared with 20.51% of the women without AD (P <.0001), which translated into an OR of 1.23 (95% confidence interval, 1.18-1.27).
Among the women with GBS, the OR of asthma was 1.08 (95% CI, 1.06-1.10) and was 1.07 (95% CI, 1.05-1.09) among those with seasonal allergies. When adjusted for potential confounders, these findings did not change substantively.
“It is not apparent why pregnant females with AD are more likely to specifically carry GBS,” the authors wrote. “However, several studies have shown that individuals with AD are more likely to carry [Staphylococcus] aureus and that individuals with AD might be deficient in host defenses against S. aureus and other pathogens,” they added.
“Individuals with AD frequently receive antibiotics as part of their AD treatment and this might alter their resident microbiome. Carriage rates may be enhanced by the inhibition of an important barrier protein called filaggrin (FLG) and FLG loss of function genetic variation is known to decrease barrier proteins thought to inhibit the colonization of S. aureus and other pathogens,” the researchers wrote.
They acknowledged certain limitations of their study, including its reliance on an administrative database that does not contain information on past disease.
Asked to comment on the results, Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was not involved with the study, characterized AD as “the poster child for cutaneous dysbiosis – an altered petri dish, so to speak, [that] facilitates survival of the few, leading to decreased microbial diversity that can both enable potential pathogen invasion and immune dysregulation.”
Though it’s not surprising that pregnant AD patients have dysbiosis, the focus on GBS, “which can be a bad actor in the perinatal period, is an interesting connection,” he said. “Will this change practices? Pregnant women should be screened for GBS regardless, but maybe more attention or counseling can be offered to AD patients about the importance of screening. Would decolonization regimens be employed early in pregnancy? This study can’t answer that but certainly raises good questions.”
Dr. Margolis disclosed that he is or recently has been a consultant for Pfizer, Leo, and Sanofi with respect to studies of atopic dermatitis and served on an advisory board for the National Eczema Association. Another author disclosed receiving grants from companies related to work with AD; other authors had no disclosures. Dr. Friedman reported having no relevant disclosures.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Pregnancy risks elevated in women with chronic pancreatitis
TOPLINE:
METHODOLOGY:
- A retrospective analysis of hospital discharge records from the National Inpatient Sample database between 2009 and 2019 was conducted.
- The sample included 3,094 pregnancies with chronic pancreatitis and roughly 40.8 million pregnancies without this condition.
- The study focused on primary maternal outcomes and primary perinatal outcomes in pregnancies affected by chronic pancreatitis after accounting for relevant covariates.
TAKEAWAY:
- Chronic pancreatitis pregnancies had elevated rates of gestational diabetes (adjusted odds ratio, 1.63), gestational hypertensive complications (aOR, 2.48), preterm labor (aOR, 3.10), and small size for gestational age (aOR, 2.40).
- Women with chronic pancreatitis and a history of renal failure were more prone to gestational hypertensive complications (aOR, 20.09).
- Women with alcohol-induced chronic pancreatitis had a 17-fold higher risk for fetal death (aOR, 17.15).
- Pregnancies with chronic pancreatitis were associated with longer hospital stays and higher hospital costs.
IN PRACTICE:
“Our study provides novel insights into the impact of chronic pancreatitis on maternal and fetal health. The implications of our findings are critical for health care professionals, particularly those involved in preconception counseling. Pregnant women with chronic pancreatitis should be under the care of a multidisciplinary team of health care providers,” the authors advise.
SOURCE:
The study was led by Chengu Niu, MD, with Rochester General Hospital, Rochester, N.Y. It was published online July 18 in Digestive and Liver Disease. The study had no specific funding.
LIMITATIONS:
The authors note potential inaccuracies because of coding in the National Inpatient Sample database, a lack of detailed information regarding medication use, and a lack of follow-up clinical information. The findings are specific to the United States and may not be applicable to other countries.
DISCLOSURES:
The authors have no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- A retrospective analysis of hospital discharge records from the National Inpatient Sample database between 2009 and 2019 was conducted.
- The sample included 3,094 pregnancies with chronic pancreatitis and roughly 40.8 million pregnancies without this condition.
- The study focused on primary maternal outcomes and primary perinatal outcomes in pregnancies affected by chronic pancreatitis after accounting for relevant covariates.
TAKEAWAY:
- Chronic pancreatitis pregnancies had elevated rates of gestational diabetes (adjusted odds ratio, 1.63), gestational hypertensive complications (aOR, 2.48), preterm labor (aOR, 3.10), and small size for gestational age (aOR, 2.40).
- Women with chronic pancreatitis and a history of renal failure were more prone to gestational hypertensive complications (aOR, 20.09).
- Women with alcohol-induced chronic pancreatitis had a 17-fold higher risk for fetal death (aOR, 17.15).
- Pregnancies with chronic pancreatitis were associated with longer hospital stays and higher hospital costs.
IN PRACTICE:
“Our study provides novel insights into the impact of chronic pancreatitis on maternal and fetal health. The implications of our findings are critical for health care professionals, particularly those involved in preconception counseling. Pregnant women with chronic pancreatitis should be under the care of a multidisciplinary team of health care providers,” the authors advise.
SOURCE:
The study was led by Chengu Niu, MD, with Rochester General Hospital, Rochester, N.Y. It was published online July 18 in Digestive and Liver Disease. The study had no specific funding.
LIMITATIONS:
The authors note potential inaccuracies because of coding in the National Inpatient Sample database, a lack of detailed information regarding medication use, and a lack of follow-up clinical information. The findings are specific to the United States and may not be applicable to other countries.
DISCLOSURES:
The authors have no relevant disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- A retrospective analysis of hospital discharge records from the National Inpatient Sample database between 2009 and 2019 was conducted.
