HM Medical Clinic

 

121115_perinatal-gazette_v16_i1_03.indd

The Perinatal Gazette
Newsletter of the Regional Perinatal Center Maria Fareri Children's Hospital at Westchester Medical Center Volume 16, Issue 1 Paracetamol Treatment for
Bioethics of Fetal Surgery
PDA Closure in Preterm Infants Maintenance of the fetal Patent Ductus Arteriosus (PDA) is critical for Fetal surgery represents a broad spectrum of techniques that are used diverting circulating blood from the non-breathing lung. Following to treat birth defects in fetuses in utero. The most common conditions birth, the closure of a PDA is the normal physiological transition to treated with fetal surgery are: neural tube defects, congenital dia- post-natal life. Persistence of the PDA in preterm infants is associated phragmatic hernias, congenital cystic adenomatoid malformations, with comorbidities such as pulmonary hemorrhage, Necrotizing En- congenital heart diseases, pulmonary sequestrations and sacrococcy- terococcus (NEC), Bronchial Pulmonary Dysplasia (BPD), Retinopathy geal teratomas.1 There are several categories of fetal surgery: 1. Open
of Prematurity (ROP), death. Management of the preterm PDA ranges fetal surgery, a method that involves completely opening the uterus to from conservative medical management, medical treatment with operate on the fetus, 2. Fetendo, an approach that uses real time video
ibuprofen or indomethacin, or surgical ligation. The timing and type imagery to guide surgical instruments into the uterus to perform sur- of this intervention is frequently debated. Since these medical and gery on the fetus, and 3. Exit procedure, a surgical technique that is
surgical interventions all carry risks to preterm infants, efficacy and used to deliver babies who have airway compression. safety of various treatment modalities are often balanced against The first fetal surgery was performed in 1981 by Dr. Michael Harrison, possible side effects. "the father of fetal surgery", at UCSF Children's Hospital.2 He per- Complicating these treatment approaches is the variable patency formed a vesicostomy for congenital hydronephrosis. After this first based on gestational age. Approximately 80% of premature infants fetal operation, new techniques with less invasive forms have allowed who are greater than or equal to 29 weeks at birth will achieve sponta- additional defects to be treated. neous permanent closure of their PDAs. It seems reasonable to man- A milestone in the history of fetal surgery is the MOMS trial. This was a age these infants conservatively-e.g., allow their PDAs to close, and multicenter randomized trial of prenatal versus postnatal repair of my- only intervene if they become hemodynamically significant. For pre- elomeningocele done in 2002. According to this trial, prenatal surgery mature infants born at 28 weeks or younger, the rates of spontaneous for myelomeningocele reduced the need for shunting and improved permanent closure drop to below 40%; and drop to approximately motor outcomes at thirty months but was associated with maternal 10% for 24-week preterm infants and below. The PDAs of ELGANs (ex- and fetal risks. The success of this trial inspired formation of The North tremely low gestational newborns < 28 weeks gestation) may there- American Fetal Therapy Network (NAFTNet) in 2005 to promote multi- fore be more suitable targets for medical treatment interventions. The institutional trials on fetal surgery in the United States and Canada.
