253

Eskes et al, Prepregnancy care

Review article

J. Perinat. Med. 20(1992)253-265

Prepregnancy care and prevention of birth defects Tom K. A. B. Eskes1, Petrus N. M. Mooij1, Regine P. M. Steegers-Theunissen1, Jos P. Lips2, and Pieternel C. M. Pasker-de Jong3

*Dept. Obstetrics and Gynecology, Academic Hospital Nijmegen, 2Dept. Obstetrics and Gynecology, Jozef Hospital Veghel, 3Dept. Medical Informatics and Epidemiology, Catholic University of Nijmegen, Nijmegen, The Netherlands

1

Introduction

Curriculum vitae

Antenatal care is now a well established feature TOM ESKES, M. D. Ph. D. of all maternity services. During the past decades FRCOG, born in 1933, is an impressive decline in perinatal morbidity and Professor of Obstetrics mortality has been achieved in most Western and Gynecology of the countries, probably due to increased socio-eco- University of Nijmegen (NL). He was trained at nomic standards and better antenatal care. Birth this University and at defects now receive an increasing attention in Case Western Reserve perinatal medicine, because they contribute a University in Cleveland, great deal towards perinatal mortality and mor- Ohio, USA. He is chief bidity. Birth defects on the fetus or newborn Editor of EJOGR and occur in 2% —5%. This percentage depends on serves in the Editorial the definition of birth defects and the period of Board of five other Journals. He is an honorary member follow-up. If one takes into account the early of five Ob-Gyn societies, and he serves the FIGO as well stages of pregnancy, defects in reproductive out- as E AGO (Secretary-General). In 1992 he received the Prize. come are much more frequent than 2% — 5% [5]. maternite His main interest is perinatology. In this field 36 Ph.D. The medical approach towards the issue of birth theses, 10 books and over 300 publications were comdefects nowadays is mainly the given emphasis pleted under his guidance. on prenatal diagnosis. Usually this selection process leads to interruption of pregnancy, a procedure that can not be listed as preventive medicine. Prepregnancy care is the logical precursor to antenatal care and allows many more Since the Thalidomide tragedy intensive monipossibilities for a couple than may be available toring of birth defects has been stimulated, but in early pregnancy. Attention is given to the prepregnancy care is still a rather seldomly used pathogenesis of malformations in an attempt to feature of maternity services. Malformations can find aspects for prevention. One of the first ap- be the result of monogenically inherited disorders proaches to the primary prevention of birth de- or more often of a multifactorial aetiology, where fects is the nationwide vaccination program for early embryonic development of a polygenically rubella in young girls to prevent embryotoxicity susceptible fetus is interfered with by environduring a rubella infection in pregnancy. A rec- mental trigger influences. Teratology can be deommendation for preconception counseling fined as the study of abnormal fetal development should be given to all women with an increased and is not only directed at understanding the risk for having a pregnancy complicated by a causes and mechanisms of abnormalities of Brought to you by | New York University Bobst Technical Services structurally or functionally malformed fetus. structure, but also at Library the disturbances of func1992 by Walter de Gruyter & Co. Berlin · New York

Authenticated Download Date | 6/6/15 11:08 PM

254

Eskes et al, Prepregnancy care

tion. Several disciplines nowadays contribute to teratology such as genetics, toxicology, pharmacology, pharmacy, epidemiology and last but not least perinatology. In 1984 we have started a research program called "Motherhood before pregnancy" [21] with emphasis on the primary prevention of congenital malformations. Our hypothesis is that much can be gained by preconceptional care. This review focusses on some aspects of prepregnancy care: medication, nutritional status, diabetes mellitus and in particular neural tube defects (NTDs). 2 Medication

A potentially preventable group of disorders are the drug-induced anomalies. Medication during pregnancy can be avoided. The impact on prevention is mainly determined by three factors: the frequency and character of medication during pregnancy, the prevalence of the known effects among the children exposed in utero, and the benefit-to-risk ratio of the drugs used.

ginal carcinoma after Diethylstilbestrol (DES) exposure in utero. Newer examples of teratogenic drugs are Isoretinoin, which is related to a syndrome of the central nervous system, craniofacial and cardiovascular defects, and valproic acid, which is related to NTDs. No research is done among pregnant women before a drug is marketed and animal experiments may not give complete and correct answers. This is even more the case for functional defects. Functional defects hardly ever have been studied in children exposed in utero, and animal experiments that are carried out may give a very incomplete view of the expected effects. Furthermore, even for the drugs studied on humans, some effects may never be remarked because the resulting anomaly is too frequent or too rare. On the other hand, a drug may be safe for use during pregnancy but is not given because of a case report on anomalies in children who were exposed in utero. This may result in higher risks for mother and child as well. 2.4

Prevention

Total eradication of medication may have negative effects on survival and development of the embryo and fetus. Rational pharmacotherapy taking benefit-to-risk analyses into account Drug comsumption patterns vary around the should be stimulated. To identify the risks and world and during the years. Figures range from benefits large enough studies in humans should 35% to 100% [33]. According to the literature, be carried out to evaluate both the long-term drug use seems to have diminished. The drugs and short-term effects on the fetus of treatment that are most often used are the most interesting and of non-treatment of a certain illness. One from a prevention point of view. These were option is to extend post-marketing surveillance analgesics and antibiotics. and follow-up of all pregnant women with a disease, either treated or non-treated, until the children are grown up. Furthermore, the infor2.2 The prevalence of the known effects among mation from all studies should be readily availthe children exposed in utero able and interpretable to everyone concerned. The prevalence of disorders in exposed children For this purpose, a classification system would is never 100%. There are several reasons as ex- be useful. In 1980, the FDA (Food and Drug plained by ARIMA and TANAKA [1]. Some children Administration) of the USA recommended the are not exposed during the critical period. Others introduction of a classification system for the do not seem to be vulnerable to the effects. teratogenic properties of drugs [2]. A modified Differences in metabolism seem to play a role in classification system is in use in Australia [3], the differences in penetrance of the effects after Sweden [6] and Switzerland [40]. In the US classification system, a letter (A, B, C, D, or X) is exposure. assigned to all drugs according to their hazard for the fetus. Information about the effects on 2.3 The benefit to risk ratio of the drugs used the functional development is included in the The teratogenic properties of many drugs are decision which category the drug should be in. unknown [7]. Well-known teratogenic effects are However, to be able to classify drugs in a useful to you | New way, York University Bobst about Library Technical Services information the effects should be focomelia after Thalidomide Brought exposure andbyva2.1

