Adam Sapirstein, M.D.

• Director, Division of Adult Critical Care Medicine
• Associate Professor of Anesthesiology and Critical Care Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0017473/adam-sapirstein

Perioperative antimicrobials for cesarean delivery: Before or after cord clamping Timing of prophylactic antibiotic administration in the uninfected laboring gravida: A randomized clinical trial medications quotes cheap 100 mg lamotrigine otc. Maternal death in the 21st century: Causes medicine pacifier buy generic lamotrigine on line, prevention medications januvia lamotrigine 50 mg online, and relationship to cesarean delivery symptoms meningitis order 25 mg lamotrigine fast delivery. Pharmacokinetics of prophylactic cefazolin in parturients undergoing cesarean delivery treatment viral meningitis buy cheap lamotrigine 200 mg on line. Cost-effectiveness of thromboprophylaxis with intermittent pneumatic compression at cesarean delivery. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Maternal mortality in the united states: Predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Decision-toincision time and neonatal outcomes: A systematic review and meta-analysis. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. The effect of antenatal steroids on fetal lung maturation between the 34th and 36th week of pregnancy. Effectiveness of antenatal corticosteroids in reducing respiratory disorders in late preterm infants: Randomised clinical trial. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: Pragmatic randomised trial. Antenatal corticosteroids for term or near-term fetal maturity: A systematic review and metaanalysis of randomized controlled trials. Coping with preoperative anxiety in cesarean section: Physiological, cognitive, and emotional effects of listening to favorite music. Music during caesarean section under regional anaesthesia for improving maternal and infant outcomes. Maternal position during caesarean section for preventing maternal and neonatal complications. Is routine indwelling catheterisation of the bladder for caesarean section necessary Preoperative skin preparation and intraoperative pelvic irrigation: Impact on postcesarean endometritis and wound infection. Chlorhexidine gluconate versus povidine iodine at cesarean delivery: A randomized controlled trial. Skin preparation for prevention of surgical site infection after cesarean delivery: A randomized controlled trial. Adjunctive intravaginal metronidazole for the prevention of postcesarean endometritis: A randomized controlled trial. The effect of incisional plastic drapes and redisinfection of operation site on wound infection following caesarean section. The effects of high perioperative inspiratory oxygen fraction for adult surgical patients. Supplemental oxygen for the prevention of postcesarean infectious morbidity: A randomized controlled trial. Perioperative oxygen supplementation and surgical site infection after cesarean delivery: A randomized trial. Antiemetics added to phenylephrine infusion during cesarean delivery: A randomized controlled trial. Joel-Cohen or Pfannenstiel incision at cesarean delivery: Does it make a difference Comparison of transverse and vertical skin incision for emergency cesarean delivery. Diathermy versus scalpel in transverse abdominal incision in women undergoing repeated cesarean section: A randomized controlled trial. Pfannesteil versus maylard incision for cesarean delivery: A randomized controlled trial. Is inferior dissection of the rectus sheath necessary during pfannenstiel incision for lower segment caesarean section Extraperitoneal versus transperitoneal cesarean section: A prospective randomized comparison of surgical morbidity. Omission of the bladder ap at caesarean section reduces delivery time without increased morbidity: A meta-analysis of randomised controlled trials. Surgical techniques for uterine incision and uterine closure at the time of caesarean section. Blunt versus sharp uterine incision expansion during low transverse cesarean delivery: A meta-analysis. Blunt expansion of the low transverse uterine incision at cesarean delivery: A randomized comparison of 2 techniques. Is cephalad-caudad blunt expansion of the low transverse uterine incision really associated with less uncontrolled extensions to decrease intra-operative blood loss Cephalad-caudad versus transverse blunt expansion of the low transverse uterine incision during cesarean delivery: A systematic review and metaanalysis. Instrumental delivery of the fetal head at the time of elective repeat cesarean: A randomized pilot study. Delivery of the impacted head of the fetus at caesarean section after prolonged obstructed labour: A randomised comparative study of two methods. A meta-analysis of reverse breech extraction to deliver a deeply impacted head during cesarean delivery. Immediate breastfeeding and skin-to-skin contact during cesarean section decreases maternal oxidative stress, a prospective randomized case-controlled study. Placental drainage of fetal blood at cesarean delivery and feto maternal transfusion: A randomized controlled trial. Placental transfusion strategies in very preterm neonates: A systematic review and meta-analysis. Comparison of two oxytocin regimens to prevent uterine atony at cesarean delivery: A randomized controlled trial. Use of additional oxytocin to reduce blood loss at elective caesarean section: A randomised control trial. Oxytocin-ergometrine co-administration does not reduce blood loss at caesarean delivery for labour arrest. Double-blind, randomized comparison of the effect of carbetocin and oxytocin on intraoperative blood loss and uterine tone of patients undergoing cesarean section. Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section. Misoprostol to reduce intraoperative and postoperative hemorrhage during cesarean delivery: A systematic review and meta-analysis. Effect of misoprostol versus oxytocin during caesarean section: A systematic review and metaanalysis. Impact of preoperative rectal misoprostol on blood loss during and after elective cesarean delivery. Extra-abdominal versus intraabdominal repair of the uterine incision at caesarean section. Extraabdominal vs intraabdominal uterine repair at cesarean delivery: A meta-analysis. Uterine cooling during cesarean delivery to reduce blood loss and incidence of postpartum hemorrhage: A randomized controlled trial. Mechanical dilatation of the cervix at non-labour caesarean section for reducing postoperative morbidity. Blunt needles for the reduction of needlestick injuries during cesarean delivery: A randomized controlled trial. Incomplete healing of the uterine incision after caesarean section: Is it preventable Suture compared with staple skin closure after cesarean delivery: A randomized controlled trial. Hypertrophic cesarean section scarring: Polyglycolic acid and nylon sutures in a randomized trial. A randomized controlled trial of early versus delayed skin staple removal following caesarean section in the obese patient. A randomized trial comparing metallic and absorbable staples for closure of a pfannenstiel incision for cesarean delivery. A randomized, controlled study comparing the cosmetic outcome of a new wound closure device with