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The use of lidocaine for fetocide in late termination of pregnancy M.V. Senata, C. Fischerb, J.P. Bernarda, Y. Villea,* Objective To assess the use of lidocaine (1%) to induce permanent fetal cardiac asystole for fetocide in late termination of pregnancy. Design Prospective observational study. Setting One tertiary referral fetal medicine unit in France. Sample Fifty patients undergoing termination of pregnancy between 20 and 36 weeks of gestation for severe abnormalities or severe maternal conditions. Methods Fetocide was performed by umbilical vein puncture under ultrasound guidance with injection of sufentanil (5 Ag) followed by 7 to 30 mL of lidocaine (1%). Main outcome measures Percentage of successful procedures to obtain permanent fetal cardiac asystole and maternal side effects. Results The procedure was successful in 92% of cases (46/50) with complete cessation of heart activity. The mean amount of lidocaine was 15.3 (6.5) mL. In three cases, fetocide was performed by cardiocentesis and in one case lidocaine was unsuccessful and fetocide was performed with KCl. There were no maternal side effects. Conclusion Lidocaine is an effective drug to perform fetocide with doses below the toxic dose for the mother. INTRODUCTION Late termination of pregnancy for fetal abnormalities is ethically and emotionally difficult for both parents and doctors 1 – 6. Some severe fetal abnormalities are still detected by ultrasound examination after 22 weeks of gestation. In France, the indication must be approved by a multidisciplinary committee. Termination of pregnancy for fetal abnormalities is only performed when the child would have been very likely to suffer from a particularly severe handicap or disease, which could not be repaired or cured at the time of prenatal diagnosis7. Maternal indications include situations in which continuation of pregnancy would seriously endanger the health of the woman. Euthanasia is illegal and parents, physicians and midwives are concerned by the risk of a live birth after prostaglandin induction when the fetus is viable. Fetocide is therefore usually indicated prior to termination of pregnancy in such late cases especially when fetal death can result in a significant shortening of the induction-to-delivery interval8. Fetal analgesia could also be advocated prior to fetocide on the probability of fetal awareness and eventually fetal pain from 24 weeks of gestation onwards9 – 12.

a

Department of Obstetric and Gynecology, CHI, Poissy, France b Department of Anesthesiology, CHI, Poissy, France * Correspondence: Professor Y. Ville, Service de Gyne´ cologie Obste´trique, Hoˆpital de Poissy, Rue du Champ Gaillard, 78300 Poissy, France. D RCOG 2003 BJOG: an International Journal of Obstetrics and Gynaecology doi:10.1016/S1470-0328(02)02217-6

Fetocide is usually performed by intracardiac injection of potassium chloride into the fetal heart13 – 16. Alternatively, analgesia and injection of potassium chloride can be given in the umbilical vein at the placental cord insertion17 – 19. The umbilical cord route needs to be performed following strict protocols and raises theoretical concerns about transplacental passage of KCl and maternal safety. To alleviate any serious maternal risk, we have studied the effectiveness of a local anaesthetic, lidocaine, to perform fetocide when injected in the umbilical vein. This choice was based on lidocaine’s property to induce fetal asystole20,21, although maternal tolerance to lidocaine is good. Indeed, this drug has been widely studied in obstetrics as a local anaesthetic in obstetric analgesia, which toxicity when accidentally injected in the maternal circulation is well known22,23. Toxic doses of lidocaine for the mother are vastly superior to those used to perform fetocide and using lidocaine also allows for fetal analgesia at the time of fetocide24,25. The aim of this study was to evaluate the use of lidocaine to induce permanent fetal cardiac asystole.

METHODS Between May 2001 and January 2002, 50 patients requested termination of pregnancy for severe fetal abnormalities or severe maternal conditions at between 20 and 36 weeks of gestation. Cases are presented as being terminations performed below or above 28 weeks to illustrate more effectively the concept of late termination. All procedures were performed at the woman’s request and were approved by the ad hoc committee. Informed consent was sought www.bjog-elsevier.com

THE USE OF LIDOCAINE FOR FETOCIDE IN LATE TERMINATION OF PREGNANCY

297

Table 1. Termination of pregnancy for fetal abnormalities before 28 weeks of gestation: indication, gestational age and dose of lidocaine used for fetocide. Maternal age (years) 31 32 36 34 40 25 28 28 25 28 25 34 37 24 28 43 38 32 36 34 27 28 29 25 27 40

Gestational age (weeks)

Pathology

Birthweight (g)

Sufentanil (Ag)

Lidocaine (mL)

20 20 21 21 22 22 23 23 23 23 23 23 23 24 24 25 25 25 25 25 26 26 26 26 26 26

Down’s Syndrome Down’s Syndrome Down’s Syndrome Trisomy 18 Down’s Syndrome Osteogenesis imperfecta type II Spina bifida Hydrocephalus Holoprosencephaly Posterior urethral valves Osteochondrodysplasia Complex cardiac malformation Down’s Syndrome Chorioamnionitis Agenesis of the corpus callosum Down’s Syndrome Chorioamnionitis Agenesis of the corpus callosum Trisomy 18 Intracerebral haemorrhage Down’s Syndrome Down’s Syndrome Triploidy Spina bifida Agenesis of the corpus callosum Complex cardiac malformation