current medications FDA-approved for treatment of PDA in preterm infants include intravenous ibuprofen lysine (Neoprofen®) and intra- Open Fetal Surgery Technique
venous indomethacin (Indocin®). As with any medication, there may Any type of fetal surgery requires a multidisciplinary approach includ- be side effects, which for these medications may include changes in ing pediatric surgeons, obstetricians, neonatologists, radiologists and platelet function, as well as variable degrees of gastrointestinal and anesthesiologists. Open fetal surgery involves administration of gen- renal toxicity. In the search for other medications for PDA closure, en- eral anesthesia to the mother in which the anesthetic agent crosses teral formulations have been utilized with variable success, and an ob- the placenta and the fetus receives satisfactory anesthesia. To control servational study published in 2011 by Hammerman et al., identified and prevent labor, tocolytics are used during and after surgery. The enterally-administered paracetamol as a possible alternative for PDA uterus is exposed with an abdominal incision and then it is lifted up. closure in preterm infants. / Continued page 2. Subsequently, another incision is made in the uterus to expose the fetus to access and perform the surgery. The fetus remains connected INSIDE THIS ISSUE
to the placenta throughout the procedure. Once the surgery is completed, the fetus is returned to the uterus and the amniotic fluid is 1. Paracetamol Treatment for PDA Closure In Preterm Infants
replaced. Then, the uterus is sutured and put back in the abdomen. / Continued on p. 2
Finally, the abdominal incision is closed. After surgery, the mother and 1. Bioethics of Fetal Surgery / Continued on p. 3
the fetus are kept under observation. The infant is usually delivered 3 4. 4th Annual Regional Perinatal Public Health Conference
/ Continued page 3. Continued from page 1, Paracetamol Treatment Continued from previous column Paracetamol is well-tolerated by infants and children for its analgesic glutathione level did not decrease over time, and the AST/ALT levels eff ects and may be used post-operatively in NICU settings. It is best were not signifi cantly elevated above 50 U/l. They also found that se- known for pain control mediated through the central nervous system. rum paracetamol reached steady state around 31 hours after the fi rst However, the use of paracetamol for PDA closure is a relatively new dose, and the metabolism changed with gestational age. Ganzewin- medication, and there is very limited data for safety and effi cacy in kel also concluded that clearance of paracetamol increased with post- this ELGAN patient population. There are currently two proposed menstrual age as well as with increasing birth weight. Though these mechanisms of action for paracetamol-mediated closure of PDA. numbers are promising in terms of the safety of IV paracetamol, it is Prostaglandin H2 synthetase (PGH2 synthetase) has two components, still unknown if the more available and less expensive oral form of the cyclooxygenase (COX) component and the peroxidase (POX) paracetamol shares the same bioavailability and pharmacokinetics as component. One theory claims that paracetamol directly inactivates the IV form; and, whether this is effi cacious in PDA closure in ELGANs. the COX component. The other hypothesis proposes that paracetamol Paracetamol is a drug used by neonatologists for pain control in pre- inactivates the POX component, which blocks the transformation of term infants; however, the proposed application of oral paracetamol prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) (Figure 1). for PDA closure is relatively new. With limited data on safety and ef- fi cacy of paracetamol (particularly enterally-administered) use in ELGANs, and in particular when used for treatment of PDA, it would seem that caution should be exercised. Pharmacokinetics following enteral administration, comparisons to established safety and effi cacy profi les of IV ibuprofen and IV indomethacin, particularly in ELGANs, would seem to be prudent before oral paracetamol achieves another medical treatment for PDA closure of ELGANs. Jennifer Hsu, MD, Neonatal Fellow, WMC
[email protected]
Lance Parton, MD, Attending Neonatologist, WMC
There are no studies that address the safety and effi cacy of paracetamol use in preterm infants. It is known that high serum paracetamol levels may cause a direct hepatotoxic insult from its me- tabolite. Paracetamol is metabolized in the body via UDP-glucurono- Koch et al "Prevalence of spontaneous closure of the ductus arteriosus in neonates at syltransferase 1A6 enzyme into paracetamol-glucuronide (APAP-G) birth weight of 1000 grams or less" Pediatrics, vol 117, number 4, April 2006 and paracetamol–sulphates (APAP-S), 1-4% is excreted unchanged Clyman "Mechanism regulating the ductus arteriosus" Biol Neo 2006; 89:330-335 through the kidneys, and 8-10% is further oxidized to 3-hydroxyl Lucas et al. "Cellular mechanisms of acetaminophen: role of cyclooxygenase" FASEB paracetamol and N-acetyl-p-benzo-quinone-imine (NAPQI) via liver Allergaert et al. "Paracetamol to induce ductus arteriosus closure: is it valid?"Arch Dis cytochrome P450 2E1. It is this NAPQI metabolite that has a direct tox- Child 