prolene suture closing caesarean wounds. Chewing gum in preventing postoperative ileus in women undergoing caesarean section: A systematic review and meta-analysis of randomised controlled trials. Effects of gum chewing on postoperative bowel motility after caesarean section: A metaanalysis of randomised controlled trials. Early oral feeding compared with delayed oral feeding after cesarean section: A meta-analysis. Early oral intake and gastrointestinal function after cesarean delivery: A systematic review and meta-analysis. Local anaesthetic wound in ltration and abdominal nerves block during caesarean section for postoperative pain relief. Is there a difference in the maternal and neonatal outcomes between patients discharged after 24h versus 72h following cesarean section Hospital discharge on the rst compared with the second day after a planned cesarean delivery: A randomized controlled trial. Continuous vs interrupted sutures for single-layer closure of uterine incision at cesarean section. Impact of single- vs double-layer closure on adverse outcomes and uterine scar defect: A systematic review and metaanalysis. Single versus two layer suturing for closing the uterine incision at caesarean section. The effect of intraabdominal irrigation at cesarean delivery on maternal morbidity: A randomized trial. Effectiveness and short-term safety of modi ed sodium hyaluronic acidcarboxymethylcellulose at cesarean delivery: A randomized trial. Bene ts and harms of adhesion barriers for abdominal surgery: A systematic review and meta-analysis. Intraperitoneal lidocaine instillation and postcesarean pain after parietal peritoneal closure: A randomized double blind placebo-controlled trial. Elective appendectomy at the time of cesarean delivery: A randomized controlled trial. Closure versus non-closure of the peritoneum at caesarean section: Short- and long-term outcomes. Nonclosure of the peritoneum during caesarean section: Long-term follow-up of a randomised controlled trial. Suture closure of subcutaneous fat and wound disruption after cesarean delivery: A meta-analysis. Prophylactic subcutaneous drainage for prevention of wound complications after cesarean 155. Extrafascial wound dehiscence: Secondary closure with suture versus noninvasive adhesive bandage. There is insuf cient evidence (no large randomized controlled trial) to compare the safety, complications, maternal, and fetal/neonatal morbidity and mortality between these two options. No screening tool is sensitive enough to be clinically useful in predicting an unsuccessful trial of labor. With term uterine rupture, the risks of fetal/neonatal morbidity/mortality are about 33% risk of pH < 7. Until the late 1970s, "Once a cesarean always a cesarean" was the general rule among most obstetricians. This phrase did not derive from formal studies and was clearly not evidence based. A classical uterine incision was used until the 1920s when the low transverse incision was rst introduced. The low transverse incision was associated with a tenfold decreased rate of uterine rupture in labor than the classical incision. It can include asymptomatic opening if the uterine scar is from prior surgery, without protrusion of fetus/fetal organs outside the uterus. Uterine rupture: Disruption or tear of the uterine muscle and visceral peritoneum, or separation of the uterine muscle with extension to the bladder or broad ligament [6]. It includes symptomatic gross rupture of the uterine scar from prior surgery, with or without protrusion of fetus/fetal parts outside the uterus. There is also a small prospective cohort study to compare these two options which also focuses on psychological outcomes, not maternal and fetal safety and complications [9]. Many studies do not differentiate between asymptomatic uterine dehiscence and true acute symptomatic uterine rupture. This information should be shared with the woman in a way best suited to her understanding. Recent prospective studies did not show any relationship although overall there appears to be a small inverse association between maternal age and the likelihood of vaginal delivery [1]. Prior Indication for Cesarean Breech presentation or other nonrecurring indication. Uterine Scar Type Vaginal delivery rates appear to be similar for low transverse, low vertical, and for unknown incision types [12,34]. In most series, rates do not seem to differ from success rates in singletons, without increased risk for maternal morbidity or uterine rupture [50,51]. The best studies used scoring systems that were validated in separate data sets and in external studies [1].

Chronos is able to support higher stimulus rates with more robust responses compared to ChR2 or sound stimulation using narrow band noise medications prescribed for anxiety lamotrigine 25 mg sale. No optically induced responses were detected in sham-injected mice medicine venlafaxine buy cheap lamotrigine 100 mg line, ruling out an optophonic artifact symptoms kidney failure dogs generic lamotrigine 25 mg overnight delivery. Other opsins symptoms uti in women lamotrigine 50 mg purchase on line, including the new ultrafast opsin Chronos medications keppra buy lamotrigine without a prescription, have also been tested in vivo (see Section 29. Correct and false-positive crossing probabilities are calculated as a function of (B) sound level and (C) laser amplitude. The slope of the linear fit of psychometric curves is used as a proxy for pulse detection. The psychometric slopes for ChR2- and Chronos-expressing mice are not significantly different across changing rates of (D) acoustic or (E) laser stimulation. Chronos- and ChR2-expressing mice exhibited similar detection slopes, while saline-injected animals performed at chance. In neurophysiological experiments, Chronos was better able to entrain high pulse rates than ChR2 (see Sections 29. However, these results did not translate into a perceptual advantage in behavioral experiments. Responses to optogenetic stimulation of the auditory midbrain are poorly encoded and quickly suppressed at the level of the auditory cortex (Guo et al. Similar suppressive responses have been shown in recordings of electrical stimulation. Further research into the perceptual outputs of optogenetic stimulation is necessary through more complicated discrimination tasks that force animals to report the saliency of light input at different frequencies when using newer opsins such as Chronos as compared with slower opsins. Optogenetic tools appear primed to do just this, given prior explanations of how light can be better targeted than non-specific electrical stimulation. Ultimately, the success of auditory implants over the past four decades serves to emphasize that the auditory prosthesis is actually a testament to the remarkable ability of the human brain to adapt. Nevertheless, there is great opportunity for novel optogenetic auditory prosthetics to improve on current technology with better stimulation of the complex neural circuits that govern auditory perception. Recent studies have demonstrated that novel opsins such as Chronos can encode a wide range of temporal stimulation rates with better discriminability compared with older generations of opsins. Simultaneous advances in the