The frequency and character of medication during pregnancy

Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

255

Eskes et al, Prepregnancy care

well-nourished populations revealed that birth and placental weights and body length in term infants depend more on prepregnancy height and weight than on changes in energy and protein intakes during pregnancy [68]. The absence of an appreciable increase in energy intake during pregnancy means that the energy balance of pregnant women shows a gap in comparison with prepregnant energy balances [71]. Part of this gap might be explained by behavioural adaptions in physical activity and lowering the energy expenditure during pregnancy [71]. These findings stress the importance of an optimal preconceptional status. In the second half of the twentieth century epidemiological studies of human malformations associated maternal nutritional defi3 Nutritional status ciency with fetal abnormalities, especially NTDs The relationship between nutrition, health and [17, 28, 78]. Increases in NTD incidence were the performance of women during reproduction noted when food was scarce in Germany after has been accepted as self-evident for a long time. World War II [18] and in the Netherlands folA deficient nutritional status in women of repro- lowing the famine of 1944 to 1945 [85]. Early ductive age affects not only the general health work in Great Britain clearly demonstrated that condition but also the fertility capacity [91]. If NTDs are more frequent in the lower social fat stores are low, menarche is delayed, ovulation classes in which diet may be poor [17]. Studies is infrequent and may even stop as can be noticed on diet in early pregnancy have confirmed low in women suffering from anorexia nervosa. intakes of all nutrients in the lower social classes When fat stores are replaced in normal women, [41] and significantly lower mean levels of redthere is usually a return of normal pituitary cell folate and white cell vitamin C [80]. In 1980 ovarian activity. A well known nutritional defi- and 1981, the results of two intervention studies ciency in obstetrical practice is megaloblastic an- were published in which vitamin supplementaaemia due to folic acid or vitamin B12 deficiency. tion around the time of conception was given to During pregnancy, the fetus acquires all its es- women who had had a pregnancy with a NTD sential nutrients from the mother. Fetal nutrition [42, 81]. These studies suggested that folic acid and fetal growth depend on placental size and or multivitamin supplementation might reduce nutrient availability. This relationship is greatly the recurrence rate. Three epidemiological studinfluenced by maternal metabolic and endocrine ies on the possible association between the vichanges during pregnancy, themselves influenced tamin intake and the presence of NTDs have by intake and nutrient availability [90]. Epide- been conducted in the USA and showed different miological evidence in the developing world is results [54, 56, 65]. These results were highly clear in demonstrating that low birth weight, controversial, because of questions concerning mostly due to intrauterine growth retardation, is the design and analysis of these studies [14]. The prevails among women with a chronic low food MRC vitamin study finally demonstrated a 72% and energy intake during pregnancy, a small protective effect after periconceptional folic acid maternal prepregnancy size in height and/or supplementation for women at risk for NTDs weight, a low or adequate body mass index and [63]. Among the many vitamins that might play low pregnancy weight gain [38, 70]. The reverse a role in the causation of NTDs, folate has situation, where relatively well-nourished women received the most attention. Folic acid and viare suddenly deprived of food during pregnancy, tamin B12 are important co-factors in the synhas important consequences as well. In utero thesis of nucleic acids. A deficiency of folic acid exposure to famine of the female fetus, even if is accompanied by disturbance in DNA synthesis followed by adequate postnatal and childhood and can disrupt fundamental biological procdiet and full adult stature, is associated with low esses, such as growth and cell division. Extreme birth weight, intrauterine growth retardation and folic acid deficiency can disturb reproductive shorter gestation in her offspring Brought [48]. Studies performance in Bobst laboratory animals Services [62]. Defito you on by | New York University Library Technical present. At present, the classification is carried out according to whether or not there is any evidence that the drug is safe or dangerous. Unfortunately, most drugs are classified as 'there is not enough evidence reported to establish safety. Do not use during pregnancy' (categories B [nothing known] or C [animal experiments gave indications for teratogenicity, nothing known about human risk]). Furthermore, this information is not readily available to the users of the drugs, but only to the prescribers. For over-thecounter drugs a similar system should be developed.

J. Perinat. Med. 20 (1992)

Authenticated Download Date | 6/6/15 11:08 PM

256

Eskes et al, Prepregnancy care

ciencies of many other individual vitamins during pregnancy in animals have been shown to have teratogenic effects on the embryo [16, 60]. An excess of vitamins, especially vitamin A, is known to be teratogenic in laboratory animals [94], but also increases the risk of birth defects in human [75]. Because of their effects on epithelial-cell differentiating, retinoic acids are often used for the treatment of severe cystic acne. High doses of vitamin A before a during pregnancy should be avoided. The vitamin status is also affected by the use of oral contraceptives causing higher levels of vitamin A and lower levels of vitamin B12 [61]. Oral contraceptive treatment itself however does not justify multivitaminsupplementation [61]. Folic acid and multivitamin supplementation in view of preconceptional satus is recommended for all women who have had a pregnancy complicated with a NTD [63], and for all women with inadequate dietary intake or increased metabolic needs. 4 Diabetes mellitus

Another important feature of prepregnancy consultation is recognizing pre-existing medical diseases and the possible effects of the disease on pregnancy. The consultation should concern the effects of the disease on the pregnancy and of pregnancy on the disease. A further aspect is the pharmacotherapy of the disease, which can have more serious impact on the fetus than the condition itself. 4.1

Specific malformations related to diabetes mellitus

syndrome, situs inversus, gross skeletal malformations, pseudohermafroditism, urological malformations and cardiac malformations. In contrast with the latter, the following disorders showed the same incidence in the diabetic group as in the reference group: malformations of the gastrointestinal tract, muscular system, other skeletal malformations, and ocular and auricular malformations. Another group of disorders occur significantly less often in neonates of diabetic women: multiple malformations, malformations of the respiratory tract, malformations of the fingers, Down's syndrome and hypospadia. A prospective study detected 137 congenital malformations in 499 neonates of diabetic women especially located in the central nervous system, the cardiovascular system and the urogenital tract [13]. MILUNSKY [55] described an occurrence rate of 19.5 promille of NTDs in group of 411 diabetic women. Two prospective studies give relative risks of 3.1 and 5 for congenital cardiac malformations, respectively [57, 76]. The functional development of the fetal central nervous system during diabetic pregnancy differs from that observed in normal pregnancy, as indicated by the delayed emergence of movement patterns in the first trimester, the delayed emergence of behavioural states in the third trimester and after birth, by the continuity of poor behavioural state organisation, immature EEG patterns and a high incidence of periodic breathing [64]. Several reports have shown that diabetes in the mother may affect behavioural and intellectual development in the offspring [74]. 4.2

Pathogenesis: hyperglycaemia and genetic factors

Neonates of women with diabetes mellitus type 1 run, compared with controls, 2 to 3 times more Most of the above-mentioned malformations are risk of congenital malformations [53, 58]. Al- the result of disturbed development in the first though certain malformations are relatively more six weeks after conception [52]. Metabolic factors prevalent no malformations are specific for di- (hyperglycaemia, hypoglycaemia, elevated conabetes. In most publications, the number of neo- centrations of beta-hydroxybutyrate and other nates is too small to calculate the relative risk ketones), exogenic teratogens (insulin, oral anfor individual specific malformations. Review of tidiabetics, oestrogens and gestagens) and other the literature showed out of 7,101 neonates 340 factors (genetic, trace elements, decreased capacmalformations in neonates of diabetic women ity for spontaneous abortion, immunological) [39]. The following malformations, in order of have been discussed in literature. In this review, relative frequency, were significantly more seen we will concentrate on hyperglycaemia and gecompared with a control group of 431,764 neo- netic factors which in combination are the most nates from the WHO Comparative Study of plausible causative mechanisms. The first indiCongenital Malformations: vertebral column cation of a possible relation between quality of glucose regulation and theTechnical incidence of congenmalformations including the Brought caudal toregression you by | New York University Bobst Library Services Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