270 350 350 225 595 310 470 600 410 550 740 580 490 705 810 700 595 700 430 665 900 1285 345 705 830 735

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

10 7 8 15 10 20 10 15 (cardiocentesis) 10 15 20 20 20 20 10 10 10 10 10 (cardiocentesis) 12 15 30 10 13 15 20

from all participants. Patients received a comprehensive explanation on the risks and benefits of fetocide to prevent the birth of an abnormal live born baby. The mother was given mifepristone (600 mg) followed 48 h later by fetocide and she was then given intravaginal misoprostol18. Maternal pre-operative sedation consisted of oral hydroxizine (50 mg) 2 hours before the procedure and she was then admitted to the delivery suite. Fetocide was performed under patient-controlled epidural analgesia using ropicovaine (0.1%) and sufentanil (0.5 Ag/mL). This technique allowed for ambulatory analgesia during cervical maturation and first stage of labour26,27. The epidural level was adjusted if necessary to obtain a T8 level just before fetocide. Fetocide was performed under ultrasonographic guidance with a 20-gauge needle by a senior member of the fetal medicine team. Placental insertion of the cord was preferentially targeted using adequate magnification and colour Doppler. Intravascular placement was confirmed by the direction to flow of flushing sterile saline. Sufentanil (5 Ag) was then injected followed 3 minutes later by lidocaine (1%). The initial dose was based on a lethal dose to be given to a 1000 g28,29 fetus which can be estimated to be around 100 mg/kg while this would remain within the safe dose regimen for the mother in the event of accidental injection in the maternal circulation (2.8 – 4.2 mg/kg)30. Failure was empirically defined as being unable to induce permanent asystole with a maximum of 300 mg of lidocaine while remaining below a toxic/convulsant dose for D RCOG 2003 Br J Obstet Gynaecol 110, pp. 296 – 300

the mother (7 mg/kg)31. Therefore, the dose injected was between 7 and 30 mL, depending on the gestational age and was given until cessation of the heart activity. The procedure was limited to 15 minutes and 2 g of KCl were available in case of failure. Immunoglobin prophylaxis was given to all Rhesus-negative women. As the procedure was done aseptically, prophylactic antibiotics were not given. After fetocide, intravaginal misoprostol 50 –200 Ag was given every 4 hours and the woman could stay in her room and use patient-controlled epidural analgesia when she was feeling pain. The woman was admitted on a delivery suite for the second stage of labour. The main outcome measure was the percentage of successful procedures to obtain permanent fetal cardiac asystole. All fetuses were sent for postmortem examination.

RESULTS Tables 1 and 2 list the indications for termination of pregnancy for fetal abnormalities and the gestational age at which fetocide was performed. Termination of pregnancy for fetal abnormalities was performed in 26 patients before 28 weeks of gestation and in 24 patients at a later gestation. Seventeen patients requested termination of pregnancy for fetal chromosomal abnormalities including 11 at less than 28 weeks of gestation. Thirty-one terminations were performed for severe fetal structural abnormalities diagnosed

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Table 2. Termination of pregnancy for fetal abnormalities after 28 weeks of gestation: indication, gestational age and dose of lidocaine used for fetocide. Maternal age (years)

Gestational age (weeks)

Pathology

Birthweight (g)

Sufentanil (Ag)

Lidocaine (mL)

28 28 29 29 29 29 30 30 30 31 32 32 32 34 34 34 34 34 34 35 35 36 36 36

Amelia Bilateral renal agenesis Agenesis of the corpus callosum Trisomy 10 Dwarfism Agenesis of the corpus callosum Intracerebral haemorrhage Lisencephaly, pulmonary hypoplasia, chondrodysplasia Fragile X Microcephaly Steinert disease Posterior urethral valves Down’s Syndrome Down’s Syndrome Steinert disease Triploidy CMV infection with brain lesions 22q1.1 deletion Complex cardiac malformation CMV infection with brain lesions Intracerebral haemorrhage with prosencephaly Dandy Walker syndrome and diaphragmatic hernia Multiple vertebral anomalies CMV infection with brain lesions

875 970 1500 1500 1100 1465 1530 340 1515 1165 1895 1785 1800 2830 2385 1620 2470 2340 2340 2105 2600 1535 2700 2900

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

15 10 10 12 30 15 10 10 (cardiocentesis) 10 10 10 15 20 30 10 10 10 15 30 20 30 15 20 Cardiocentesis KCl: 1 g