safe application of viral vectors in clinical therapies and in the design of miniature optical arrays that are suitable for use in auditory implants may expedite the start of human trials. These projects underscore the complexity of the central auditory neural circuits that prostheses aim to manipulate and set a foundation for future experiments aiming at a superior optogenetic auditory implant. Colletti, Vittorio, Robert Shannon, Marco Carner, Sheila Veronese, and Liliana Colletti. Dittgen, Tanjew, Axel Nimmerjahn, Shoji Komai, Pawel Licznerski, Jack Waters, Troy W. Gradinaru, Viviana, Feng Zhang, Charu Ramakrishnan, Joanna Mattis, Rohit Prakash, Ilka Diester, Inbal Goshen, Kimberly R. Kang, Robert, Grace Liu Nimmons, Ward Drennan, Jeff Longnion, Chad Ruffin, Kaibao Nie, Jong Ho Won, Tina Worman, Bevan Yueh, and Jay Rubinstein. Keppeler, Daniel, Victor Hernandez, Anna Gehrt, Marcus Jeschke, Christian Wrobel, Gerhard Hoch, Christian Goßler, et al. Hight, Xiankai Meng, Alyson Kaplan, Ashton Lehmann, Edward Boyden, Albert Edge, M. Pool, Stephan Hermening, Angelina Huseinovic, Eric Timmermans, Bas Blits, and Joost Verhaagen. Nevison, Barry, Roland Laszig, Wolf-Peter Sollmann, Thomas Lenarz, Olivier Sterkers, Richard Ramsden, Bernard Fraysse, et al. Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 29 (8): 1147­54. Wells, Jonathon, Chris Kao, Peter Konrad, Tom Milner, Jihoon Kim, Anita MahadevanJansen, and E. This transduction has an extraordinary temporal and spectral resolution and an amazing intensity sensibility. Alessandro Volta first stimulated the auditory system with electricity in the late eighteenth century by inserting two metal rods into his own ears. In this chapter, we will highlight one of those efforts: stimulating the auditory nerve not with an electrical current, but with light by employing optogenetics. The very low number of electrodes dramatically limits the stimulation of this tonotopic arrangement. This is due to the widespread electrical field around an electrode contact (Kral et al. Electrical coding of the intensity of sound is also limited, with an output dynamic range typically below 20 dB (Zeng et al. It has also been proposed that poor pitch resolution is due to the limits of electrical stimulation of the cochlea. Their interpretation was that these abnormalities could be due to a combination of the broad electric field, distant intracochlear electrode placement and non-uniform spiral ganglion cell distribution due to the variable number of surviving neurons after deafness and the implantation itself (Zeng et al. These problems are not easily resolved as they are inherent to the implants and the characteristics of each organ to be implanted. In an effort to overcome these limitations, some alternatives are to use bipolar, tripolar or partially tripolar electrical stimulation (Donaldson et al. Thus, optical stimulation and particularly optogenetics has emerged as an attainable alternative for stimulating the auditory system and therefore as a therapeutic strategy, mainly for one of its most frequent and severe presentations, sensorineural hearing loss. The energy requirements of a laser beam are much higher than traditional electrical implants (Zierhofer et al. Moreover, optogenetics today offers a flexible approach, allowing modulation of the stimulus in multiple ways. A more detailed explanation about the general mechanisms of optogenetics will be provided later in this chapter. To achieve this control, light-sensitive proteins that are naturally found in different species of microbes are genetically introduced into the nervous system. In such a way, depending on the kinetics of the protein, it is possible to change the activity of the neural circuit of interest or even of a single neuron under light stimulation. In 2002, the group of Spudich was the first to identify that a couple of rhodopsins are responsible for phototaxis in the microscopic alga Chlamydomonas reinhardtii (Sineshchekov et al. That same year, Nagel and collaborators characterized for the first time the electrical properties of this protein and called it channelrhodopsin1-A (Nagel et al. Moser (ChR2), a related protein of the same alga, in oocytes and mammalian cells, showing that it is a cation-selective channel, and they proposed its use in controlling neural activity (Nagel et al. Soon after, the group of Karl Deisseroth exploited this idea for the first time, showing that ChR2 is safely and stably expressed in neurons and, when activated with light, it is possible to evoke action and synaptic potentials (Boyden et al. Since then, ChR2 has undergone different modifications at the molecular level to change its kinetics and light sensibility. Thanks to this and to different strategies of gene delivery, optogenetics today has great spatiotemporal accuracy and has been used to help us to understand a wide range of different neural processes, as well as to open up the possibility of therapy for neurological disorders. Nevertheless, it also represents a disadvantage, as the scattering is larger and thus the ability to penetrate deeply into tissues is very low (Aravanis et al. Another disadvantage of ChR2 is that it has a very slow time constant of closing (Nagel et al. In an effort to improve the slow kinetics of the channel, to change the light sensitivity and to move to red shifted-sensitive proteins, many different mutations of the channel have been created (Yizhar et al. All of these new technological advances have also provided a boost for the development of new optoelectronic devices, even at the micro and nano levels (Deisseroth et al. Actually, some of these molecular variants have already been used to demonstrate neural activation with auditory implants (Hernandez et al. It is not the scope of this chapter to review their use in basic neuroscience, and therefore we will focus on therapeutic research, specifically hearing prosthesis development. The initial question to address is how to express an exogenous protein in the hearing nervous system. One strategy is to develop transgenic animals that express ChR in a stable and widespread manner. For a detailed review of this field, the reader can refer to Knöpfel and Boyden (2012) and Ting and Feng (2013). The activity evoked in the cochlea also activated deeper regions of the auditory pathway. Extracellular recordings from individual neurons in the auditory nerve and cochlear nucleus clearly revealed activation by cochlear optogenetics. The high reliability and temporal precision of the action potentials recorded in the auditory nerve are remarkable. This precision was slightly lost and jitter appeared when recording from the ipsilateral cochlear nucleus. In the first one, light stimulation was used to mask the cochlear response to a pure tone. Such "light-on-tone" masking provided a first estimate of the spread of light-evoked cochlear excitation. The frequency range at which light masking was observed was corroborated with the tonotopic position of the cochleostomy related to the tracing of the basilar membrane, as identified by high-resolution X-ray phase-contrast tomography (Bartels et al. The frequency range embraced by a typical cochleostomy was estimated to be 8­12 kHz based on a previously established