Paternal Contribution to Small for Gestational Age Babies: A Multicenter Prospective Study

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1 nture publishing group Pternl Contribution to Smll for Gesttionl Age Bbies: A Multicenter Prospective Study Lesley ME McCown 1, Robyn A. North 2, Ee Min Kho 1, Michel A. Blck 3, Eliz HY. Chn 1, Gustf A. Dekker 4, Lucill Poston 2, Renne S. Tylor 1 nd Clire T. Roberts 5 Our ims were to investigte whether men who fthered smll for gesttionl ge (SGA) infnts themselves hd lower birthweight, were more likely to be obese, hve centrl diposity nd elevted blood pressure in dult life compred with men who fthered non-sga infnts. A totl of 2,002 couples prticipting in the Screening for Pregnncy Endpoints (SCOPE) study were enrolled in erly pregnncy nd pregnncy outcome dt collected prospectively. SGA ws defined s birthweight <10th customized centile, obesity s BMI 30 kg/m 2, centrl diposity s wist circumference >102 cm. Logistic regression ws used to compre rtes of obesity, nd centrl diposity between men who fthered SGA infnts compred with those with non-sga infnts nd the finl model ws djusted for mternl nd pternl confounders. The men who fthered n SGA infnt (209 (10.4%)) themselves hd lower men birthweight (3,291 (530) g vs. 3,472 (584) g, P < ), were more likely to be obese (50 (24.8%) vs. 321 (18.3%), djusted odds rtio (OR) 1.50, 95% confidence intervl , djusted for mternl nd pternl fctors) nd to hve centrl diposity (52 (25.1%) vs. 341 (19.2%), djusted OR 1.53, 95% confidence intervl ) compred with men who fthered non-sga infnt. Elevted pternl blood pressure ws not ssocited with SGA. In conclusion, we report novel reltionship between pternl obesity/centrl diposity nd birth of n SGA infnt, which ppers to be independent of mternl fctors ssocited with fetl growth restriction. Obesity (2010) doi: /oby Introduction Being born smll for gesttionl ge (SGA) significntly increses the risk of morbidity nd mortlity in the perintl period (1,2). In dult life, SGA birth hs been ssocited with incresed rtes of obesity, centrl diposity nd hypertension s well s type 2 dibetes nd other crdiovsculr diseses (3 6). Although mny uthors hve investigted mternl risk fctors for SGA, few hve investigted the potentil contribution of the fther. Erlier studies reported tht mternl obesity ws ssocited with reduced risk of SGA (7,8), but recent dt from obese cohorts hve found tht mternl obesity is ssocited with n incresed risk of SGA (9,10). The few studies investigting the reltionship between pternl fctors nd either birthweight or SGA in the offspring hve recently been reviewed (11). The mjority of these reported tht pternl weight or BMI ws either not independently ssocited with offspring weight (12 14) or there ws positive reltionship between pternl BMI nd offspring birthweight (15). Previous studies included cohorts recruited before the obesity epidemic (15) nd some were underpowered (13). It is lso possible tht reltionship between pternl obesity nd low birthweight in the offspring could hve been msked by coexisting ssocition between pternl obesity nd lrge bbies (16). None of these previous studies investigted the reltionship between pternl BMI nd risk of SGA offspring. Both mternl nd pternl birthweight hve been positively correlted with infnt birthweight (15,17). Furthermore recent study reported both men nd women who were SGA t birth were more likely thn those with norml birthweight to prent n SGA infnt (18). In the current study, we hve investigted the reltionship between pternl vribles nd birth of n SGA infnt in the prospective Screening for Pregnncy Endpoints (SCOPE) study, which hs contemporry records of both mternl nd pternl dt. In view of the reported ssocition of SGA birth with lter obesity nd hypertension nd lso between SGA birth in the fther nd offspring SGA we hypothesised tht fthers of SGA infnts would hve (i) lower birthweight nd (ii) higher rtes of obesity, centrl diposity, nd high blood pressure thn fthers of non-sga infnts. 1 Deprtment of Obstetrics nd Gynecology, University of Aucklnd, Aucklnd, New Zelnd; 2 Division of Reproduction nd Endocrinology, King s College, London, UK; 3 Deprtment of Biochemistry, University of Otgo, Dunedin, New Zelnd; 4 Deprtment of Obstetrics nd Gynecology, University of Adelide, Lyell McEwin Hospitl, Adelide, South Austrli, Austrli; 5 Discipline of Obstetrics nd Gynecology, School of Peditrics nd Reproductive Helth, University of Adelide, Adelide, South Austrli, Austrli. Correspondence: Lesley Me McCown (l.mccown@ucklnd.c.nz) Received 25 My 2010; ccepted 3 October 2010; dvnce online publiction 2 December doi: /oby obesity 1