- The sample included 3,094 pregnancies with chronic pancreatitis and roughly 40.8 million pregnancies without this condition.
- The study focused on primary maternal outcomes and primary perinatal outcomes in pregnancies affected by chronic pancreatitis after accounting for relevant covariates.
TAKEAWAY:
- Chronic pancreatitis pregnancies had elevated rates of gestational diabetes (adjusted odds ratio, 1.63), gestational hypertensive complications (aOR, 2.48), preterm labor (aOR, 3.10), and small size for gestational age (aOR, 2.40).
- Women with chronic pancreatitis and a history of renal failure were more prone to gestational hypertensive complications (aOR, 20.09).
- Women with alcohol-induced chronic pancreatitis had a 17-fold higher risk for fetal death (aOR, 17.15).
- Pregnancies with chronic pancreatitis were associated with longer hospital stays and higher hospital costs.
IN PRACTICE:
“Our study provides novel insights into the impact of chronic pancreatitis on maternal and fetal health. The implications of our findings are critical for health care professionals, particularly those involved in preconception counseling. Pregnant women with chronic pancreatitis should be under the care of a multidisciplinary team of health care providers,” the authors advise.
SOURCE:
The study was led by Chengu Niu, MD, with Rochester General Hospital, Rochester, N.Y. It was published online July 18 in Digestive and Liver Disease. The study had no specific funding.
LIMITATIONS:
The authors note potential inaccuracies because of coding in the National Inpatient Sample database, a lack of detailed information regarding medication use, and a lack of follow-up clinical information. The findings are specific to the United States and may not be applicable to other countries.
DISCLOSURES:
The authors have no relevant disclosures.
A version of this article appeared on Medscape.com.
Number of cervical cancer screenings linked to higher preterm birth risk
For each additional recommended screening before childbirth, there was a direct increase in absolute PTD risk of 0.073 (95% confidence interval, 0.026-0.120), according to a study led by Rebecca A. Bromley-Dulfano, MS, an MD candidate at Stanford (Calif.) University and a PhD candidate in health policy at Harvard University, Cambridge, Mass.
There was no significant change in very preterm delivery (VPTD) risk, but mothers with hypertension or diabetes were at higher PTD risk.
Women in this younger age group are more prone to PTD. According to the study’s estimate, an additional 73 PTDs per 100,000 women could be expected for every 1 additional recommended screening before childbirth. For the year 2018, that translated to an estimated 1,348 PTDs that could have been averted, with reduced screening requirements (3% relative reduction).
“If you screen someone for cervical cancer and find a cervical lesion, the possible next steps can include a biopsy and an excisional procedure to remove the lesion,” Ms. Bromley-Dulfano explained, “and these procedures which remove a small (mostly diseased) part of the cervix have been shown to slightly increase the risk of PTD. Particularly in young individuals with a cervix who are known to have high rates of lesion regression and who have more potential childbearing years ahead of them, it is important to weigh the oncological benefits with the adverse birth outcome risks.”
Young women are more likely to have false-positive results on Papanicolaou tests and lesion regression within 2 years but may undergo unnecessary treatment, the authors noted.
Cervical excision procedures have previously been associated in clinical trials with an increase in PTB risk.
In their 2017 decision model in a fictive cohort, for example, Kamphuis and colleagues found the most intensive screening program was associated with an increase in maternal life years of 9%, a decrease in cervical cancer incidence of 67%, and a decrease in cervical cancer deaths of 75%. But those gains came at the cost of 250% more preterm births, compared with the least intensive program.
“These results can be used in future simulation models integrating oncological trade-offs to help ascertain optimal screening strategies,” the researchers wrote.
While the optimal screening strategy must trade off the oncologic benefits of cancer detection against the neonatal harms of overtreatment, the ideal age of cervical cancer screening onset and frequency remain uncertain, the authors noted. Recent American Cancer Society guidelines recommending less frequent screening for some diverge from those of other societies.
“The first and foremost priority is for gynecologists to continue to have individualized conversations with patients about all of the benefits and risks of procedures that patients undergo and to understand the benefits and risks influencing screening guidelines,” Ms. Bromley-Dulfano said.
Cross-sectional study
The study used data from the Centers for Disease Control and Prevention’s National Center for Health Statistics to analyze associations between cervical cancer screening guidelines and birth outcomes women who had a singleton nulliparous birth from 19916 to 2018. Gestational age and maternal characteristics were drawn from birth certificates.
The mean age of the 11,333,151 multiracial cohort of women was 20.9 years, and 6.8% had hypertension or diabetes. The mean number of guideline-recommended screenings by time of childbirth was 2.4. Overall, PTD and very PTD occurred in 1,140,490 individuals (10.1%) and 333,040 (2.9%) of births, respectively.
Those with hypertension or diabetes had a somewhat higher PTD risk: 0.26% (95% CI, 0.11-0.4) versus 0.06% (95% CI, 0.01-0.10; Wald test, P < .001).
Offering an outsider’s perspective on the analysis, ob.gyn. Fidel A. Valea, MD, director of gynecologic oncology at the Northwell Health Cancer Institute in New Hyde Park, N.Y., urged caution in drawing conclusions from large population analyses such as this.
“This study had over 11 million data points. Often these large numbers will show statistical differences that are not clinically significant,” he said in an interview. He noted that while small studies have shown a possible impact of frequent Pap tests on cervical function, “this is not 100% proven. Research from Texas showed that screening made a difference only in cases of dysplasia.”
Dr. Valea also noted that screening guidelines have already changed over the lengthy time span of the study and do reflect the concerns of the study authors.
“We know that the HPV virus is cleared more readily by young women than older women and so we have made adjustments and test them less frequently and we test them less early.” He added that conservative options are recommended even in the case of dysplasia.