frequency map of the mouse cochlea (Müller et al. In this case, the response was evoked by the insertion of a 250-m optical fiber through the round window into the scala tympani. This approach also permitted the recording of the activity in the nucleus evoked by monopolar electric stimulation. Optogenetic responses showed spatial tuning that was at least as narrow as that for acoustic stimulation, as would be expected with stimulation of the high-frequency cochlear base; however, responses to electrical stimulation were spatially more extended. In the same work, the ability of cochlear optogenetics to activate the auditory pathway in mouse models of human deafness was shown. In this case, optogenetic stimulation was also able to evoke responses in the auditory pathway. It is desirable to use cochlear optogenetics in other species and translated into clinical applications, so an alternative to transgenic animals must be proposed. They open up the possibility to translate this technology to the bedside, offering an improvement in the hearing functionality of implanted patients and improving their quality of life. This is the case in trauma involving the inner ear or tumors, typically vestibular schwannomas. Optogenetic virus-mediated transfection of the cochlear nucleus has been successfully performed without apparent deleterious effects on hearing even 18 months after expression (Shimano et al. After the end of light stimulation, ChR2 closes with a very low time constant (in the order of milliseconds); therefore, sustained action potential rates are limited to below 50 Hz (Boyden et al. One of the next objectives in auditory optogenetics is to improve the maximal firing rates. Recently, a new member of the family has appeared, called Chronos, which has faster kinetics (having the fastest inactivation time constant described so far) and is more light sensitive (Klapoetke et al. Therefore, it seems that Chronos would enable neurons to follow stimulation at hundreds of Hertz. Even though Chronos seems to be an excellent tool for reaching a higher rate of stimulation, red-shifted ChR will help to promote optogenetics as a valuable stimulation option in auditory research and prosthetics. Before jumping to human translation, optogenetics must be established for species other than murine models, including non-human primates. Thus, vectors and application techniques need to be tested before thinking about their applicability in preclinical trials. Multichannel optical devices, with hundreds of active sites, each one individually controlled and coded, will need to be developed. The optical implants have to be tested in chronic implanted animal models and then assessed for their reliability and safety, in addition to their auditory perception and frequency and intensity resolution of coding. Place-pitch discrimination of single- versus dual-electrode stimuli by cochlear implant users (L). Speech recognition in noise as a function of the number of spectral channels: comparison of acoustic hearing and cochlear implants. Superior temporal resolution of Chronos versus channelrhodopsin-2 in an optogenetic model of the auditory brainstem implant. Optical parameter variability in laser nerve stimulation: a study of pulse duration, repetition rate, and wavelength. Laser stimulation of auditory neurons: effect of shorter pulse duration and penetration depth. Spatial resolution of cochlear implants: the electrical field and excitation of auditory afferents. Electrical excitation of the acoustically sensitive auditory nerve: single-fiber responses to electric pulse trains. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Spread of cochlear excitation during stimulation with pulsed infrared radiation: inferior colliculus measurements. The number of spectral channels required for speech recognition depends on the difficulty of the listening situation. Moser channelrhodopsin-2 and halorhodopsin in brainstem neurons mediating auditory signaling. Two rhodopsins mediate phototaxis to low- and high-intensity light in Chlamydomonas reinhardtii. Improving speech perception in noise with current focusing in cochlear implant users. Acoustic events and "optophonic" cochlear responses induced by pulsed near-infrared laser. Development of transgenic animals for optogenetic manipulation of mammalian nervous system function: progress and prospects for behavioral neuroscience. Visual properties of transgenic rats harboring the channelrhodopsin-2 gene regulated by the Thy-1.

Antenatal day care units versus hospital admission for women with complicated pregnancy symptoms anemia effective lamotrigine 50 mg. The effect of olive oil and the Saj cream in prevention of striae gravidarum: A randomized controlled clinical trial symptoms quit drinking cheap lamotrigine 200 mg mastercard. Use of a speci c anti-stretch mark cream for preventing or reducing the severity of striae gravidarum medications covered by blue cross blue shield discount lamotrigine 25 mg free shipping. Managing nocturnal leg cramps-calf-stretching exercises and cessation of quinine treatment: A factorial randomized controlled trial symptoms 6dpo purchase 50 mg lamotrigine overnight delivery. Interventions for preventing and treating low-back and pelvic pain during pregnancy medicine hat alberta canada discount lamotrigine 25 mg buy on line. Conservative management of symptomatic and/or complicated haemorrhoids in pregnancy and the puerperium. Failure to understand these physiologic changes of pregnancy may result in both undue alarm and costly evaluation of normal symptoms of pregnancy or in the neglect of pathologic conditions due to which the presentation is dismissed as another "discomfort of pregnancy. In most cases, it is not possible to consider the effect of pregnancy on laboratory values in a simplistic or formulaic way. Rather, it is the understanding of the underlying physiology that these laboratory values re ect that is the most important in their evaluation during pregnancy. Even the ultimate clinical emergency of cardiac arrest is complicated by hemodynamic changes which are unique to pregnancy. Hemodynamic changes in pregnancy that have been well established include an increase in cardiac output and a decrease in both systemic and pulmonary vascular resistance. There is an overall increase in the heart rate and a decrease in the blood pressure. Blood volume, plasma volume, and erythrocyte volume increase, with a greater relative increase in the plasma volume resulting in a dilution lowering of hematocrit and other blood indices. There is also a redistribution of cardiac output with an increase in ow to the uterus, kidneys, skin, and breasts [1]. The increase in stroke volume and cardiac output creates a more audible physiologic ow murmur and splitting of the S2 sound during pregnancy, which may be striking upon physical examination. One longitudinal study followed maternal hemodynamics as measured by thoracic electrical bioimpedance monitoring in 50 healthy pregnant women [4]. The results showed an increase in the mean heart rate from 87 ± 2 beats per minute (bpm) at 10­18 weeks to 92 ± 1 bpm at 34­42 weeks. This study also found a signi cantly higher mean cardiac output in nulliparous women compared with