Eskes et al, Prepregnancy care

ital malformations was given by KARLSSON and KJELLMER [35], PEDERSEN and MÖLSTED-PEDERSEN [69, 59]. LESLIE et al. [44] showed a direct relation between the quality of glucose regulation during the period of morfogenesis and the incidence of congenital malformations by measurement of glycosylated haemoglobin (GlyHb) during pregnancy. The concentration of GlyHb is related to the blood glucose level during the previous period of 1 to 2 months [49]. Women with a high GlyHb during the first trimester of pregnancy have a significantly increased change of major congenital malformations in their offspring [23, 27, 45, 47, 51]. A direct relation between glucose concentrations and the incidence of congenital malformations was demonstrated by FUHRMANN et al. [23, 24]. The Diabetes in Early Pregnancy (DIEP) study examined prospectively the relation between GlyHb-level, the blood glucose concentration and the incidence of congenital malformations [53]. The results of the DIEP study could not confirm the relation between the incidence of congenital malformations and the level of glucose concentration. This apparent discrepancy may be explained by a threshold effect. Most patients in the DIEP study had only slightly elevated GlyHb concentrations, probably because they have been recruited before pregnancy. The incidence of congenital malformations in this group was increased, however not as much as seen in the other studies. The absence of a relation between the incidence of congenital malformations and the glucose concentrations in early pregnancy does not imply that this relation does not exist. The DIEP study did not answer the question whether optimal glucose concentrations in the critical period of morfogenesis will normalize the incidence of congenital malformations. The aetiology of malformations in neonates of diabetic women is probably multifactorial. Genetic factors are possibly involved in the sensitivity of the conceptus to teratogenic enrivonmental circumstances as increased glucose concentrations [20, 30, 77]. Current research will reveal whether the maternal HLA-DR status is involved [79].

257

lated to the quality of glucose regulation. It is most likely that energy supply on cell level is brought in a state of disorder by hyperglycaemia and possibly also by increased concentrations of beta-hydroxybutyrate, resulting in a delay in the metabolic processes [72]. In combination with other unknown factors, possibly genetic, this could result in congenital malformations. Yet the indications that optimal adjustment of diabetes in early pregnancy results in a decrease of the percentage of congenital malformations are in favour of aiming at an optimal adjustment of the diabetes in early pregnancy. Ideally, the first aim of patient and physician will be to achieve an optimal glucose control before contraceptive measures are cancelled. Patient education on their diabetes, planned pregnancies after excellent metabolic control, and optimal management of diabetes during pregnancy will give optimal perinatal results with a minimum of major congenital anomalies in the offspring [15, 37]. The possible association between ketonaemia in metabolically well-regulated women with diabetes during pregnancy and lower IQ [74] stresses the importance of avoiding ketoacidosis and accelerated starvation during pregnancy.

5 Neural tube defects 5.1 Definition

NTDs are the largest and most disabling of birth defects and are major malformations of the central nervous system in which the central canal of the malformed brain or spinal cord is persistently open to the outside environment. Degeneration of the exposed nervous tissue leads either to a severely damaged brain or to local disruption of the vertebrae and spinal nerve pathways. This review follows the widespread convention of placing all NTDs in only two categories — anencephaly which includes craniorachischisis, and spina bifida aperta which comprises meningocele, myelocele and encephalocele. 5.2

4.3

Prevalence

Preventive measures: good quality of glucose regulation before and during pregnancy

NTDs are among the most prevalent of all the congenital malformations and are second only The increased incidence of congenital malfor- to congenital heart defects as a cause of perinatal mations in newborn infants of diabetic women mortality due to birth defects [66]. The birth Brought and to you York University Library Services prevalence rate ofBobst NTDs is Technical decreasing due to appears to be metabolically determined re-by | New J. Perinat. Med. 20 (1992)

Authenticated Download Date | 6/6/15 11:08 PM

258

Eskes et al, Prepregnancy care

secular trends and pregnancy termination after prenatal diagnosis. Differences in the birth prevlaneces of NTDs have been established between countries and between socio-economic and ethnic groups. In low risk areas, such as Japan and France, the birth prevalence rate is less than 1 per 1,000 births [22, 86] and up to 7 per 1,000 births among Sikhs [26]. The recurrence risk for NTDs is about 10 times the population risk [19].

5.3 Pathogenesis

importance of folic acid supplementation in the preventation of NTD recurrences [63]. This is in line with the report of THIRSCH who showed an association between NTDs and prenatal exposure to aminopterin and methotrexate, which are folate antagonists [87]. Anticonvulsants reduce folate levels as well, although the exact teratogenic mechanism is not clear [36]. Epileptic women using anticonvulsant drugs have an increased risk of having an infant with a congenital malformation, including NTDs [4]. A genetic predisposition to NTDs possibly activated by reduced folate levels, might be responsible for this [83]. The recent finding that epoxide hydrolase activity in amniotic fluid seems to be useful to determine infants at increased risk for congenital malformations induced by anticonvulsant therapy, is highly encouraging [8]. A new risk factor in the aetiology of NTDs might be an increased blood level of homocysteine due to an absolute or relative lack of folate, vitamin B12 or remethylation enzymes [84]. It revealed that one third of women with a previous NTD infant suffered from hyperhomocysteinemia. It is of significance that, independent of the folate status, folate therapy enhances the reduction of the toxic homocysteine concentrations by stimulating of the remethylation of homocysteine to methionine [88]. While maternal folate supplementation is recommended to reduce the recurrence risk of NTDs, one must be aware that folic acid supplementation in pharmacological dose might interfere with the intestinal absorption of zinc [93]. Zinc is an essential trace element for normal cellular growth and differentiation and plays an important role in the developing nervous system [32]. A maternal zinc deficiency might be teratogenic [31], which is supported by a case report in which an association between a maternal lack of zinc and an anencephalic was considered [10].

NTDs develop in humans very early in pregnancy: in the third and fourth weeks after conception. These malformations can be part of the array of abnormalities produced by some mutant genes, but the general hypothesis is that the great majority of NTDs results from an interaction between a genetically susceptible embryo and environmental trigger influences around the time of conception [9]. The concept that environmental as well as polygenetic factors participate in the aetiology of NTDs is supported by changes in the prevalence of NTDs in time and by the observations that NTDs are more common in females, spring conceptions, firstborn infants and the offspring of highly fertile women [19, 43]. Little is known about the genetic predisposition of NTDs. Early embryonic development involves the orchestrated establishment of a large multisegmented, multicellulair organism. The multiple organs are built up from a large number of single cell units. This embryonic body plan is possible because of a network of control genes (master-genes): cells provided with a unique positional imprinting. In the hierarchy of developmental gene networks operating during embryonic development, these mechanisms are likely to be essential if not crucial to normal organogenesis [67]. The precise precipitating environmental factors in the aetiology of NTDs are unknown, but several possible aetiological fac5.4 Prenatal diagnosis of neural tube defects tors have been reported. NTDs are more common in less educated and poorer families. There- Women with an increased risk for having a NTD fore, the linkage between socio-economic class infant, i. e. previous NTD infant, use of anticonand nutrition appeared to be one of the most vulsants and folate antagonists during the first important environmental factors in the causation trimester of pregnancy, should be offered preof NTDs [81]. In 1965 [28] HIBBARD and SMI- natal diagnosis. Antenatal screening of open THELLS, first suggested that an underlying defect NTDs includes ultrasonography and the meain the metabolism of the essential B-vitamin fol- surement of alpha-foetoprotein (AFP) in materate was responsible for the malformed offspring nal serum (MSAFP) and AFP and acetylcholinin many folate-deficient patients [28]. Just re- esterase in amniotic fluid. Ultrasonography is an Brought to you by |the New York University Library Technical Services effective wayBobst to identify neurulation disorders, cently, the MRC Vitamin Study established Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