In defense of the Pap smear test, he added: “It has virtually wiped out cervical cancer in the U.S., bringing it from No. 1 to No. 13.” While broadening HPV vaccination programs may impact guidelines in the future, “vaccination is still in its infancy. We have to wait until women have lived long to enough to see an impact.”
As to why this age group is more vulnerable to PTD, Dr. Valea said, “It’s likely multifactorial, with lifestyle and other factors involved.” Although based on U.S. data, the authors said their results may be useful for other public health entities, particularly in countries where cervical cancer is considerably more prevalent.
This work received no specific funding. The authors and Dr. Valea disclosed no competing interests.
For each additional recommended screening before childbirth, there was a direct increase in absolute PTD risk of 0.073 (95% confidence interval, 0.026-0.120), according to a study led by Rebecca A. Bromley-Dulfano, MS, an MD candidate at Stanford (Calif.) University and a PhD candidate in health policy at Harvard University, Cambridge, Mass.
There was no significant change in very preterm delivery (VPTD) risk, but mothers with hypertension or diabetes were at higher PTD risk.
Women in this younger age group are more prone to PTD. According to the study’s estimate, an additional 73 PTDs per 100,000 women could be expected for every 1 additional recommended screening before childbirth. For the year 2018, that translated to an estimated 1,348 PTDs that could have been averted, with reduced screening requirements (3% relative reduction).
“If you screen someone for cervical cancer and find a cervical lesion, the possible next steps can include a biopsy and an excisional procedure to remove the lesion,” Ms. Bromley-Dulfano explained, “and these procedures which remove a small (mostly diseased) part of the cervix have been shown to slightly increase the risk of PTD. Particularly in young individuals with a cervix who are known to have high rates of lesion regression and who have more potential childbearing years ahead of them, it is important to weigh the oncological benefits with the adverse birth outcome risks.”
Young women are more likely to have false-positive results on Papanicolaou tests and lesion regression within 2 years but may undergo unnecessary treatment, the authors noted.
Cervical excision procedures have previously been associated in clinical trials with an increase in PTB risk.
In their 2017 decision model in a fictive cohort, for example, Kamphuis and colleagues found the most intensive screening program was associated with an increase in maternal life years of 9%, a decrease in cervical cancer incidence of 67%, and a decrease in cervical cancer deaths of 75%. But those gains came at the cost of 250% more preterm births, compared with the least intensive program.
“These results can be used in future simulation models integrating oncological trade-offs to help ascertain optimal screening strategies,” the researchers wrote.
While the optimal screening strategy must trade off the oncologic benefits of cancer detection against the neonatal harms of overtreatment, the ideal age of cervical cancer screening onset and frequency remain uncertain, the authors noted. Recent American Cancer Society guidelines recommending less frequent screening for some diverge from those of other societies.
“The first and foremost priority is for gynecologists to continue to have individualized conversations with patients about all of the benefits and risks of procedures that patients undergo and to understand the benefits and risks influencing screening guidelines,” Ms. Bromley-Dulfano said.
Cross-sectional study
The study used data from the Centers for Disease Control and Prevention’s National Center for Health Statistics to analyze associations between cervical cancer screening guidelines and birth outcomes women who had a singleton nulliparous birth from 19916 to 2018. Gestational age and maternal characteristics were drawn from birth certificates.
The mean age of the 11,333,151 multiracial cohort of women was 20.9 years, and 6.8% had hypertension or diabetes. The mean number of guideline-recommended screenings by time of childbirth was 2.4. Overall, PTD and very PTD occurred in 1,140,490 individuals (10.1%) and 333,040 (2.9%) of births, respectively.
Those with hypertension or diabetes had a somewhat higher PTD risk: 0.26% (95% CI, 0.11-0.4) versus 0.06% (95% CI, 0.01-0.10; Wald test, P < .001).
Offering an outsider’s perspective on the analysis, ob.gyn. Fidel A. Valea, MD, director of gynecologic oncology at the Northwell Health Cancer Institute in New Hyde Park, N.Y., urged caution in drawing conclusions from large population analyses such as this.
“This study had over 11 million data points. Often these large numbers will show statistical differences that are not clinically significant,” he said in an interview. He noted that while small studies have shown a possible impact of frequent Pap tests on cervical function, “this is not 100% proven. Research from Texas showed that screening made a difference only in cases of dysplasia.”
Dr. Valea also noted that screening guidelines have already changed over the lengthy time span of the study and do reflect the concerns of the study authors.
“We know that the HPV virus is cleared more readily by young women than older women and so we have made adjustments and test them less frequently and we test them less early.” He added that conservative options are recommended even in the case of dysplasia.
In defense of the Pap smear test, he added: “It has virtually wiped out cervical cancer in the U.S., bringing it from No. 1 to No. 13.” While broadening HPV vaccination programs may impact guidelines in the future, “vaccination is still in its infancy. We have to wait until women have lived long to enough to see an impact.”
As to why this age group is more vulnerable to PTD, Dr. Valea said, “It’s likely multifactorial, with lifestyle and other factors involved.” Although based on U.S. data, the authors said their results may be useful for other public health entities, particularly in countries where cervical cancer is considerably more prevalent.
This work received no specific funding. The authors and Dr. Valea disclosed no competing interests.
For each additional recommended screening before childbirth, there was a direct increase in absolute PTD risk of 0.073 (95% confidence interval, 0.026-0.120), according to a study led by Rebecca A. Bromley-Dulfano, MS, an MD candidate at Stanford (Calif.) University and a PhD candidate in health policy at Harvard University, Cambridge, Mass.
There was no significant change in very preterm delivery (VPTD) risk, but mothers with hypertension or diabetes were at higher PTD risk.