multiparous women. Mean cardiac output and stroke volume, which show an overall increase during pregnancy, were found to decrease in the third trimester in this study [4]. However, the change in cardiac output during the third trimester showed signi cant individual variation and has not been consistent in other longitudinal studies, demonstrating the need for further research for a more conclusive understanding of how this parameter changes across gestation [5]. Another longitudinal study performed serial echocardiography studies on 35 healthy pregnant women from the early second trimester to 6­12 weeks postpartum [6]. This study showed a signi cant increase in the cardiac output that peaked in the early third trimester and was maintained until term. Some of these physiologic changes are advantageous to the growth and survival of the fetus. Others enhance the ability of the maternal system to compensate for demands of pregnancy, prepare for stress of delivery, and recover from delivery. Understanding physiologic changes in pregnancy is important in evaluating common symptoms associated with pregnancy, interpreting laboratory values in the parturient, and understanding pathologic conditions to which pregnant women are susceptible. Failure to understand the normal physiologic changes of pregnancy may result in both undue alarm and costly evaluation of normal symptoms of pregnancy or in the neglect of pathologic conditions due to which the presentation is dismissed as another discomfort of pregnancy. The patient will most likely be better served by the physician who carefully addresses her symptoms while keeping in mind the questions "how is this presentation affected by the physiology of pregnancy The reader will note that some values show signi cant overlap between pregnant and nonpregnant states. The detected 46%­51% increase in the cardiac output was attributed to a 15% increase in heart rate and a 24% increase in stroke volume [6]. The changes in heart rate occur early in pregnancy, whereas those of stroke volume occur later, with the net effect of a progressively increasing cardiac output as gestation progresses. Again, signi cant variation in cardiac output changes in the late third trimester was attributed to patient factors, precluding con dent conclusions regarding the behavior of cardiac output at the very end of pregnancy. Maternal cardiac output was found to correlate with maternal body surface area and with fetal birth weight. Left ventricular mass and left ventricular mass index increased to maximal levels at term but remained well below the cutoff for a diagnosis of left ventricular hypertrophy. This increase corresponded to an increase in the mean blood pressure at term as well as to an increase in the left atrial size and a decrease in the left ventricular diastolic lling value. Perhaps the most common hemodynamic complaint that must be evaluated during pregnancy is that of syncope or nearsyncope, which provides a useful example of how an understanding of pregnancy physiology is useful in clinical evaluation. Syncope is de ned as a transient loss of consciousness and posture, caused by decreased cerebral perfusion that may result from hypotension, changes in heart rate, or changes in blood volume or redistribution. The overwhelming majority of syncopal episodes are benign neurocardiogenic syncope but there are also several potentially dangerous conditions in the differential diagnosis of syncope. An understanding of the vasovagal re ex at the root of most syncopal episodes helps the clinician to manage benign syncopal episodes while being alert for signs and symptoms that may point to a more serious underlying condition. The most common trigger of syncope is venous pooling that results in a drop in venous return and a subsequent drop in cardiac output. This results in stimulation of arterial baroreceptors which trigger catecholamine stimulation of atria and ventricles. The resultant vigorous cardiac contraction in volume-depleted chambers stimulates cardiac mechanoreceptors or C- bers which, in susceptible individuals, can result in paradoxical stimulation of the dorsal vagal nucleus. The re ex may be initiated by emotional stimuli in some individuals or may be initiated by compression of the inferior vena cava by the gravid uterus causing a decrease in venous return and intracardiac pressure. Less common conditions that may present with symptoms of syncope include cerebrovascular accidents, seizures, cardiac arrhythmias or valvular disease, cardiomyopathy, pericardial tamponade, myocardial infarction, congenital heart defects, thromboembolic phenomenon, anemia, hypoglycemia, or electrolyte disorders [7]. The above events that are precipitated by a decrease in venous return can also explain the occurrence of supine hypotension in pregnancy. The commonly recommended "leftward tilt" position is intended to displace the uterus off of the inferior vena cava, which runs to the right of midline. This position should be used to avoid supine hypotension when recumbent as well as when performing surgery on the parturient in the second half of pregnancy. A more extreme application of this physiology comes in the performance of perimortem cesarean section during maternal cardiac arrest. The procedure is purported to allow fetal survival and also the evacuation of the uterus, which may allow an increase in venous return and cardiac output that may increase the chance of maternal survival [8]. In order to optimize maternal and fetal survival, it is recommended that the procedure should be performed within 4 minutes of cardiac arrest due to the inadequacy of chest compressions in producing adequate cardiac output during pregnancy and the susceptibility of both mother and fetus to anoxic brain injury [8] (see also Chapters 1 and 2 in Maternal-Fetal Evidence Based Guidelines). These are important in the evaluation of dyspnea in pregnancy, the management of pregnancy with coexisting pulmonary diseases such as asthma, and the recognition of acute pulmonary complications of pregnancy. Pregnancy is associated with a signi cant increase in ventilatory drive both at rest and during exercise [9]. Minute ventilation increases mostly due to an increase in tidal volume with little or no increase in respiratory rate [3,9,10]. Pulmonary edema may occur as a result of preeclampsia, peripartum cardiomyopathy, or the use of certain tocolytics. It is important that the prevalence of pulmonary symptoms in pregnancy should not be met with complacency by the obstetrician, for it may signify a lifethreatening condition for the pregnant woman. This may be due to stimulation of the ventilatory drive by progesterone and/or estrogen. The underlying mechanism for the increased ventilatory drive during pregnancy is not fully understood, but theories have included an increased sensitivity to chemore exive drives to breathe (due to hypercapnia or hypoxia) versus a hormone-mediated increase in the neural drive to breathe [9]. Uterine enlargement and abdominal distension result in a 4- to 5-cm cephalad displacement of the diaphragm and a 5- to 7-cm increase in thoracic circumference. This results in a decrease in expiratory reserve volume, residual volume, and functional residual