259

Eskes et al, Prepregnancy care

but also to characterize the extent and location of the NTD. Detailed ultrasound evaluation should be performed at 16 — 18 weeks gestation to detect NTDs, however an anencephalic fetus can be diagnosed from the 12th week of gestation. Furthermore, fetal behaviour can be studied by ultrasound as well. It has been reported that fetal movements are different from controls when NTDs are present, especially in cases of anencephalus [89]. This is an area of research that could be of importance in not only diagnosing an anatomical defect, but also its pathophysiologic function and the possible prediction of the degree of handicap. Ultrasound evaluation is always a necessary additional method to MSAFP and amniocentesis, however will fail to detect approximately 15 — 20 percent of all spinal defects in experienced hands [82, 92]. It is recommended to offer high-risk women amniocentesis at the time of the ultrasound examination the determination of amniotic fluid AFP and acetylcholinesterase. The combined use of these two modalities would detect 92 to 95 percent of all NTDs [25]. A false positive result may be due to mixture of amniotic fluid with fetal blood, omphalocele, unreliability of pregnancy duration and Down's syndrome. MSAFP screening is a widely used method for the detection of open NTDs and will detect about 80 percent of spina bifida's [29]. Closed NTDs do not increase MSAFP and amniotic fluid AFP levels. False positive results occur in cases of omphalocele, ectopia vesicae or intrauterine death [12]. The sensitivity depends on the reliability of pregnancy duration, the exclusion of twin pregnancy and the use of additional techniques as amniocentesis and ultrasound. Pregnancy termination as a result of a raised MSAFP level without the available additional methods is not justified.

growth and recovery potential of the fetal brain has so far not been much explored [50]. The measures to be taken before pregnancy to prevent the development of a NTD can be listed as primary prevention and differ between highrisk women and those who are not known to have an increased risk of a NTD infant. Following the UK Medical Research Council trial' highrisk women should be treated with folic acid supplementation starting before conception or, at least before the fourth postconceptional week. Women with unrecognised malnutrition, malabsorption, and gastric bypass operations should use similar supplementation therapy if they are planning a pregnancy. The same advice should be given to women taking folate-antagonists, and possibly to those who are taking anticonvulsants [4]. For women with no obstetric history of NTDs who may become pregnant, the role of vitamin supplementation is not clarified. If prepregnancy care is being offered, this should include a careful review of the daily nutrition and nutritional state, and if necessary dietary assessment [11]. If vitamin supplements are indicated, they should be in physiological doses. 6

Discussion

Regular antenatal examinations were a strange innovation in the beginning of the twenties century, but nowadays both consumers and professionals see the advantage of such services. At the end of this century, dramatic improvement in perinatal mortality and morbidity rates stresses the importance of a reduction in the incidence of congenital malformations, since they contribute a great deal towards perinatal mortality and morbidity. This stimulated the creation of an additional feature to maternity services: prepregnancy care. Primary prevention of birth defects should be an important public health issue in 5.5 Preventive measures terms of costs and ethics. For example, the health Avoidance of NTDs has been possible for more costs for spina bifida in the USA are more than than a decade by prenatal diagnosis resulting in 20 million dollars a year [46]. Reduction in birth termination of pregnancy. Fetal therapy is a form defects prevalence has important social and inof secondary prevention of congenital malfor- dividual implications. Monitoring programs for mations. Fetal therapy without opening the birth defects are therefore of great importance uterus is still largely at an early stage of research not only for international registration of congendevelopment. Surgical intervention after opening ital malformations and trend detection, but also the uterus is still mainly at the stage of animal for stimulating scientific investigations on the experiments. Fetal therapy for NTDs is not pos- pathogenesis of malformations. A further chalsible yet, but improvements in therapeutical tech- lenge to start basic and preventive studies, is that to you by | New University Library niques can be expected. EspeciallyBrought the enormous the York causes of birthBobst defects areTechnical largely Services unknown J. Perinat. Med. 20 (1992)

Authenticated Download Date | 6/6/15 11:08 PM

260

Eskes et al, Prepregnancy care

and only purely genetic in a small number of cases [34]. Much can be gained when risk factors can be identified and appropriate measures can be taken. Randomised clinical trials provide the best evidence of efficacy for medical and public health interventions. A positive result from a randomised trial can confidently be ascribed to a certain intervention and provides the opportunity to look for undesired side-effects of an intervention. The feasibility of a clinical trial will be threatened by difficulties in recruitment, compliance, ethical constraints, adverse impact of publicity and high costs [73]. The issues affecting whether a study is ethical are complex, but a crucial condition is that no subject should have disadvantages by entering a trial. Randomisation is ethical only when there is no consensus about a particular arm of a trial. If there is good evidence that a proposed intervention is useless or harmful, it is unethical. Decisions of ethics committees not to allow a clinical trial based on inconclusive reports can be criticized, because it results in bad science. The history of medicine is replete with examples of regimens that appeared to be efficious, but turned out to be harmful. Examples are stilbestrol to prevent spontaneous abortion, thalidomide and the use of excessive oxygen in the treatment of premature babies. Clinical trials on the primary prevention of birth defects are sometimes not feasible because of the low occurrence rates of the studied malformation, high costs or ethical problems. A casecontrol study may be considered as an alternative to a randomised clinical trial [73]. Public health costs will be much lower to perform a case-

control study and preliminary results will not influence the study ethically. The price paid for availing oneself of the advantages of case-control studies are the problems of recall bias and the appropriate choice of controls [73]. Preconceptionally instituted measures should be based on consistent, coherent evidence, which are gathered using the best possible study designs. In case of an increased risk for congenital malformations, a women should be counselled before pregnancy to evaluate risk factors, to ensure that the mother avoids exposure to teratogens in early pregnancy and to check basic maternal health condition. Women with pre-existing medical diseases should be counselled on the effects of the disease and medication on the fetus, and on the effects of the pregnancy on the disease. Therefore, research into the benefits and risks associated with the medication should be carried out, probably in the form of Long-term Post Marketing Surveillance. Furthermore, the informations should be made readily available to users and prescribers through the use of a rating system. At the prepregnancy clinic, advice can be given to avoid any persistent dietary excesses so that appropriate nutrition is provided for the growing fetus. Especially vitamins and folic acid are focuses of interest. It has to be pointed out that the natural history of many fetal disorders is not yet well understood and urges further research into this area. Better ways of determining selection criteria for treatment and improvement in prevention techniques are needed to enhance the benefits of prepregnancy care.

Abstract

Birth defects and disturbances in growth and development need an increasing attention in perinatal medicine. It is remarkable that so little attention has been paid to the pathogenesis of malformations in the literature in an approach to find aspects of prevention. Primary prevention of birth defects is an important public health issue as malformations have important consequences both for society and the individuals con-

cerned. Prepregnancy care as a logical precursor to antenatal care, offers risk-assessment, advice and occasionally treatment before pregnancy, in order to avoid congenital malformations. It is therefore that we started a research program with emphasis on primary prevention of congenital malformations. In this respect medication, maternal nutritional status, diabetes mellitus and neural tube defects are discussed.