Women in this younger age group are more prone to PTD. According to the study’s estimate, an additional 73 PTDs per 100,000 women could be expected for every 1 additional recommended screening before childbirth. For the year 2018, that translated to an estimated 1,348 PTDs that could have been averted, with reduced screening requirements (3% relative reduction).
“If you screen someone for cervical cancer and find a cervical lesion, the possible next steps can include a biopsy and an excisional procedure to remove the lesion,” Ms. Bromley-Dulfano explained, “and these procedures which remove a small (mostly diseased) part of the cervix have been shown to slightly increase the risk of PTD. Particularly in young individuals with a cervix who are known to have high rates of lesion regression and who have more potential childbearing years ahead of them, it is important to weigh the oncological benefits with the adverse birth outcome risks.”
Young women are more likely to have false-positive results on Papanicolaou tests and lesion regression within 2 years but may undergo unnecessary treatment, the authors noted.
Cervical excision procedures have previously been associated in clinical trials with an increase in PTB risk.
In their 2017 decision model in a fictive cohort, for example, Kamphuis and colleagues found the most intensive screening program was associated with an increase in maternal life years of 9%, a decrease in cervical cancer incidence of 67%, and a decrease in cervical cancer deaths of 75%. But those gains came at the cost of 250% more preterm births, compared with the least intensive program.
“These results can be used in future simulation models integrating oncological trade-offs to help ascertain optimal screening strategies,” the researchers wrote.
While the optimal screening strategy must trade off the oncologic benefits of cancer detection against the neonatal harms of overtreatment, the ideal age of cervical cancer screening onset and frequency remain uncertain, the authors noted. Recent American Cancer Society guidelines recommending less frequent screening for some diverge from those of other societies.
“The first and foremost priority is for gynecologists to continue to have individualized conversations with patients about all of the benefits and risks of procedures that patients undergo and to understand the benefits and risks influencing screening guidelines,” Ms. Bromley-Dulfano said.
Cross-sectional study
The study used data from the Centers for Disease Control and Prevention’s National Center for Health Statistics to analyze associations between cervical cancer screening guidelines and birth outcomes women who had a singleton nulliparous birth from 19916 to 2018. Gestational age and maternal characteristics were drawn from birth certificates.
The mean age of the 11,333,151 multiracial cohort of women was 20.9 years, and 6.8% had hypertension or diabetes. The mean number of guideline-recommended screenings by time of childbirth was 2.4. Overall, PTD and very PTD occurred in 1,140,490 individuals (10.1%) and 333,040 (2.9%) of births, respectively.
Those with hypertension or diabetes had a somewhat higher PTD risk: 0.26% (95% CI, 0.11-0.4) versus 0.06% (95% CI, 0.01-0.10; Wald test, P < .001).
Offering an outsider’s perspective on the analysis, ob.gyn. Fidel A. Valea, MD, director of gynecologic oncology at the Northwell Health Cancer Institute in New Hyde Park, N.Y., urged caution in drawing conclusions from large population analyses such as this.
“This study had over 11 million data points. Often these large numbers will show statistical differences that are not clinically significant,” he said in an interview. He noted that while small studies have shown a possible impact of frequent Pap tests on cervical function, “this is not 100% proven. Research from Texas showed that screening made a difference only in cases of dysplasia.”
Dr. Valea also noted that screening guidelines have already changed over the lengthy time span of the study and do reflect the concerns of the study authors.
“We know that the HPV virus is cleared more readily by young women than older women and so we have made adjustments and test them less frequently and we test them less early.” He added that conservative options are recommended even in the case of dysplasia.
In defense of the Pap smear test, he added: “It has virtually wiped out cervical cancer in the U.S., bringing it from No. 1 to No. 13.” While broadening HPV vaccination programs may impact guidelines in the future, “vaccination is still in its infancy. We have to wait until women have lived long to enough to see an impact.”
As to why this age group is more vulnerable to PTD, Dr. Valea said, “It’s likely multifactorial, with lifestyle and other factors involved.” Although based on U.S. data, the authors said their results may be useful for other public health entities, particularly in countries where cervical cancer is considerably more prevalent.
This work received no specific funding. The authors and Dr. Valea disclosed no competing interests.
FROM JAMA HEALTH FORUM
Kangaroo mother care may cut death risk for premature babies by a third
, according to new research published online in BMJ Global Health.
Starting the contact, which involves mothers carrying the newborn in a sling, within 24 hours of birth and continuing it for at least 8 hours a day both appear to amplify the effect on reducing mortality and infection, the paper states.
Sindhu Sivanandan, MD, with the department of neonatology at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, and Mari Jeeva Sankar, MD, in the pediatrics department of the All India Institute of Medical Sciences, New Delhi, looked at existing studies to compare KMC with conventional care and to compare starting the intervention within 24 hours of birth versus a later start.
Their review looked at 31 trials that included 15,559 low-birthweight and preterm infants collectively. Of the 31 trials, 27 studies compared KMC with conventional care and four compared early with late initiation of KMC.
Mortality risk reduction
Analysis showed that, compared with conventional care, KMC appeared to cut mortality risk by 32% (relative risk, 0.68; 95% confidence interval, 0.53-0.86) during birth hospitalization or by 28 days after birth, while it seemed to reduce the risk of severe infection, such as sepsis, by 15% (RR, 0.85; 95% CI, 0.76-0.96; low-certainty evidence.)
That mortality-risk reduction was found regardless of gestational age or weight of the child at enrolment, time of starting KMC, and whether the intervention was started in a hospital or community.
The studies that had compared early with late-initiated KMC showed a reduction in neonatal mortality of 33%.