capacity. There is a compensatory increase in inspiratory capacity, while total lung capacity and vital capacity do not change [9]. Chest wall compliance is increased but inspiratory muscle strength is preserved with an overall increase in the oxygen cost of breathing [9]. Physiologic dyspnea of pregnancy, experienced by 60%­70% of healthy pregnant women, must be clinically distinguished from more serious respiratory conditions. Physiologic dyspnea tends to be an isolated symptom that begins in early pregnancy, plateaus, or improves as pregnancy progresses, and does not interfere with daily activities [11]. The perception of physiologic dyspnea during pregnancy has been associated with increased sensitivity to hypoxia and hypercapnia, suggesting an increased chemosensitivity causing an increased central inspiratory drive in pregnant women who experience dyspnea. However, the chemical stimuli of hypoxia and hypercapnia are both reduced in pregnancy, causing others to suggest a neural mechanism [9]. Despite the common symptom of physiologic dyspnea, pregnancy has not been found to be associated with a decrease in aerobic work capacity or with an increased perception of breathlessness during exercise [9]. Again, these parameters do not change due to pregnancy, so any detected worsening should be treated appropriately and not attributed to pregnancy or to physiologic dyspnea. In the evaluation of severe acute asthma exacerbations with the potential for impending respiratory arrest, knowledge of physiologic changes of pregnancy is particularly important in the interpretation of blood gases (Table 3. There is a signi cant contribution of steroid hormone secretion by the fetal-placental unit. This section provides a brief description of the changes in reproductive hormones during gestation followed by a more in-depth review of the behavior and clinical application of thyroid hormones during pregnancy. Relaxin is secreted by the corpora lutea of pregnancy and thought to have an important role in early pregnancy maintenance that has not yet been clearly elucidated [13]. The reproductive hormones estradiol, progesterone, testosterone, prolactin, and 17-hydroxyprogesterone, all increase signi cantly during gestation. The elevated estradiol levels stimulate increased hepatic production of sex hormone­binding globulin and thyroxin-binding globulin. Estrogen also induces hypertrophy and hyperplasia of pituitary lactotrophs with a resultant increase in prolactin levels corresponding to the increase in estradiol levels throughout gestation [14]. Meanwhile, there is a re exive decrease in follicle-stimulating hormone and luteinizing hormone to almost undetectable levels, as would be expected. One longitudinal study assayed reproductive hormone levels in the blood of 60 healthy women drawn during the rst, second, and third trimesters of uncomplicated pregnancies [14]. Mean 17-hydroxyprogesterone levels are more stable during the rst and second trimesters at 12. Mean sex hormone-binding globulin levels increase rapidly during the rst half of gestation from 71 nmol/L at 5 weeks to 392 nmol/L at 25 weeks, and then remain relatively constant until 40 weeks. Other hormonal alterations include an increase in aldosterone, cortisol, parathyroid hormone, parathyroid-related hormone, and renin [2]. Androstenedione increases with an increase in the transformation to estrone and estradiol [1]. There is an increase in melanocyte-stimulating hormone to which can be attributed the pregnancy-related increases in pigmentation seen in the areola, the linea nigra, and in chloasma [1]. The function of the thyroid gland is crucial to a healthy gestation (see also Chapters 6 and 7 in Maternal-Fetal Evidence Based Guidelines). The interplay between maternal and fetal thyroid function can cause confusion for the obstetrician. Early fetal development is dependent on maternal thyroid function, and both hypothyroidism and hyperthyroidism can have important maternal and fetal effects and risks of thyroid dysfunction extend well into the postpartum period. Symptoms of hyperthyroidism and hypothyroidism can mimic symptoms of normal pregnancy. For example, symptoms such as fatigue, muscle cramps, palpitations, thyromegaly, and constipation can be common in normal pregnancy, but progressive symptoms of insomnia, intellectual slowness, or weight loss should be evaluated [15]. Thyroid-binding globulin increases due to stimulation of synthesis by estrogen as well as decreased hepatic clearance. However, these changes, sometimes referred to as gestational transient thyrotoxicosis, are typically self-limited and do not tend to result in values that are outside the normal range for nonpregnant individuals [16] (see also Chapters 6 and 7 in Maternal-Fetal Evidence Based Guidelines). Iodine requirements during pregnancy increase by greater than 50% due to increased maternal thyroxine production to maintain maternal and fetal euthyroidism and increased renal iodine clearance [17]. Longitudinal studies of thyroid ultrasonography in pregnancy show a mean increase in the thyroid size of 18%, which is noticeable in most women but not associated with abnormalities in thyroid function tests [16]. Iodine supplementation results in a less substantial increase in the thyroid gland size [17]. While ultrasound or laboratory evaluation is not necessary in the pregnant patient with a mild diffuse increase in the thyroid size, a signi cant goiter or thyroid nodule must be evaluated as in any patient. A woman who is marginally iodine de cient may be able to compensate with increased thyrotropin stimulation of the thyroid to achieve euthyroidism, but become hypothyroid when faced with the increasing iodine requirements of pregnancy [17]. Thyroid hormone necessary for fetal brain development before this time is provided by the maternal system [15,18]. Thyroid hormone synthesis in the fetus is controlled by the fetal pituitary gland by 20 weeks. Maternal hypothyroidism has been associated with abnormal intelligence quotient testing and pediatric neurodevelopment in offspring, particularly when untreated [18]. While severe maternal iodine de ciency can lead to cretinism in the offspring, it is less clear whether mild-to-moderate iodine de ciency leads to more subtle cognitive or neurologic dysfunction. Iodine supplementation in iodine-de cient populations has been found to substantially reduce the relative risk of cretinism and to improve psychomotor and cognitive test scores in the offspring [17]. However, this is largely transitory and rarely associated with clinical hyperthyroidism. Thus, routine measuring of thyroid function in hyperemesis is not indicated in the absence of other signs of hyperthyroidism such as weight loss or persistent tachycardia [16]. A large prospective observational study of 25,765 pregnant women who underwent thyroid screening in pregnancy showed no difference in pregnancy complications or in perinatal morbidity and mortality in women with subclinical hyperthyroidism [20]. These changes can be adaptive to normal pregnancy but can also put the pregnant women at increased risk for certain pathologic conditions. Anemia and thrombocytopenia are commonly diagnosed during pregnancy, as will be discussed below.