Keywords: Birth defects, prepregnancy care, primary prevention. Zusammenfassung

zin sollte sich die Aufmerksamkeit auf Fehlbildungen Die Schwangerenvorsorge ist inzwischen ein etabliertes richten, da sie einen hohen Anteil an der perinatalen Brought to you by | New York University Libraryhaben. Technical Services werMortalität undBobst Morbidität Fehlbildungen Instrument in der Geburtshilfe. In der PerinatalmediSchwangerenvorsorge und Prevention von Fehlbildungen

Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

261

Eskes et al, Prepregnancy care den pränatal diagnostiziert und die Schwangerschaft kann dann eventuell abgebrochen werden. Dieses Vorgehen kann nicht als „Prävention" bezeichnet werden. Der Schwerpunkt sollte auf die präkonzeptionelle Phase verschoben werden, um so eine primäre Prävention von angeborenen Fehlbildungen zu erreichen. In dieser Übersicht werden einige Aspekte einer Betreuung vor der Schwangerschaft betrachtet; dazu gehören Medikamenteneinnahme, Ernährungsstatus, Diabetes mellitus und Fehlbildungen sowie Neuralrohrdefekte. Die medikamenteninduzierten Anomalien stellen eine Gruppe von möglicherweise vermeidbaren Störungen dar. Die teratogene Potenz vieler Substanzen ist nicht bekannt. Das gilt für strukturelle Defekte, aber mehr noch für funktionelle Störungen. In einigen Fällen wird ein totales Absetzen der Medikation in der Schwangerschaft negative Einflüsse auf das Überleben bzw. die Entwicklung des Embryo/Feten haben. Eine rationale Pharmakotherapie setzt eine Nutzen/Risikoanalyse voraus, die nur auf der Basis einer genauen Anamnese erfolgen kann. Darüberhinaus ist eine Klassifizierung der Medikamente wie sie von der American Food and Drug Administration vorgeschlagen wird, hilfreich. Fetale Ernährung und fetales Wachstum hängen vom Plazentasitz und von der Funktionsfahigkeit der Plazenta ab, die wiederum durch graviditätsbedingte metabolische und endokrine Veränderungen auf Seiten der Mutter beeinflußt wird. Um eine optimale Versorgung zu erreichen, sollte nicht nur die Ernährung während der Schwangerschaft ausreichend sein; auch der mütterliche Ernährungsstatus vor der Konzeption spielt eine große Rolle. Es gibt Studien, die einen Zusammenhang zwischen einem Vitaminmangel und Neuralrohrdefekten belegen. Als ursächlicher Faktor scheint insbesondere der Folsäuremangel eine große Rolle zu spielen. Bei Risikoschwangeren und Frauen mit einem erhöhten Stoffwechsel sollte man präkonzeptionell und in der frühen Schwangerschaft Folsäure substituieren.

Neugeborene von Frauen mit Diabetes Typ l haben zwei- bis dreimal häufiger angeborenen Fehlbildungen, wobei diese nicht „diabetesspezifisch" sind. Die meisten Fehlbildungen sind Folge einer gestörten Entwicklung in den ersten 6 Wochen post conceptionem. Eine Hyperglykämie in Kombination mit genetischen Faktoren erscheint als Ursache noch am ehesten plausibel. Neuralrohrdefekte stellen die häufigsten und zum Teil schwerwiegensten angeborenen Fehlbildungen dar. Sie entstehen in der 4. Woche post conceptionem. Es wurde die Hypothese aufgestellt, daß die meisten Neuralrohrdefekte bei genetisch disponierten Embryonen, die auf einen Umwelttrigger reagieren, entstehen. Solche Trigger können sein ein Folsäuremangel, Einnahme von Antikonvulsiva und ein erhöhter Homocysteinspiegel im Blut, der auf einen absoluten oder realtiven Mangel an Folsäure, Vitamin B oder Enzymen zur Methylierung zurückgeht. Frauen, die Risikofaktoren für Neuralrohrdefekte haben, sollten vor der Konzeption betreut werden und dann auch eine pränatale Diagnostik durchführen lassen. Angeborene Fehlbildungen stellen unter Kostengesichtspunkten wie auch unter ethischen Aspekten ein wichtiges Thema im öffentlichen Gesundheitswesen dar. Eine primäre Prävention von Fehlbildungen ist für die Gesellschaft wie für das Individuum von Vorteil. Darum sollten nicht nur Programme zur Erfassung von Fehlbildungen gefördert werden, sondern vielmehr auch wisenschaftliche Untersuchungen zur Pathogenese unterstützt werden. Randomisierte klinische Versuchsreihen liefern Ergebnisse, auf deren Basis medizinische und gesundheitspolitische Konsequenzen gezogen werden können. Ist ein solches Vorgehen aus ethischen oder praktischen Gründen nicht möglich, müssen manchmal auch Fallstudien ausreichen. Die Beratung und gelegentlich auch Behandlung vor der Schwangerschaft bieten Möglichkeiten zur Vermeidung angeborener Fehlbildungen. Benötigt werden genauere Selektionskriterien für die Betreuung und verbesserte therapeutische Ansätze.

Schlüsselwörter: Angeborene Fehlbildungen, präkonzeptionelle Betreuung, primäre Prävention.

Resume

des malformations congenitales. Cette revue est centrees sur certains aspects des soins anterieurs ä la La surveillance prenatale est maintenant devenue une grossesse: medications, status nutritionnel et diabete realite bien etablie dans toutes les maternites. Les mal- en relation avec les malformations congenitales, et tout formations congenitales font Fobjet d'une attention particulierement les malformations du tube neural croissante en medecine perinatale, car elles sont etroi- (MTN). tement liees avec la mortalite et la morbidite perina- Les anomalies induites par des medicaments repretales. Uapproche medicale concernant le devenir des sentent un ensemble de troubles potentiellement evimalformations congenitales est principalement centree tables. Les effets teratogenes de nombreux medicasur le diagnostic prenatal et Finterruption de grossesse ments sont inconnus, ä la fois pour leur effet inducteur que Fön ne peut situer dans le cadre d'une medecine de malformations structurelles et plus encore pour leur preventive. On devrait insister sur les soins avant la effet inducteur de pathologies fonctionnelles. L'eradicationYork totale des medicaments au Technical cours de laServices grossesse conception, dans le cadre d'une prevention Broughtprimaire to you by | New University Bobst Library Soins avant la grossesse et prevention des malformations congenitales

J. Perinat. Med. 20 (1992)

Authenticated Download Date | 6/6/15 11:08 PM

262

Eskes et al, Prepregnancy care

peut parfois avoir des effets negatifs sur la survie et le developpement de Fembryon et du foetus. II faut appuyer une pharmacotherapie rationelle pour laquelle une analyse des risques et des benefices peut etre effectuee sur la base d'une information complete. En outre, un Systeme de classification des medicaments tel que celui propose par la Food and Drug Administration americaine pourait etre utile. La nutrition et la croissance foetales dependent de la taille du placenta et de la disponibilite en nutriments et, elles sont influencees par les modification maternelles metaboliques at endocriniennes au cours de la grossesse. Pour des performances reproductives optimales, les seuls apports en energie et en nutriements, au cours de la grossesse, ne sauraient suffire, intervient egalement le status nutritionnel pre-conceptionnel de la mere. Des etudes anterieures ont montre 1'association entre deficiences vitaminiques et MTN. Parmi les nombreuses vitamines pouvant jouer un role causal des MTN, ce sont les folates qui ont ete le plus etudies. On recommande une supplementation chez les femmes a risques eleves et chez celles qui ont des besoins metaboliques accrus, pour ameliorer le status preconceptionnel et en debut de grossesse. Les nouveaux-nes de femmes avec un diabete de type 1 ont un risque 2 a 3 fois plus eleve d'avoir un enfant porteur de malformations congenitales, mais il n'y a pas de malformations specifiques du diabete. La pluspart de ces malformations resultent d'un developpement perturbe au cours des 6 semaines suivant la conception. Uhyperglycemie et les facteurs genetiques combines representent les mecanismes causals les plus plaisibles. L'eqilibre optimal du diabete, en debut de grossesse, entraine une diminution du pourcentage de malformations congenitales.