Low- and middle-income countries have the highest rates of premature births (gestational age of less than 37 weeks) and low birthweight (less than 2,500 grams). Premature births and low birthweight both are key causes of death and disability.
The World Health Organization recommends KMC as the standard of care among low birthweight infants after clinical stabilization. The American Academy of Pediatrics also promotes immediate KMC.
Relevance in the U.S.
Grace Chan, MD, MPH, PhD, an epidemiologist and pediatrician with the Harvard School of Public Health, Boston, said though the practice is promoted by the WHO and AAP, recommendations to families vary widely by providers.
She said the health benefits for KMC are numerous. One of the biggest is that skin-to-skin contact can help transfer heat to newborns who may have trouble regulating their own temperature. That is especially important in cold climates in places where there may be insufficient indoor heat.
She said it’s well-known that preterm babies are at higher risk for apnea, and listening to a mother’s heartbeat may stimulate the child to breathe regularly.
Additionally with KMC, there’s an inherent benefit of a mother or caregiver being able to see any change in a newborn’s color immediately when the baby is held so closely, as opposed to a nurse watching several babies at a time in a neonatal intensive care unit.
This is evidence that starting KMC right away is important, because the risk of death for premature and low-weight newborns is highest in the first 24 hours of life, Dr. Chan noted.
Barriers of time
There are some barriers, she noted, in that mothers or other caregivers caring for several young children may not have the time to carry a child in a sling for 8 or more hours at a time.
The authors conclude that their findings have policy implications, particularly for low- and middle-income countries: “KMC should be provided to all low birth weight and preterm infants irrespective of the settings – both health facilities and at home,” they wrote.
The authors caution that, “very low birth weight, extremely preterm neonates, and severely unstable neonates were often excluded from studies. More evidence is needed before extrapolating the study results in these high-risk groups.”
The study authors and Dr. Chan report no relevant financial relationships.
, according to new research published online in BMJ Global Health.
Starting the contact, which involves mothers carrying the newborn in a sling, within 24 hours of birth and continuing it for at least 8 hours a day both appear to amplify the effect on reducing mortality and infection, the paper states.
Sindhu Sivanandan, MD, with the department of neonatology at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, and Mari Jeeva Sankar, MD, in the pediatrics department of the All India Institute of Medical Sciences, New Delhi, looked at existing studies to compare KMC with conventional care and to compare starting the intervention within 24 hours of birth versus a later start.
Their review looked at 31 trials that included 15,559 low-birthweight and preterm infants collectively. Of the 31 trials, 27 studies compared KMC with conventional care and four compared early with late initiation of KMC.
Mortality risk reduction
Analysis showed that, compared with conventional care, KMC appeared to cut mortality risk by 32% (relative risk, 0.68; 95% confidence interval, 0.53-0.86) during birth hospitalization or by 28 days after birth, while it seemed to reduce the risk of severe infection, such as sepsis, by 15% (RR, 0.85; 95% CI, 0.76-0.96; low-certainty evidence.)
That mortality-risk reduction was found regardless of gestational age or weight of the child at enrolment, time of starting KMC, and whether the intervention was started in a hospital or community.
The studies that had compared early with late-initiated KMC showed a reduction in neonatal mortality of 33%.
Low- and middle-income countries have the highest rates of premature births (gestational age of less than 37 weeks) and low birthweight (less than 2,500 grams). Premature births and low birthweight both are key causes of death and disability.
The World Health Organization recommends KMC as the standard of care among low birthweight infants after clinical stabilization. The American Academy of Pediatrics also promotes immediate KMC.
Relevance in the U.S.
Grace Chan, MD, MPH, PhD, an epidemiologist and pediatrician with the Harvard School of Public Health, Boston, said though the practice is promoted by the WHO and AAP, recommendations to families vary widely by providers.
She said the health benefits for KMC are numerous. One of the biggest is that skin-to-skin contact can help transfer heat to newborns who may have trouble regulating their own temperature. That is especially important in cold climates in places where there may be insufficient indoor heat.
She said it’s well-known that preterm babies are at higher risk for apnea, and listening to a mother’s heartbeat may stimulate the child to breathe regularly.
Additionally with KMC, there’s an inherent benefit of a mother or caregiver being able to see any change in a newborn’s color immediately when the baby is held so closely, as opposed to a nurse watching several babies at a time in a neonatal intensive care unit.
This is evidence that starting KMC right away is important, because the risk of death for premature and low-weight newborns is highest in the first 24 hours of life, Dr. Chan noted.
Barriers of time
There are some barriers, she noted, in that mothers or other caregivers caring for several young children may not have the time to carry a child in a sling for 8 or more hours at a time.
The authors conclude that their findings have policy implications, particularly for low- and middle-income countries: “KMC should be provided to all low birth weight and preterm infants irrespective of the settings – both health facilities and at home,” they wrote.
The authors caution that, “very low birth weight, extremely preterm neonates, and severely unstable neonates were often excluded from studies. More evidence is needed before extrapolating the study results in these high-risk groups.”
The study authors and Dr. Chan report no relevant financial relationships.
, according to new research published online in BMJ Global Health.
Starting the contact, which involves mothers carrying the newborn in a sling, within 24 hours of birth and continuing it for at least 8 hours a day both appear to amplify the effect on reducing mortality and infection, the paper states.
Sindhu Sivanandan, MD, with the department of neonatology at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India, and Mari Jeeva Sankar, MD, in the pediatrics department of the All India Institute of Medical Sciences, New Delhi, looked at existing studies to compare KMC with conventional care and to compare starting the intervention within 24 hours of birth versus a later start.
Their review looked at 31 trials that included 15,559 low-birthweight and preterm infants collectively. Of the 31 trials, 27 studies compared KMC with conventional care and four compared early with late initiation of KMC.