A single antenatal ultrasound that detects a placenta previa treatment quotes images 200 mg lamotrigine buy mastercard, however chapter 9 medications that affect coagulation buy cheap lamotrigine 50 mg on-line, may not indicate that a placenta previa will be present at delivery symptoms congestive heart failure buy 200 mg lamotrigine with visa, as the relative position of the placenta with respect to the internal os will change as gestation progresses [2] medications bad for liver purchase cheapest lamotrigine. The reason for this change in relative position is not placental migration but likely due to the growth and development of the lower uterine segment medicine reactions order on line lamotrigine. Atrophy of placental cells overlying the os also has been postulated as a contributing factor to this apparent positional change. This phenomenon has been cited as the reason that vasa previa can be seen in this setting. Because of the reliability of ultrasound for diagnosis of previa, the technique of double setup examination is unnecessary. If employed, double setup examination should be performed in a setting with the ability to proceed in a prompt fashion with cesarean delivery if indicated. There is no evidence to support the use of autologous blood donation/transfusion for placenta previa [13]. There has been no evidence of any clear advantage to a policy of home versus routine hospital care, with similar maternal and fetal outcomes demonstrated in the trials that do exist. The only difference is that, compared with hospitalization, management at home, not surprisingly, has been associated with a reduced length of stay in the hospital [12]. There are no data to allow certainty as to who are the optimal candidates for inpatient management. Women who, traditionally, have been more likely to be managed in the hospital even though they are not acutely symptomatic are those who have had recurrent episodes of antepartum hemorrhage. As such, depending upon the distance of the placental edge from the internal os as well as other factors, these patients. In women with the placenta 2 cm or more from the internal os, a trial of labor should be encouraged. Often, after an initial antenatal bleeding episode related to placenta previa, if several days of no further bleeding have occurred and there is no other indication for hospitalization, women may be managed as outpatients. Cervical cerclage has not been proven to be an effective intervention for women with placenta previa [12]. Acute bleeding with instability of the mother or fetus is considered a contraindication to tocolysis. There are insuf cient data to assess the usefulness of routine antenatal testing in improving outcomes, and this strategy is presently not indicated. Those with a placenta not covering the internal os but in the lower segment may have a trial of labor offered, with individual circumstances. In a recent series, 26/28 (93%) women who had a placental edge to cervical os distance of 1­20 mm and who underwent a trial of labor delivered vaginally [8,17]. Women with a placental edge that is within 1 cm of the internal os can have uncomplicated vaginal deliveries, although their risk of bleeding and requiring a cesarean is higher than Table 28. The diagnosis of this condition can be quite dif cult, as full ascertainment would require postpartum histologic examination of the entire uteroplacental interface with both placenta and uterus available. Since this is not typically possible, in cases of clinically suspected placenta accreta, failure to demonstrate abnormal villous invasion by pathologic examination cannot always be used to exclude this diagnosis [19]. Epidemiology/Incidence Traditionally 1/2500 deliveries, although evidence of increasing frequency (3/1000 or more), thought to be related to the increased rate of cesarean delivery, has been reported [20,21]. Etiology/Pathophysiology Abnormal adherence of chorionic villi to myometrium, associated with total or partial lack of the decidua basalis layer. Cesarean scar pregnancy is diagnosed by ultrasound often in the rst trimester, and can be an early sign of later development of placenta accreta [22]. Classification Abnormally invasive placentas may be categorized according to the depth of their invasion [23]. Placenta percreta: Placental villi invade through the myometrium into the uterine serosa; adjacent organs. Workup No one imaging modality has been shown to be able to accurately diagnose placenta accreta with 100% sensitivity or speci city. Ultrasonographic ndings that have been reported in association with placenta accreta are shown in Table 28. However, even the combination of all these signs is not 100% sensitive for the diagnosis of accreta, and the sensitivity, speci city, positive and negative predictive values for individual signs and combinations of signs have varied substantially in published studies, but have been commonly reported to be about >60%­80% [31,32]. It may useful as an adjunctive tool if the placenta is posterior or to assess invasion of adjacent organs in suspected percreta [33]. Cystoscopy can be considered as an adjunctive tool to assess for the possibility of placenta percreta in cases where bladder invasion is highly suspected due to radiologic studies or to signs such as frank blood in the urine. Preparations and Plans for Delivery If placenta accreta is suspected, appropriate counseling and preparations should be made (Table 28. Labor and delivery staff (nursing and anesthesia) as well as blood bank should be noti ed regarding delivery plans, and the delivery should occur in a location that has the capacity to provide large volumes of blood transfusion and emergent surgery (including hysterectomy). It should be considered whether the particular circumstances would suggest the need for additional surgical services. The patient (and family members if available) should be counseled regarding risks, complications, and management. The possible need for hysterectomy as a life-saving procedure should be discussed with the patient. Plans for future reproduction should be discussed and weighted against the risk of retaining the uterus. Other preventive or therapeutic interventions as described above and below should be discussed. Fetal maturity testing has been advocated by some and not by others, and one recent decision analysis suggests that it does not help to improve overall health outcomes. The nal timing for delivery will need to be individualized, and take into account the risks of prematurity to the infant and the risks of major morbidity to the mother. General intraoperative considerations include the possibility of a planned vertical skin incision. The uterine incision should be made, if possible, away from the placenta, the position of which can be determined by ultrasound beforehand. Intraoperative ultrasound with a sterile cover over the probe placed on the exposed uterus may be helpful if preoperative ultrasound is not informative. The two most common approaches to management of suspected placenta accreta are hysterectomy without attempt at placental removal versus attempt at placental removal. While there are different potential approaches for managing placenta accreta after delivery of the baby by