2013;98:462–466. ic eff ect on hepatocytes (seen in acetaminophen overdose). When the E Nadir et al. "Paracetamol treatment of patent ductus arteriosus in preterm infants" Journal of Perinatology (2014) 34, 748-749 serum level of paracetamol is within range, endogenous glutathione Yurttutan, et al. "A diff erent fi rst-choice drug in the medical management of patent further conjugates NAPQI into cysteine and mercaptic acid into non- ductus arteriosus: oral paracetamol" J Maternal Fetal Neonatal Med, 2013; 26(8)L toxic forms that are excreted. It has been proposed that when increas- ing serum paracetamol levels overwhelm endogenous glutathione, Dang et al. "Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial" PLOS ONE November NAPQI accumulates and acts directly on hepatocytes, and manifests 2013 Volume 8 Issue 11 e77888 as liver injury with elevated aspartate transaminase (AST) and alanine Oncel et al "Oral Paracetamol versus Oral Ibuprofen in the Management of Patent transaminase (ALT) levels. Ductus Arteriosus in Preterm Infants: A Randomized Controlled Trial" J Peds, Vol. 164, No. 3 March 2014 Though there are studies that are currently in print claiming success Dash et al. "Enteral paracetamol or Intravenous Indomethacin for Closure of Patent Ductus Arteriosus in Preterm Neonates:A Randomized Controlled Trial" Indian Pediat- of PDA closure using paracetamol, these studies are mainly observa- rics, Vol 52, July 15, 2015 tional, with small patient numbers, using diff erent dosages (ranging Rolland et al "Natural evolution of patent ductus arteriosus in the extremely preterm from oral 7.5 -15mg/kg/dose q6h) with variable treatment durations infant"Arch Dis Child Fetal Neonatal Ed 2015;100:F55–F58. (ranging from 3-7days). The subjects were more mature preterm in- Pacifi ci et al. "Clinical Pharmacology of Paracetamol in Neonates: A Review" Current Therapeutic Research 77 (2015) 24–30 fants, who were born with birth weights above 1 kg. One of the major Ganzewinkel et al "Multiple intravenous doses of paracetamol result in a predictable criticisms for these studies is that the background spontaneous clo- pharmacokinetic profi le in very preterm infants" Acta Pædiatrica 2014 sure rates were not taken into consideration. Therefore it is unknown Kluckow et al. "A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus" Arch Dis Child Fetal Neonatal Ed 2014;99:F99–F104. doi:10.1136/ from these studies whether paracetamol is truly eff ective in facilitat- ing closure of PDA. Rozé et al. "Association Between Early Screening for Patent Ductus Arteriosus and In- Hospital Mortality Among Extremely Preterm Infants" JAMA. 2015;313(24):2441-2448. Currently the eff ective serum level for PDA closure in preterm infants with paracetamol has yet to be established. In addition, potential Koch J. et al. Pediatrics.2006;117: 1113-1121 hepatotoxicity eff ects have not been investigated in preterm infants. Clyman RI. "Ibuprofen and patent ductus arteriosus". N Engl J Med 2000; 343: To address the issues of serum steady state elimination, and toxicity Irena Kessel et al. "Paracetamol eff ectiveness, safety and blood level monitoring dur- of paracetamol in preterm infants, Ganzewinkel et al investigated ing patent ductus arteriosus closure: a case series". J Matern Fetal Neonatal Med, Early the pharmacokinetics of paracetamol (IV) when given for pain con- Online: 1–3 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2013.871630 trol. Fifteen preterm infants born less then 32 weeks gestational age Afi f El-Khuff ash et al. "Effi cacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies" Pediatric Re- were given fi ve repeated doses (7.5mg/kg/dose) of IV paracetamol for SeARCh Volume 76 Number 3 September 2014 pain control. They found that with repeated IV doses, the endogenous Gianluca Terrin et al. "Effi cacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates" Italian Journal of Pediatrics 2014, 40:21 Continued next column Continued from page 1, Bioethics of Fetal Surgery Continued from previous column by planned caesarian section at approximately 36 weeks gestation, is viable, the needs of the fetus may take precedence over the wishes of unless premature labor or other complications occur before that time.3 the pregnant woman. If the fetus is not viable, the pregnant woman's decision should be respected. Bioethical aspects of fetal surgery
The pregnant woman should be allowed the freedom to decide upon One ethical consideration for the clinician with fetal surgery is to assess alternative courses of therapy based on her values and beliefs10. How- the benefits and risks of the procedure to both pregnant woman and the ever, society expects that pregnant women to be altruistic. The ideas of fetus. The clinician should respect the autonomy of the pregnant wom- maternal altruism do not fit into an autonomy-based ethic system.11 an and obtain informed consent for the procedure 4,5 The consent should be taken by a physician competent to explain the intervention and its Another potential conflict can arise when the maternal and paternal de- alternatives with its risks and benefits. The consent should be non-direc- sires are not the same. US federal regulations are distinctive in the inter- tive and should avoid therapeutic misconception.