Mortality risk reduction
Analysis showed that, compared with conventional care, KMC appeared to cut mortality risk by 32% (relative risk, 0.68; 95% confidence interval, 0.53-0.86) during birth hospitalization or by 28 days after birth, while it seemed to reduce the risk of severe infection, such as sepsis, by 15% (RR, 0.85; 95% CI, 0.76-0.96; low-certainty evidence.)
That mortality-risk reduction was found regardless of gestational age or weight of the child at enrolment, time of starting KMC, and whether the intervention was started in a hospital or community.
The studies that had compared early with late-initiated KMC showed a reduction in neonatal mortality of 33%.
Low- and middle-income countries have the highest rates of premature births (gestational age of less than 37 weeks) and low birthweight (less than 2,500 grams). Premature births and low birthweight both are key causes of death and disability.
The World Health Organization recommends KMC as the standard of care among low birthweight infants after clinical stabilization. The American Academy of Pediatrics also promotes immediate KMC.
Relevance in the U.S.
Grace Chan, MD, MPH, PhD, an epidemiologist and pediatrician with the Harvard School of Public Health, Boston, said though the practice is promoted by the WHO and AAP, recommendations to families vary widely by providers.
She said the health benefits for KMC are numerous. One of the biggest is that skin-to-skin contact can help transfer heat to newborns who may have trouble regulating their own temperature. That is especially important in cold climates in places where there may be insufficient indoor heat.
She said it’s well-known that preterm babies are at higher risk for apnea, and listening to a mother’s heartbeat may stimulate the child to breathe regularly.
Additionally with KMC, there’s an inherent benefit of a mother or caregiver being able to see any change in a newborn’s color immediately when the baby is held so closely, as opposed to a nurse watching several babies at a time in a neonatal intensive care unit.
This is evidence that starting KMC right away is important, because the risk of death for premature and low-weight newborns is highest in the first 24 hours of life, Dr. Chan noted.
Barriers of time
There are some barriers, she noted, in that mothers or other caregivers caring for several young children may not have the time to carry a child in a sling for 8 or more hours at a time.
The authors conclude that their findings have policy implications, particularly for low- and middle-income countries: “KMC should be provided to all low birth weight and preterm infants irrespective of the settings – both health facilities and at home,” they wrote.
The authors caution that, “very low birth weight, extremely preterm neonates, and severely unstable neonates were often excluded from studies. More evidence is needed before extrapolating the study results in these high-risk groups.”
The study authors and Dr. Chan report no relevant financial relationships.
FROM BMJ GLOBAL HEALTH
At-term birth timing may cut preeclampsia risk in half
Timed birth strategies include scheduled labor inductions and cesarean deliveries.
In this observational analysis of nearly 90,000 pregnancies, at-term preeclampsia occurred with similar frequency among women routinely screened during the first trimester and among at-risk women screened during the third trimester.
Overall, on average, at-risk women delivered at 40 weeks, with two-thirds experiencing spontaneous onset of labor. About one-fourth had cesarean deliveries.
“We anticipated that timed birth at 37 weeks could reduce the occurrence of more than half of preeclampsia, [but] this is not an intervention that could be recommended, as complications for the baby would be increased,” Laura A. Magee, MD, of King’s College London, told this news organization.
“However, we were delighted to see that a personalized approach to timed birth, based on an individual woman’s risk of preeclampsia, could prevent a similar number of cases of preeclampsia, with fewer women requiring timed birth and at later gestational ages, when newborn problems would be less frequent.”
Although not currently recommended to prevent at-term preeclampsia, “timed birth by labor induction is a very common timing of birth strategy,” she noted. “At least one-third of women currently undergo labor induction at term gestational age, and one in six choose to deliver by elective cesarean.”
The study was published online in the journal Hypertension.
Screening at 35-36 weeks superior
The investigators analyzed data from a nonintervention cohort study of singleton pregnancies delivering at ≥ 24 weeks, without major anomalies, at two U.K. hospitals.
At routine visits at 11-13 weeks’ gestation, 57,131 pregnancies were screened, and 1,138 term preeclampsia cases developed.
Most of these women were in their early 30s, self-identified as White, and had a BMI at the upper limits of normal. About 10% were smokers; fewer than 3% had a medical history of high blood pressure, type 2 diabetes, or autoimmune disease; and 3.9% reported a family history of preeclampsia.
At 35-36 weeks, in a different cohort, 29,035 pregnancies were screened and term preeclampsia developed in 619 women. Demographics and pregnancy characteristics were similar to those screened at 11-13 weeks, although the average BMI was higher – in the overweight range – and there were fewer Black women, although they still made up 10% of the screened population.
Patient-specific preeclampsia risks were determined by the United Kingdom National Institute for Health and Care Excellence (NICE) guidance, and the Fetal Medicine Foundation competing-risks model, available through an online calculator.
Timing of birth for term preeclampsia prevention was evaluated at 37, 38, 39, and 40 weeks or depending on preeclampsia risk by the competing-risks model at 35-36 weeks.
The primary outcomes were the proportion of term preeclampsia prevented, and number-needed-to-deliver to prevent one term preeclampsia case.
The investigators found that overall, the proportion of term preeclampsia prevented was highest, and number-needed-to-deliver lowest, for preeclampsia screening at 35-36 weeks rather than at 11-13 weeks.
For delivery at 37 weeks, fewer cases of preeclampsia were prevented with NICE criteria (28.8%) than with the competing-risks model (59.8%), and the number-needed-to-deliver was higher (16.4 vs 6.9, respectively).
At 35-36 weeks, the risk-stratified approach had similar preeclampsia prevention (57.2%) and number-needed-to-deliver (8.4), but fewer women would be induced at 37 weeks (1.2% vs. 8.8%).