Les MTN representent les malformations congenitales les plus importantes et les plus invalidantes et, elles surviennent, dans Pespece humaine, au cours des 4 semaines suivant la conception. Uhypothese generate est que la grande majorite des MTN proviennent d'une interaction entre un embryon ayant une susceptibilite genetique et des influences d'environnement declenchantes. Ces influences sont representees par la carence en acide folique, Putilisation de medicaments anticonvulsivants et une elevation des taux sanguins d'homocysteine secondaire ä un deficit relatif ou absolu en folates, en vitamine B 12 et en enzymes de remethylation. Les femmes a rique de MTN devraient recevoir des soins en preconceptionnel et un diagnostic prenatal. La diminution des recurrences de MTN peut etre obtenue par une supplementation periconceptionnelle en acide folique. Les malformations congenitales representent une question de sante publique importante en terme de coüt et d'ethique, et la prevention primaire des malformations congenitales a fait la preuve de son interet pour la societe et les individus concernes. Neanmoins, il ne faut pas seulement encourager les programmes de surveillance de la prevalence des malformations congenitales, mais egalement les recherches scientifiques etudiant la pathogenic des malformations. Les essais cliniques randomises fournissent les meilleures preuves de Fefficacite des interventions medicates et de sante publique, mais, parfois, c'est l'approche avec des cas temoins qui est adoptee, du fait de contraintes ethiques et pratiques. Les soins anterieurs ä la grossesse comprennent des conseils et eventuellement des traitements avant la grossesse afin d'eviter des malformations foetales. II est necessaire d'avoir de meilleures votes pour determiner les criteres de selection pour les traitements et pour amelioration des techniques therapeutiques. Mots-cles: Malformations congenitales, prevention primaire, soins avant la grossesse.

References

[5] BOUE JA, P BOUE, P LAZAR: Retrospective and prospective epidemiological studies of 1500 karyotyped spontaneous human abortion. Teratology 12(1975) 11 [6] BRIGGS GG, RK FREEMAN, SJ YAFFE: Drugs in pregnancy and lactation. 2nd edn. Eds., Williams & Wilkins, Baltimore 1986 [7] BRIGGS GG, RK FREEMAN, SJ YAFFE: A reference guide to fetal and neonatal risk; Drugs in pregnancy and lactation. 3rd edition. Eds., Williams & Wilkins, Baltimore 1990 [8] BUEHLER BA, D DELIMONT, M VAN WAES, R FINNELL: Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 322 (1990) 1567 [9] CARTER CO: Multifactorial inheritance revisited. In: FRÄSER FR, VA McKusiCK: Congenital malformations. Excerpta Amsterdam Brought to you by | New York University Bobst LibraryMedica, Technical Services 1969

[1] ARIMA M, H TANAKA: Developmental anomalies — Variance in the expressivity and pattern of affected organs. Int J Neurol 16-17 (1983) 61 [2] Australian Drug Evaluation Committee: Medicines in pregnancy. An Australian categorization of risk. Australian Government Publishing Services, Canberra 1989 [3] BERGLUND F, H FLODH, P LUNDBORG, B FRAME, R SANNERSTEDT: Drug use during pregnancy and breast feeding. A classification system for drug information. Acta Obstet Gynecol Scand 126 (1984) 1 [4] BIALE , LEWENTHAL: Effect of folic acid supplementation on congenital malformation due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod Biol 18 (1984) 211

Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

263

Eskes et al, Prepregnancy care

[10] CAVDOR AO, A ARCASOY, T BAYCU, Ο ΗΙΜΜΕ- [27] HANSON U, B PERSSON, S THUNELL: Relationship between haemoglobin Ale in early type 1 (insulinTOGLU: Zinc deficiency and anencephaly in Turdependent) diabetic pregnancy and the occurrence key. Teratology 22 (1980) 141 of spontaneous abortion and fetal malformation [11] CEFALO A, MK Moos (eds): Preconceptional in Sweden. Diabetologia 33 (1990) 100 health promotion, a practical guide. Aspen pub[28] HIBBARD ED, RW SMITHELLS: Folic acid metablishers Inc, Rockville, Maryland 1988 olism and human embryopathy. Lancet i (1965) [12] CHRISTIAENS GCML, M KRBEK, M KORENROMP: 1254 Prenatale diagnostiek met behulp van amniocentese. In: KLOOSTERMAN MD: Prenatale diag- [29] HOBBINS JC: Diagnosis and management of neural-tube defects today. N Eng J Med 324 nostiek in de eerste helft van de zwangerschap. (1991) 690 Medicom Europe BV 1987 [13] CHUNG CS, NC MYRIANTHOPOULOS: Effect of ma- [30] HOBT JJ: The etiology of congenital malformations in infants of diabetic mothers: environmenternal diabetes on congenital malformations. tal and genetic interaction. In: JOVANOVIC L: DiBirth defects XI-10 (1975) 23 [14] COCKROFT DL: Vitamin deficiencies and neuralabetes and pregnancy. Teratology, toxicity and tube defects: human and animal studies. Hum treatment. Praeger New York 1986 Reprod 6 (1991) 148 [31] HURLEY LS: Teratogenesis of trace-element defi[15] DAMM P, L M LSTED-PEDERSEN: Significant deciency. Physiol Rev 61 (1981) 249 crease in congenital malformations in newborn [32] HURLEY LS: Teratogenic effects of manganese, infants of an unselected population of diabetic zinc and copper deficiencies. In: SAKAR B: Biowomen. Am J Obstet Gynecol 161 (1989) 1163 logical aspects of metal and metal-related diseases. [16] DAVIS SD, T NELSON, TH SHEPARD: TeratogenRaven Press, New York 1983 icity of vitamin B6 deficiency: omphalocele, skel- [33] JONG DE PCM, WS NIJDAM, GA ZIELHUIS, TKAB etal and neural tube defects, and splenic hypoplaESKES: Medication during low-risk pregnancy. sia. Science 169 (1970) 1320 Eur J Obstet Gynecol Reprod Biol 41 (1991) 191 [17] EDWARDS JH: Congenital malformations of the [34] KALTER H, WARKANY: Congenital malformations. central nervous system in Scotland. Br J Prev Soc Etiologic factors and their role in prevention. N Med 12(1958) 115 Eng J Med 308 (1983) 424 [18] EICHMAN E, H GESENIUS: Die Mi geburtenzu- [35] KARLSSON K, I KJELLMER: The outcome of dianahme in Berlin und Umgebung in den Nachbetic pregnancies in relation to the mother's blood kriegsjahren. Arch Gynak 181 (1950) 168 sugar level. Am J Obstet Gynecol 112 (1972) 213 [19] ELWOOD JM, JH ELWOOD: Epidemiology of anen- [36] KELLY TE: Teratogenicity of anticonvulsant drugs cephalus and spina bifida. Oxford University I: Review of the literature. Am J Med Genet 19 Press, Oxford 1980 (1984) 413 [20] ERIKSSON UJ, J STYRUD: Congenital malforma- [37] KITZMILLER JL, LA GAVIN, GD GIN, L JOVAtions in diabetic pregnancy: the clinical relevance NOVIC-PETERSON, EK MAIN, WD ZIGRANG: Preof experimental animal studies. Acta Paediatr conception care of diabetes. Glycemic control preScand 320 (1985) 72 vents congenital anomalies. JAMA 265 (1991) 731 [21] ESKES TKAB, JP LIPS, PNM Moon, WS NIJDAM, [38] KRAMER MS: Determinants of low birth weight: VGHJ KIRKELS: Preconceptionale zorg. (PreconMethodological assessment and meta-analysis. ceptional care) Metamedica 64 (1985) 336 Bull Wrld Hlth Org 65 (1987) 663 [22] Eurocat Working Group: Prevalence of neural [39] KUCERA J: Rate and type of congenital anomalies tube defects in 20 regions of Europe and the among offspring of diabetic women. J Reprod impact of prenatal diagnosis, 1980—1986. J EpiMed 7 (1971) 61 demiol Community Hlth 45 (1991) 52 [40] KUNZ J, SCHREINER WE: Pharmakotherapie w h[23] FUHRMANN K, H REIHER, K SEMMLER, F FISCHER, rend Schwangerschaft und Stillperiode. Georg M FISCHER, E GL CKNER: Prevention of congenThieme Verlag, Stuttgart 1982 ital malformations in infants of insulin-dependent [41] LAURENCE KM, N JAMES, MH MILLER, H CAMPdiabetic mothers. Diabetes Care 6 (1983) 219 BELL: Increased risk of recurrence of pregnancies [24] FUHRMANN K, H REIHER, K SEMMLER, E GL CKcomplicated by fetal neural tube defects in mothNER: The effect of intensified conventional insulin ers receiving poor diets, and possible benefit of therapy before and during pregnancy on the maldietary counseling. Br Med J 281 (1980) 1592 formation rate in offspring of diabetic mothers. [42] LAURENCE KM, N JAMES, MH MILLER, GB TENExp Clin Endocrinol 83 (1984) 173 NANT, H CAMPBELL: Double-blind randomised [25] HADDOW JE: Screening for spinal defects. Hosp controlled trial of folate treatment before concepPractice 4 (1982) 128 tion to prevent recurrence of neural tube defects. [26] HALL JG, JM FRIEDMAN, BA KENNA, J ΡΟΡΚΓΝ, Br Med J 282 (1981) 1509 M JAWANDA, W ARNOLD: Clinical, genetic, and [43] LECK I: Epidemiological clues to the causation of epidemiological factors in neural tube defects. Am neural tube defects. In: Prevention of spina bifida Brought to you by | New York Bobst Library Technical Services J Hum Genet 43 (1988) 827 and University other neural tube defects. DOBBING J (ed): Academic Press, London 1983 Authenticated J. Perinat. Med. 20 (1992)