national context in continuing to require the consent of the father for fetal research, including maternal fetal surgery. This allows undue influ- The mother, the fetus, the physicians and on a larger scale the society ence or even control over the pregnant woman's autonomy by someone may benefit from fetal surgery. Fetal surgery might mitigate the anxiety who bears none of the medical risks. The ACOG Committee Opinion is as for the mother caused by awaiting the birth of a fetus with known med- follows: "Although it may be appropriate and helpful for the father to be ical problems. Fetal surgery can also improve the condition of the fetus involved in these decisions and have complete access to information, to or it can possibly prevent its death. The physicians may be relieved to act assign him any authority to assent or dissent would unjustifiably erode upon a known fetal threatening diagnosis. There could also be a de- the autonomous decision-making capacity of the pregnant woman." crease in the burden of sick or disabled people to the society. Progress in medical practice depends on innovation; however surgery All these benefits have to be balanced with the risks of the procedure. on the fetus is always surgery on the pregnant woman as well. Ethical The overall perinatal mortality after open surgery has been estimated to obligations to both must be taken into account in the design and con- be approximately 6%. The safety depends on the specific procedure, the duct of research on maternal-fetal surgery.
gestational age and the condition of the fetus. The costs of the proce-dure have to be taken into account as well. In conclusion, fetal surgery is still not yet standard of care and
can be justified when:
The specific risks for the pregnant woman in open fetal surgery include: uterine rupture, additional C-sections, premature labor and delivery, ex- (1) There is reasonable certainty that the fetus will suffer irrevocable posure to multiple drugs and prolonged hospitalization. The risks for the and substantial harm without the intervention; fetus involve premature delivery, exposure to anesthesia, failure of sur- (2) The intervention has been shown to be effective and it has a realistic gery and fetal demise6. There is a risk of incremental harm from inter- chance of saving the life of the fetus or preventing serious and irre- vention, possibility of iatrogenic versus natural disability, a child with a versible disease and disability.
severe disability versus a child with milder disabilities or no child.
(3) The risk to the health and well-being of the pregnant woman In summary, the trade-offs for the pregnant woman who has a fetal can- didate for surgery include: her risks versus her benefits, her fetus's risks versus her fetus's benefits, her risks versus her fetus's benefits and her (4) The pregnant woman can give appropriate informed consent to the fetus's risks versus her benefits. The physicians have obligations to the fetus as well as to the expecting Cosmina Mandru, MD, Neonatal Fellow, WMC
mother. An ethical dilemma exists when the desires of the mother op- pose needs of her fetus. This dilemma is resolved by taking into consid-eration the viability of the fetus. Viability is defined as the ability of the Semsa Gogcu, MD Attending Neonatologist, WMC
fetus to exist ex utero with or without technological support. If the fetus / Continued next column References:
1. Adzick, NS; Thom EA, Spong CY, Brock III JW, Burrows PK, Johnson MP, Howell LJ, Farrell
JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D'Alton ME, Farmer DL "A Random- ized Trial of Prenatal versus Postnatal Repair of Myelomeningocele". New England Journal of Medicine 364 (11): 993–1004 2. Jancelewicz, T; Harrison, M "A history of fetal surgery" Clin Perinatol, 2009 Jun;36(2):227-36 3. Sutton LN. "Fetal surgery for neural tube defects". Best Pract Res Clin Obstet Gynaecol 22 (1): 175–88.