Although personalized timed birth at term may be an effective way to address at-term preeclampsia, “clinicians should wait for definitive clinical trial evidence,” Dr. Magee said.
‘Stay tuned’
Vesna D. Garovic, MD, PhD, Mayo Clinic, Rochester, Minn., and chair of the 2021 AHA Scientific Statement, “Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy,” agrees.
The new data “set the stage for adequately designed and powered studies that will provide ultimate response/evidence regarding the efficacy of this approach,” she told this news organization.
“Future studies need to address the safety of this approach,” she added, “as close to 10 timed/planned deliveries will be needed to prevent one case of preeclampsia.”
For now, she said, “While these preliminary data are promising, they are not sufficient to adopt timed birth in daily practice. Prospective studies that will provide sufficient evidence regarding the efficacy and safety of this approach are likely to follow. Stay tuned.”
Indeed, Dr. Magee noted that the Fetal Medicine Foundation is about to launch a randomized trial of a personalized “timing of birth” strategy at term based on the preeclampsia risk described in her group’s study vs. usual care at term – that is, “watchful waiting, and delivery should preeclampsia or another indication for birth develop.”
The study was supported by grants from the Fetal Medicine Foundation, United Kingdom, and various biotech companies provided reagents and relevant equipment free of charge. Dr. Magee and Dr. Garovic reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Timed birth strategies include scheduled labor inductions and cesarean deliveries.
In this observational analysis of nearly 90,000 pregnancies, at-term preeclampsia occurred with similar frequency among women routinely screened during the first trimester and among at-risk women screened during the third trimester.
Overall, on average, at-risk women delivered at 40 weeks, with two-thirds experiencing spontaneous onset of labor. About one-fourth had cesarean deliveries.
“We anticipated that timed birth at 37 weeks could reduce the occurrence of more than half of preeclampsia, [but] this is not an intervention that could be recommended, as complications for the baby would be increased,” Laura A. Magee, MD, of King’s College London, told this news organization.
“However, we were delighted to see that a personalized approach to timed birth, based on an individual woman’s risk of preeclampsia, could prevent a similar number of cases of preeclampsia, with fewer women requiring timed birth and at later gestational ages, when newborn problems would be less frequent.”
Although not currently recommended to prevent at-term preeclampsia, “timed birth by labor induction is a very common timing of birth strategy,” she noted. “At least one-third of women currently undergo labor induction at term gestational age, and one in six choose to deliver by elective cesarean.”
The study was published online in the journal Hypertension.
Screening at 35-36 weeks superior
The investigators analyzed data from a nonintervention cohort study of singleton pregnancies delivering at ≥ 24 weeks, without major anomalies, at two U.K. hospitals.
At routine visits at 11-13 weeks’ gestation, 57,131 pregnancies were screened, and 1,138 term preeclampsia cases developed.
Most of these women were in their early 30s, self-identified as White, and had a BMI at the upper limits of normal. About 10% were smokers; fewer than 3% had a medical history of high blood pressure, type 2 diabetes, or autoimmune disease; and 3.9% reported a family history of preeclampsia.
At 35-36 weeks, in a different cohort, 29,035 pregnancies were screened and term preeclampsia developed in 619 women. Demographics and pregnancy characteristics were similar to those screened at 11-13 weeks, although the average BMI was higher – in the overweight range – and there were fewer Black women, although they still made up 10% of the screened population.
Patient-specific preeclampsia risks were determined by the United Kingdom National Institute for Health and Care Excellence (NICE) guidance, and the Fetal Medicine Foundation competing-risks model, available through an online calculator.
Timing of birth for term preeclampsia prevention was evaluated at 37, 38, 39, and 40 weeks or depending on preeclampsia risk by the competing-risks model at 35-36 weeks.
The primary outcomes were the proportion of term preeclampsia prevented, and number-needed-to-deliver to prevent one term preeclampsia case.
The investigators found that overall, the proportion of term preeclampsia prevented was highest, and number-needed-to-deliver lowest, for preeclampsia screening at 35-36 weeks rather than at 11-13 weeks.
For delivery at 37 weeks, fewer cases of preeclampsia were prevented with NICE criteria (28.8%) than with the competing-risks model (59.8%), and the number-needed-to-deliver was higher (16.4 vs 6.9, respectively).
At 35-36 weeks, the risk-stratified approach had similar preeclampsia prevention (57.2%) and number-needed-to-deliver (8.4), but fewer women would be induced at 37 weeks (1.2% vs. 8.8%).
Although personalized timed birth at term may be an effective way to address at-term preeclampsia, “clinicians should wait for definitive clinical trial evidence,” Dr. Magee said.
‘Stay tuned’
Vesna D. Garovic, MD, PhD, Mayo Clinic, Rochester, Minn., and chair of the 2021 AHA Scientific Statement, “Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy,” agrees.
The new data “set the stage for adequately designed and powered studies that will provide ultimate response/evidence regarding the efficacy of this approach,” she told this news organization.
“Future studies need to address the safety of this approach,” she added, “as close to 10 timed/planned deliveries will be needed to prevent one case of preeclampsia.”
For now, she said, “While these preliminary data are promising, they are not sufficient to adopt timed birth in daily practice. Prospective studies that will provide sufficient evidence regarding the efficacy and safety of this approach are likely to follow. Stay tuned.”
Indeed, Dr. Magee noted that the Fetal Medicine Foundation is about to launch a randomized trial of a personalized “timing of birth” strategy at term based on the preeclampsia risk described in her group’s study vs. usual care at term – that is, “watchful waiting, and delivery should preeclampsia or another indication for birth develop.”