Download Date | 6/6/15 11:08 PM

264

Eskes et al, Prepregnancy care

[44] LESLIE RDG, DA PYKE, PN JOHN, JM WHITE: Haemoglobin Al in diabetic pregnancy. Lancet ii (1978) 958 [45] LIPS JP: Het aantal kinderen met aangeboren afwijkingen van vrouwen met diabetes mellitus type l in verband met het percentage geglycosyleerd hemoglobine vroeg in de zwangerschap. Ned Tijdschr Geneeskd 132 (1988) 357 [46] LIPSETT MB, JC FLETCHER: Do vitamins prevent neural tube defects (and can we find out ethically)? The Hasting Center Report, 1983 [47] LUCAS MJ, KJ LEVENO, ML WILLIAMS, P RASKIN, PJ WHALLEY: Early pregnancy glycosylated hemoglobin, severity of diabetes, and fetal malformations. Am J Obstet Gynecol 161 (1989) 426 [48] LUMEY LH: Obstetric performance of women after in utero exposure to the dutch famine (1944— 1945). Thesis Columbia University, USA (1980) [49] MAYER TK, ZR FREEDMAN: Protein glycosylation in diabetes mellitus: a review of laboratory measurements and of their clinical utility. Clin Chem Acta 127 (1983) 147 [50] MICHEJDA M, J BACHER: Functional and anatomical recovery in the monkey brain following excision of fetal encephalocele. Pediat Neurosi 12 (1985-1986)90 [51] MILLER E, JW HARE, JP CLOHERTY, PJ DUNN, RE GLEASON, JS SOELDNER, JL KITZMILLER: Elevated maternal hemoglobin Al in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 304 (1981) 1331 [52] MILLS JL, L BAKER, AS GOLDMAN: Malformations in infants of diabetic mothers occur before the seventh gestational week. Diabetes 28 (1979) 292 [53] MILLS JL, RH KNOPP, JL SIMPSON, L JOVANOVICPETERSON, BE METZGER, LB HOLMES, JH AARONS, Z BROWN, GF REED, FR BIEBER, M VAN ALLEN, I HOLZMAN, C OBER, CM PETERSON, MJ WITHIAM, A DUCKLES, E MUELLER-HEUBACH, BF POLK, and the National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study: Lack of relation of increased malformation rates in infants of diabetic mothers to glycaemic control during organogenesis. N Engl J Med 318 (1988) 671 [54] MILLS JL, GG RHOADS, JL SIMPSON et al: The absence of a relation between the periconceptional use of vitamins and neural tube defects. N Eng J Med 321 (1989) 430 [55] MILUNSKY A, E ALPERT, JL KITZMILLER, MD YOUNGER, RK NEFF: Prenatal diagnosis of neural tube defects. VII. The importance of serum alphafetoprotein screening in diabetic pregnant women. Am J Obstet Gynecol 142 (1982) 1030 [56] MILUNSKY A, H JICK, SS JICK et al: Multivitamins/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. J Am Med Assoc 262 (1989) 2847

[57] MITCHELL SC, AH SELLMANN, MC WESTPHAL, J PARK: Etiologic correlates in a study of congenital heart disease in 56,109 births Am J Cardiol 28 (1971) 653 [58] MÖSTED-PEDERSEN L, I TYGSTRUP, J PEDERSEN: Congenital malformations in newborn infants of diabetic women. Correlation with maternal diabetic vascular complications. Lancet i (1964) 1124 [59] MÖLSTED-PEDERSEN L: Pregnancy and diabetes: a survey. Acta Endocrinol [suppl] 238 (1980) 13 [60] MONDE IW, MM NELSON, HM EVANS: Abnormalities of the urinary system of rat embryos resulting from maternal pteroylglutamic acid deficiency. AnatRec 120(1954) 119 [61] MOOIJ PNM, CMG THOMAS, WH DOESBURG, TKAB ESKES: Multivitamin supplementation in oral contraceptive users. Contraception 44 (1991) 277 [62] MOOIJ PNM, MGAJ WOUTERS, CMG THOMAS, WH DOESBURG, TKAB ESKES: Disturbed reproductive performance in extreme folic acid deficient golden hamsters. Eur J Obstet Gyn Reprod Biol 43 (1992) 71 [63] MRC VITAMIN STUDY RESEARCH GROUP: Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 338 (1991) 131 [64] MULDER EJH: Fetal behaviour. Studies on normal and diabetic pregnancy. Thesis University of Groningen, Groningen, The Netherlands 1990 [65] MULINARE J, JF CORDERO, JD ERICKSON,