4. Beauchamp, T; Childress, J -Principles of Biomedical Ethics 38 (4th ed. 1994)5. Chervenak, F; McCullough, L "A Practical Method of Analysis of Obligations to Mother and Fetus". Perinatal Ethics 66 OBSTETRICS & GYNECOLOGY 442 (1985).
6. Johnson, M. P.; Sutton, L. N.; Rintoul, N.; Crombleholme, T. M.; Flake, A. W.; Howell, L. J.; Hedrick, H. L.; Wilson, R. D.; Adzick, N. S. (2003). "Fetal myelomeningocele repair: short- term clinical outcomes". American journal of obstetrics and gynecology 189 7. E. F. Werner at al. "Evaluating the cost-effectiveness of prenatal surgery for myelomenin- gocele: a decision analysis" Ultrasound Obstet Gynecol 2012; 40: 158–164 8. Fasouliotis, S.J. & Schenker, J.G." Maternal-fetal conflict" Eur. J. Obstet. Gynecol. Reprod. Biol. 89, 101-107 (2000).
9. Oduncu, F.S., Kimmig, R., Hepp, H. & Emmerich, B "Cancer in pregnancy: maternal-fetal conflict" J. Cancer Res. Clin. Oncol. 129, 133-146 (2003).
10. Isaacs, D. "Moral status of the fetus: fetal rights or maternal autonomy?" J. Paediatr. Child Health 39, 58-59 (2003).
11. Anna Smajdor "Ethical challenges in fetal surgery" J Med Ethics 2011;3712. American College of Obstetricians and Gynecologists, Committee on Ethics. ACOG Committee Opinion No. 377: research involving women. Obstet Gynecol. 2007;110(3): 14th Annual Hudson Valley
to predict heart disease, how research and collaboration can be fa- Regional Perinatal Public Health cilitated through social media, and the necessity of responsible social The afternoon keynote presentation was delivered by Jermane Bond, PHD, Program Director, Boys & Men of Color, National Collaborative The 14th annual Hudson Valley Regional Perinatal Public Health for Health Equity. Dr. Bond presented "The Paternal Factor: Evidence,
Conference, "Hot Topics in Perinatal Health: Social Media, Donor
Strategies, & Innovations," a talk focused on the important role of pa-
Milk, Paternal Impact, and Reproductive Environmental Health"
ternal involvement in pregnancy. The session touched on historical was held November 4th, 2015 at the DoubleTree in Tarrytown, NY. and contemporary aspects of fatherlessness, related socioeconomic The conference was hosted by the Regional Perinatal Center at Ma- factors, and recommendations to better involve fathers, as well as re- ria Fareri Children's Hospital(MFCH)/Westchester Medical Center search on paternal impact.
Health Network, the Lower Hudson Valley Perinatal Network (LHVPN) Dr. Boriana Parvez, Medical Director, Donor Preterm Human Milk and Maternal Infant Services Network with major sponsorship from Bank, Westchester Medical Center Health Network, presented Children's Health & Research Foundation and March of Dimes. Over "Benefits of Donor Milk in the NICU", a talk focused on the impor-
120 health, medical and human services professionals from the sev- tance of breastfeeding and how to increase rates. She described how en counties of the Lower Hudson Valley attended.
donor milk banks help improve short and long term outcomes of Dr. Michael Gewitz, William Russell McCurdy Physician-in Chief; Chief, both infants and mothers. Initial results at MFCH showed significant Pediatric Cardiology, Maria Fareri Children's Hospital, gave the wel- improvements in breastfeeding as a result of donor milk availability.