cesarean, many experts would recommend that if there is proven placenta accreta. In these controlled situations, maternal morbidity of gravid hysterectomy may be decreased, but fertility is lost. During hysterectomy, the uterine serosa overlying the placenta should not be dissected, including trying to avoid bladder dissection. The blood supply to the placenta is not just from the uterine arteries but also from many collateral vessels. Care should be given to dissection of this extensive blood supply by attempting uterine artery dissection laterally, and then continuing down without incising the placenta. Total hysterectomy is generally necessary, as subtotal hysterectomy may leave behind part of the lower segment, where the placenta is abnormally attached and cause bleeding if a previa is present. If the diagnosis is possible but not certain, and the patient desires to make attempts at avoiding hysterectomy despite having been counseled regarding risks, it is not unreasonable to wait for signs of placental separation, although abnormal adherence or signi cant hemorrhage should be ascertained and acted upon promptly. If spontaneous placental delivery fails, the operator must decide if either manual placental removal in pieces or hysterectomy is the next intervention, based on several factors, including the degree of invasiveness and amount of bleeding. If only a small area of the placenta is adherent and a focal area of the placental bed is bleeding, sewing over this area with sutures can be considered, but usually these are in Table 28. This example does not indicate that certain evaluations or consultations are anticipated or expected in all cases. Some have suggested ligation of pelvic vessels (such as the internal iliac artery) in the setting of signi cant hemorrhage, although this may not be bene cial, given the many collateral vessels, and may incur risks as well. Pelvic packing has been used in some cases as a measure to temporarily lessen bleeding and allow attainment of hemodynamic stability. Hysterectomy may be necessary if uterine bleeding cannot be controlled, hopefully before massive blood loss and cardiovascular instability. When bleeding is from the lower part of the uterus in the setting of an accreta and placenta implanted low in the uterus. Gravid hysterectomy has been associated with an incidence of maternal mortality of up to 7%, with a 90% incidence of transfusion, 28% incidence of postoperative transfusion, and a 5% incidence of ureteral injuries or stula formation [19,39]. In some cases, a woman who has not completed childbearing may strongly want to avoid hysterectomy. There are several case reports of expectant (also called "conservative") or medical management in the setting of placenta accreta. In these circumstances, the placenta is left in situ and the cord ligated close to its origin, either with no therapy or with an adjunctive therapy such as methotrexate and/or arterial embolization. Antibiotic prophylaxis has been suggested given the risk of infection, as have short-term uterotonics for postpartum hemorrhage prevention, but there are no trials of these interventions. Symptoms Asymptomatic unless membranes rupture, at which time vaginal bleeding may be noted. Management Principles Timing of bleeding with antenatally diagnosed vasa previa is variable and impossible to predict. Since the fetal vessels are not protected by placental tissue or Wharton jelly, compression may lead to reduced fetal blood ow and bradycardia, and rupture of membranes with subsequent vessel laceration may result in rapid fetal exsanguination. Vasa previa is diagnosed if a vessel is visualized over the cervix with color Doppler demonstrating a rhythm consistent with the fetal heart rate. Thus, not all vasa previa will be detected prenatally, even by adequate examinations and experienced operators using color Doppler. Women whose vasa previa has been diagnosed prenatally have been reported to have lower perinatal mortality than those with vasa previas that are undiagnosed (3% vs. The Apt test may be used to distinguish between fetal and maternal sources of vaginal bleeding, although this test may be of little use in many clinical situations with bleeding from a vasa previa, as bleeding can lead to rapid deterioration of the fetal status and require urgent delivery before an Apt test can be completed. Therapy Level 1 data to guide the management of antenatally diagnosed vasa previa are currently lacking. While some experts suggest that hospitalization at some time after viability may be reasonable, this strategy is unsupported by any adequately powered trials. Women with vasa previa should be delivered by cesarean at a center capable of providing immediate neonatal blood transfusion if needed [53]. Persistence of placenta previa according to gestational age at ultrasound detection. The association of placenta previa with history of cesarean delivery and abortion: A meta-analysis. The likelihood of placenta previa with greater number of cesarean deliveries and higher parity. Pregnancy outcomes for women with placenta previa in relation to the number of prior cesareans. The relevance of placental location at 20­23 weeks gestational weeks for prediction of placenta previa at delivery: Evaluation of 8650 cases. Diagnosis of lowlying placenta: Can migration in the third trimester predict outcome Prenatal diagnosis of placenta previa accreta by transabdominal color Doppler ultrasound. Sonographic detection of placenta accreta in the second and third trimesters of pregnancy. Magnetic resonance imaging in 300 cases of placenta accreta: Surgical correlation of new ndings. Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta. Prenatal identi cation of invasive placentation using ultrasound: Systematic review and meta-analysis. Placenta accreta: Comparison of cases managed with and without pelvic artery balloon catheters. Prophylactic balloon occlusion of the internal iliac arteries to treat abnormal placentation a cautionary case. Arterial embolus during common iliac balloon catheterization at cesarean hysterectomy. Effectiveness of timing strategies for delivery of patients with placenta previa and accreta. Elective non-removal of the placenta and prophylactic uterine artery embolization postpartum as a diagnostic imaging approach for the management of placenta percreta: A case report. Failure of methotrexate and internal iliac balloon catheterization to manage placenta percreta. Massive postpartum hemorrhage after uterus-conserving surgery in placenta percreta: the danger of the partial placenta percreta. Maternal outcome after conservative management of placenta percreta at cesarean section: A report of three cases and a review of the literature. Fertility and pregnancy outcomes following conservative treatment for placenta accreta. Prenatal sonographic diagnosis of vasa previa: Ultrasound ndings and obstetric outcome in ten cases. A systematic review on the diagnostic accuracy of ultrasound in the diagnosis of vasa previa. The association with thrombophilias has for the most part not been con rmed by prospective studies. History, physical examination, laboratory and ultrasonographic studies guide management.

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