34 28 28 24 38 37 26 25 18 34 28 30 37 33 31 28 27 31 29 37 37 40 30 28

on ultrasound examination including 13 cases before 28 weeks of gestation. Only two terminations were performed for maternal indications at 24 and 25 weeks of gestation. The mean gestational age (FSD) at termination of pregnancy was 27.7 (F4.8) weeks of gestation. The mean maternal age (FSD) was 30.9 (5.2) years. Fetal karyotype was obtained in all cases. The mean amount of lidocaine injected into the umbilical vein was 15.3 (6.5) mL (range: 10– 30 mL) and the dose did not exceed 30 mL. Complete cessation of heart activity was obtained in 2 (1.5) minutes and the procedure was successful in 46 of the 50 (92%) cases. In three cases, the umbilical vein at the placental cord insertion was not accessible and fetocide was performed by cardiocentesis. In one case, 30 mL of lidocaine (1%) was unsuccessful to arrest the heart activity, this was followed by the injection of 2 g of KCl in the umbilical vein but this procedure was not effective either. Cardiac asystole could only be obtained with the injection of 1 g of potassium chloride into the fetal heart. No live birth occurred and there were no maternal complications.

DISCUSSION The issue of late termination of pregnancy for fetal abnormalities is controversial as laws vary from country to country both in terms of gestation and indications5. Fetal viability is established from 24 weeks onwards. In 1995, Green4 reported that only 13%, 21% and 8% of obstetricians

would perform late termination for Down’s Syndrome, spina bifida and cystic fibrosis, respectively. In some countries, such as France, termination of pregnancy for fetal abnormalities can be performed up to term for lethal, severe and non-curable fetal conditions. We performed fetocide in two cases as early as 20 weeks to comply with the parents’ request despite extensive information. The main situations where the question of termination of pregnancy for fetal abnormalities is raised in the third trimester are: (i) fetal disease is suspected in the second trimester but confirmed only in the third trimester such as in cases of microcephaly or lissencephaly; (ii) diagnosis established in the second trimester but when the prognosis can only be established in the third trimester such as in progressive ventriculomegaly evolving towards hydrocephalus; (iii) fetal malformations which were amenable to early prenatal diagnosis but were missed on an earlier scan. In France, this applies to around one-third of all late terminations32. In countries where late termination of pregnancy is an option, fetocide should be performed in a humane way and our practice was to perform fetal analgesia followed by injection of potassium chloride in the umbilical vein as a one-step procedure of fetal umbilical phlebotomy, which allows for the fetus to die without pain18. Our results show that lidocaine is appropriate to perform fetocide: Effective and rapid cessation of the heart activity was obtained with an amount of drug that remained below the toxic doses for the mother30,31. This proved sufficient in all cases but one. Electrophysiological studies have D RCOG 2003 Br J Obstet Gynaecol 110, pp. 296 – 300

THE USE OF LIDOCAINE FOR FETOCIDE IN LATE TERMINATION OF PREGNANCY

demonstrated that local anaesthetics can depress the maximal rate of the cardiac action potential in a dose-dependent manner33. Additionally, local anaesthetic agents depress the cardiac sodium channels, cardiac conduction and finally, cardiac contractility. The first clinical manifestation of toxicity is seizure and this occurs before cardiac depression. Resuscitation after a toxic injection is more often successful with lidocaine than with bupivacaine29. This makes lidocaine safer for the mother than any other local anaesthetic in this indication. In most cases, the lidocaine dose used for fetocide was 20 mL or less. Although we reported that fetal umbilical access followed by KCl injection was a safe procedure for the mother18, there is a theoretical possibility of maternal injection of KCl, through placental lakes, which could lead to maternal cardiac arrest. If accidentally injected into the maternal circulation, the dose of lidocaine used would be safe as direct injection of 2.8 –4.2 mg/kg has been reported30 without any adverse effect and convulsant doses in healthy volunteers are above 7.3 mg/kg31. Moreover, pregnancy does not alter lidocaine toxicity23. Other drugs have been reported to obtain fetal asystole such as digoxin (1.5 – 2.0 mg) or hyperosmolar urea (40 g) given intracardially34. There has been only one previous report of mid-trimester fetocide by cardiocentesis providing success rates. Isada14 described that asystole could not be obtained in one of 21 fetuses. Otherwise, the literature on intracardiac injection does not provide success rates15,16. We could find three studies on funicular injection of potassium chloride17 – 19. The success rates were of 86.7%, 100% and 95.2%, respectively, which is not different from that in this study (92%). It is therefore critical to check that cardiac arrest is permanent once fetocide has been performed as recommended by the RCOG35. On the ground of fetal pain and fetal awareness, fetal analgesia should optimally precede fetocide11. This is usually a two-step procedure where cordocentesis is only used to give sufentanil into the umbilical vein prior to cardiocentesis to perform fetocide. Lidocaine is an anaesthetic drug which use should also alleviate the need for sufentanil to be given prior to fetocide when umbilical vein access is used. These results should encourage fetal medicine specialists to abandon intracardiac access, which often remains technically and emotionally more difficult.

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