coming remarks commenting on the importance of public health Dr. Edmund F. La Gamma, FAAP, Chief, Division of Newborn Medi- conferences in shaping healthcare and reaching communities. cine, Professor of Pediatrics, Biochemistry and Molecular Biology, The first speaker of the day was Dr. Andrew Elimian, FACOG, Profes- NY Medical College; Chief, Regional Neonatal Center, Maria Fareri sor, OB/GYN, NY Medical College; Director, Maternal Fetal Medicine, Children's Hospital at WMC presented "State of the Region's Perina- WMC, who presented "Premature Birth: Can it be Prevented?" The
tal Health". He spoke on national trends in births, prematurity and talk focused on causes, pathways, and trends of preterm birth. Dr. related ethical issues, breastfeeding, and drug related discharges. Dr. Elimian addressed the global impact of prematurity and the numer- La Gamma touched on the RPC at WMC and its role as a referral cen- ous international prevention efforts. ter for the region, as well as various NYS DOH public health initiatives. Dr. La Gamma also spoke briefly about the emerging problem of high The morning keynote speaker was Dr. Marya G. Zlatnik, MMS, Associ- rates of survival just below the upper limit of a legal termination of ate Director, Maternal Fetal Health & the Environment, UCSF-Western pregnancy at 24 weeks gestation and how this represents a paradox States Pediatric Environmental Health Specialty Unit, presenting for clinicians in the delivery room regarding whether a child's right to "Environmental Contaminants & Reproductive Health: What Should
a trial of therapy as valued by the provider can be superseded by a We Tell Women?" Dr. Zlatnik addressed the increase in chemicals
parental right to decline care. The option of delivery room hospice in our everyday lives, their potentially harmful role in reproduc- was discussed as a compromise position in extraordinary circum- tive health, and how to counsel pregnant women regarding these stances where no clear path to reconciliation materializes.
environmental hazards. She concluded her talk with 10 easy to fol- low steps on avoiding contaminants, such as which foods to choose Closing remarks were made by Cheryl Hunter-Grant, LMSW, CLC, based on likely levels of pesticide residuals, organic vs. non-organic.
Executive Director, LHVPN. Her take-home message was one of col- laboration on all fronts in an effort to provide access to health care The late morning keynote speaker, Dr. Nathaniel DeNicola, MSHP, FA- and promote health equity toward improving perinatal health out- COG, Faculty in Obstetrics & Gynecology at University of Pennsylva- comes throughout our region. nia; Senior Fellow, Penn Social Media & Health Innovation Lab, presented "The Doctor Will Tweet You Now: Professional Use of Digi-
David Aboudi, BA, Data Manager, Regional Perinatal Center, WMC
tal & Social Media in Public Health Advocacy". Dr. DeNicola discussed
the role of social media in healthcare, including online data being used / Continued next column. We are interested in providing you with a newsletter that is Please visit www.westchestermedicalcenter.com/RPC
relevant and of interest to you. Please contact us with perinatal for information about the Regional Perinatal Center at the topics you would like to see addressed.
Maria Fareri Children's Hospital at Westchester Medical Center For a copy of our newsletter or to be placed on our mailing list, and to locate previous issues of The Perinatal Gazette.
contact us by phone or e-mail.
State Perinatal Database Howard Blanchette, M.D., FACOG
Heather Brumberg, M.D. M.P.H.,
Desmond White, MD, FACOG,
Team & Perinatal Gazette Professor & Chairman of the FAAP, Associate Director Maternal Fetal Medicine, Dept. Department of Obstetrics & Regional Perinatal Center OB/GYN (914) 493-2250 Gynecology (914) 594-2113 Donna Dozor, R.N.,M.S. Neonatal
Andrew Elimian, MD, FACOG Chief
Edmund LaGamma, M.D., FAAP,
Data Collection (914) 493-8309 Susan Sippel, R.N., M.S., Editor,
of Perinatal Medicine, Department Director Newborn Medicine & Coordinator, Regional Perinatal of Obstetrics and Gynecology RPC (914) 493-8558 Center (914) 493-8590 The Regional Perinatal CenterMaria Fareri Children's Hospital At Westchester Medical Center100 Woods Road, Valhalla, New York 10595

Source: http://bchphysicians.org/wp-content/uploads/2016/01/Newsletter-1-16-Perinatal-Gazette.pdf