The study was supported by grants from the Fetal Medicine Foundation, United Kingdom, and various biotech companies provided reagents and relevant equipment free of charge. Dr. Magee and Dr. Garovic reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Timed birth strategies include scheduled labor inductions and cesarean deliveries.
In this observational analysis of nearly 90,000 pregnancies, at-term preeclampsia occurred with similar frequency among women routinely screened during the first trimester and among at-risk women screened during the third trimester.
Overall, on average, at-risk women delivered at 40 weeks, with two-thirds experiencing spontaneous onset of labor. About one-fourth had cesarean deliveries.
“We anticipated that timed birth at 37 weeks could reduce the occurrence of more than half of preeclampsia, [but] this is not an intervention that could be recommended, as complications for the baby would be increased,” Laura A. Magee, MD, of King’s College London, told this news organization.
“However, we were delighted to see that a personalized approach to timed birth, based on an individual woman’s risk of preeclampsia, could prevent a similar number of cases of preeclampsia, with fewer women requiring timed birth and at later gestational ages, when newborn problems would be less frequent.”
Although not currently recommended to prevent at-term preeclampsia, “timed birth by labor induction is a very common timing of birth strategy,” she noted. “At least one-third of women currently undergo labor induction at term gestational age, and one in six choose to deliver by elective cesarean.”
The study was published online in the journal Hypertension.
Screening at 35-36 weeks superior
The investigators analyzed data from a nonintervention cohort study of singleton pregnancies delivering at ≥ 24 weeks, without major anomalies, at two U.K. hospitals.
At routine visits at 11-13 weeks’ gestation, 57,131 pregnancies were screened, and 1,138 term preeclampsia cases developed.
Most of these women were in their early 30s, self-identified as White, and had a BMI at the upper limits of normal. About 10% were smokers; fewer than 3% had a medical history of high blood pressure, type 2 diabetes, or autoimmune disease; and 3.9% reported a family history of preeclampsia.
At 35-36 weeks, in a different cohort, 29,035 pregnancies were screened and term preeclampsia developed in 619 women. Demographics and pregnancy characteristics were similar to those screened at 11-13 weeks, although the average BMI was higher – in the overweight range – and there were fewer Black women, although they still made up 10% of the screened population.
Patient-specific preeclampsia risks were determined by the United Kingdom National Institute for Health and Care Excellence (NICE) guidance, and the Fetal Medicine Foundation competing-risks model, available through an online calculator.
Timing of birth for term preeclampsia prevention was evaluated at 37, 38, 39, and 40 weeks or depending on preeclampsia risk by the competing-risks model at 35-36 weeks.
The primary outcomes were the proportion of term preeclampsia prevented, and number-needed-to-deliver to prevent one term preeclampsia case.
The investigators found that overall, the proportion of term preeclampsia prevented was highest, and number-needed-to-deliver lowest, for preeclampsia screening at 35-36 weeks rather than at 11-13 weeks.
For delivery at 37 weeks, fewer cases of preeclampsia were prevented with NICE criteria (28.8%) than with the competing-risks model (59.8%), and the number-needed-to-deliver was higher (16.4 vs 6.9, respectively).
At 35-36 weeks, the risk-stratified approach had similar preeclampsia prevention (57.2%) and number-needed-to-deliver (8.4), but fewer women would be induced at 37 weeks (1.2% vs. 8.8%).
Although personalized timed birth at term may be an effective way to address at-term preeclampsia, “clinicians should wait for definitive clinical trial evidence,” Dr. Magee said.
‘Stay tuned’
Vesna D. Garovic, MD, PhD, Mayo Clinic, Rochester, Minn., and chair of the 2021 AHA Scientific Statement, “Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy,” agrees.
The new data “set the stage for adequately designed and powered studies that will provide ultimate response/evidence regarding the efficacy of this approach,” she told this news organization.
“Future studies need to address the safety of this approach,” she added, “as close to 10 timed/planned deliveries will be needed to prevent one case of preeclampsia.”
For now, she said, “While these preliminary data are promising, they are not sufficient to adopt timed birth in daily practice. Prospective studies that will provide sufficient evidence regarding the efficacy and safety of this approach are likely to follow. Stay tuned.”
Indeed, Dr. Magee noted that the Fetal Medicine Foundation is about to launch a randomized trial of a personalized “timing of birth” strategy at term based on the preeclampsia risk described in her group’s study vs. usual care at term – that is, “watchful waiting, and delivery should preeclampsia or another indication for birth develop.”
The study was supported by grants from the Fetal Medicine Foundation, United Kingdom, and various biotech companies provided reagents and relevant equipment free of charge. Dr. Magee and Dr. Garovic reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM HYPERTENSION
FDA withdraws approval of Makena
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.
The Food and Drug Administration has decided to withdraw approval of Makena and generic versions of the drug, the agency announced April 6.
The medication was approved in 2011 to reduce the risk for preterm birth in women who had previously experienced spontaneous preterm birth. The treatment had been approved under an accelerated pathway that required another trial to confirm clinical benefit.
A postmarketing study did not show clinical benefit, however, and the agency proposed withdrawing the drug, hydroxyprogesterone caproate injection, in 2020. The drug’s sponsor requested a hearing on the decision, and that meeting was held in October 2022.
The FDA commissioner and chief scientist subsequently reviewed submitted reports, comments, and transcripts, and made the decision to withdraw the drug.
“Effective today, Makena and its generics are no longer approved and cannot lawfully be distributed in interstate commerce,” the agency said.
“It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes – particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women,” FDA Commissioner Robert M. Califf, MD, said in a statement.
Risks associated with the drug include thromboembolic disorders, allergic reactions, decreased glucose tolerance, and fluid retention, regulators have noted. The agency acknowledged that some supplies of the product have already been distributed. Patients with questions should talk to their health care provider, the FDA advised.