RJ

BERRY: Periconceptional use of multivitamins and the occurrence of neural tube defects. J Am Med Assoc 2260 (1988) 3141 [66] Office of population: Censuses and survey. Mortality statistics. Series DH3, no 18. Her Majesty's Stationary Office, London 1985 [67] OUDEJANS CBM: Transcription of homeobox and major histocampatibility complex class I genes in extra-embryonic tissue. Thesis free University of Amsterdam, Amsterdam, The Netherlands 1989 [68] PAPIERNIK E, R FRYDMAN, J BELAISCH: Nutrition in slim, normal and obese pregnant women. In: DOBBING J (ed): Maternal nutrition in pregnancy. Eating for two? Academic, London, 1981 [69] PEDERSEN J, L MÖLSTED-PEDERSEN: Congenital malformations: the possible role of diabetes care outside pregnancy. In: Ciba Foundation Symposium 63. Pregnancy metabolism, diabetes and the fetus. Excerpta Medica, Amsterdam 1979 [70] PRENTICE AM, RG WHITEHEAD, SB ROBERTS et al: Longterm energy balance in childbearing Gambian women. Am J Clin Nutr 34 (1981) 2790 [71] RAAY VAN JMA, SH VERMAAT-MIEDEMA, CM SCHONK, MEM PEEK, JGAJ HAUTVAST: Energy requirements of pregnancy in the Netherlands. Lancet (1987) 953 [72] REECE EA, JC HOBBINS: Diabetic embryopathy: Pathogenesis, prenatal diagnosis and prevention. Brought to you by | New York Obstet University Bobst Surv Library Services Gynecol 41Technical (1986) 325 Authenticated Download Date | 6/6/15 11:08 PM

J. Perinat. Med. 20 (1992)

265

Eskes et al, Prepregnancy care [73] RHOADS GG, JL MILLS: The role of the casecontrol study in evaluating health interventions. Am J Epidemiol 120 (1984) 803 [74] Rizzo T, BE METZGER, WJ BURNS, K BURNS: Correlations between antepartum maternal metabolism and intelligence of offspring. N Engl J Med 325 (1991) 911 [75] ROSA FW, AL WILK, FO KELSEY: Teratogen update: vitamin A congeners. Teratology 33 (1986) 355 [76] ROWLAND TW, JP HUBBELL, AS NADAS: Congenital heart disease in infants of diabetic mothers. J Pediatr 83 (1973) 815 [77] SAMUEL J: Birth defects research: 1980 and after. Am J Med 72 (1982) 119 [78] SCOTT DE, PJ WARKANY, JA PRITCHARD: Maternal folate deficiency and pregnancy wastage II. Fetal malformations. Obstet Gynecol 36 (1970) 26 [79] SIMPSON JL, JL MILLS, C OBER, LB HOLMES, R KNOPP, L JOVANOVIC, BE METZGER, JH AARONS, Z BROWN, M CONLEY: DR3+ and DR4+ diabetic women have increased risk for anomalies: evidence for genetic susceptibility in diabetic embryopathy. Society for Gynecologic Investigation, St Louis, Missouri, USA Abstr (1990) 391 [80] SMITHELLS RW, S SHEPPARD, CJ SCHORAH: Vitamin deficiencies and neural tube defects. Arch Dis Child 51 (1976) 944 [81] SMITHELLS RW, S SHEPPARD, CJ SCHORAH et al: Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet i (1980) 339 [82] SOLLIE JE: Antenatale echoscopische diagnostiek van congenitale afwijkingen. Thesis, Free University, Amsterdam 1985 [83] SPEIDEL BD, MEADOW SR: Maternal epilepsy and abnormalities of the fetus and newborn. Lancet 2 (1972) 839 [84] STEEGERS-THEUNISSEN RPM, GHJ BOERS, JMF TRUBELS, TKAB ESKES: Neural-tube defects and derangement of homocysteine metabolism. N Eng J Med 324 (1991) 199

J. Perinat. Med. 20 (1992)

[85] STEIN Z, M SUSSER: Maternal starvation and birth defects. In: KELLY S, E HOOK, D JANERICH, IH PORTER (ed): Birth defects: risks and consequenses. New York, Academic Press 1976 [86] TAGUCHI H: (Letter) Lancet 2 (1991) 506 [87] THIERSCH JB: Therapeutic abortions with a folic acid antagonist 4-amino-pteroylglutamic acid administered by the oral route. Am J Obstet Gynecol 63 (1952) 1298 [88] UELAND PM, H REFSUM: Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 114(1989)473 [89] VISSER GHA, RN LAURINI, JIP DE VRIES, DJ BEKEDAM, HFR PRECHTL: Abnormal motor behaviour in anencephalic fetuses. Early Hum Dev 12 (1985) 173 [90] VITERI FE, L SCHUMACHER, K SILLMANN: Maternal malnutrition and the fetus. Semin Perinatol 13 (1989) 236 [91] WARREN M: Effects of underautrition on reproductive function. Endocrinology Review 4 (1983) 363 [92] WEINBAUM PJ, SB CASSIDY, AM VINTZILEOS, WA CAMPBELL, L CIARLEGLIO, DJ NOCHTMSON: Prenatal detection of a neural tube defect after fetal exposure to valproic acid. Obstet Gynecol 67 (1986) 31S [93] WILSON PC: The effects of folic acid on the intestinal absorption of zinc. Clin Res 31 (1983) A760 [94] YIP JE, VG KOKICH, TH SHEPARD: The effect of high doses of retinoic acid on prenatal craniofacial development in Macaca nemestrina. Teratology 21 (1980) 29 TKAB Eskes, M.D., Ph.D., FRCOG Department of Obstetrics and Gynaecology University Hospital St. Radboud PO Box 9101 6500 HB Nijmegen The Netherlands

Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/6/15 11:08 PM

W. Kanzel, M.Kirsclibaum, University of Giessen (Eds.)

OXYGEN

Basis of the Regulation of Vital Functions in the Fetus 1992. XVI, 244 pp. 87 figs. 17 tabs. Hardcover DM 156,- ISBN 3-540-55413-0

Formation of the maternal placental vascular bed by maternal tissue (right, epitheliochorial placenta) and by the trophoblast (left, hemochorial placenta).

An adequate oxygen supply is vital for the undisturbed development of the fetus and its functions. This book gives a synopsis of the ruling influence that oxygen has in multiple regulation systems in the mother and especially in the fetus. The authors consider oxygen as a manipulated variable or as a corrective element during normal pregnancy, during delivery and during acute and chronic oxygen deficiency. Furthermore, they deal with the consequences that oxygen deficiency has on the fetus. Price is subject to change without notice.

Springer-Verlag D Heidelberger Platz 3, W-1000 Berlin 33, F.R. Germany D175 Fifth Ave., New York, N Υ 10010, USA D 8 Alexandra Rd., London SW19 7JZ, England D 26, rue des Cannes, F-75005 Paris, France G 37-3, Hongo 3-chome, Bunkyo-ku, Tokyo 113, Japan D Room 701, Mirror Tower, 61 Mody Road, Tsimshatsui, Kowloon, Hong Kong D Avinguda Diagonal, 468-4° C, E-08006 Barcelona, Spain D Wesselenyi u. 28, H-1075 Budapest, Hungary

Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/6/15 11:08 PM