2 Methods nd Procedures The SCOPE study is n interntionl, multicenter, prospective screening study which ims to develop erly pregnncy screening tests for preeclmpsi, SGA bbies, nd spontneous preterm birth. Helthy nulliprous women with singleton pregnncies were recruited between November 2004 nd July 2007 in Aucklnd, New Zelnd nd Adelide, Austrli. Women considered t high risk of preeclmpsi, SGA or spontneous preterm birth becuse of underlying medicl conditions, previous gynecologicl history or who received interventions tht my modify these outcomes were excluded. Those who greed to prticipte were interviewed nd exmined by reserch midwife t 15 ± 1 nd 20 ± 1 weeks gesttion. At the time of the interview, dt were entered into n internet ccessed uditble dtbse developed by MedSciNet AB, Sweden. Pregnncy outcome dt nd infnt mesurements were collected following the birth, usully within 72 h. Ethicl pprovl ws gined from locl ethics committees (New Zelnd AKX/02/00/364 nd Austrli REC 1712/5/2008) nd ll women nd prtners provided written informed consent. If prticipnt ws certin of the identity of the infnt s fther nd she consented, the fther ws invited to prticipte in the SCOPE study. Mle prticipnts provided written informed consent nd were interviewed t either the 15 ± 1 or 20 ± 1 weeks SCOPE visit. Pternl dt collected included ge, ethnicity, job sitution, socioeconomic index (19), birthweight nd history of dibetes, hypertension, nd ischemic hert disese. The men were sked to confirm their birthweight from their newborn helth records where possible. If birthweight could not be obtined from the helth record or ws not known by the fther this dt-point ws not completed. Pternl height, weight, bdominl circumference, nd blood pressure were mesured by the reserch midwife. The estimted dte of delivery ws clculted from certin lst menstrul period dte. The estimted dte of delivery ws only djusted if either (i) scn performed t <16 weeks gesttion found difference of 7 dys between the scn gesttion nd tht clculted by the lst menstrul period or (ii) on 20-week scn difference of 10 dys ws found between the scn gesttion nd tht clculted from the lst menstrul period. If the lst menstrul period dte ws uncertin, then scn dtes were used to clculte the estimted dte of delivery. The estimted dte of delivery ws djusted by scn findings in 387/2,002 (21.3%) of prticipnts. Outcome mesures SGA ws defined s birthweight <10th customized birthweight centile (20). Obesity ws defined s BMI 30 kg/m 2 nd centrl diposity s wist circumference >102 cm (21,22). Pternl high blood pressure ws defined s either systolic blood pressure of 140 mm Hg nd/or distolic blood pressure of 90 mm Hg. Univrite sttisticl nlyses were performed using SAS system 9.1 for comprisons between SGA nd non-sga infnts. For continuous vribles two-smple Student s t-test, or Wilcoxon rnk sum test, ws used s pproprite. For ctegoricl vribles comprisons were performed using the χ 2 test. R version ( ws used to fit logistic regression models to ech of the end points (SGA vs. non- SGA), with the regression coefficients used to provide estimtes of ORs. Undjusted ORs were clculted nd if significnt, djusted ORs were then clculted in two stges; first by dding pternl nd then mternl confounding fctors. For the pternl BMI nd centrl diposity nlyses, the following pternl vribles were dded to the logistic regression model: ge, ethnicity, socioeconomic index, employment, blood pressure, nd medicl history. The finl step for both nlyses ws djustment using both the pternl nd mternl covrites. These mternl vribles were: ge, ethnicity, BMI, blood pressure, smoking sttus, grvidity, nd mternl birthweight. To investigte whether men who were smll t birth nd now obese were t incresed risk of SGA offspring, the rtio of pternl birthweight to pternl BMI nd pternl birthweight to pternl wist circumference were clculted nd clssified ccording to qurtiles. The rte of SGA ws compred cross pternl birthweight/bmi rtio qurtiles nd pternl birthweight/wist circumference rtio qurtiles using the Cochrn Armitge test for trend. A logistic regression model ws then developed to investigte whether mternl BMI hd significnt effect on the reltionship between the bove rtios nd risk of SGA. Dt were vilble for >97% of prticipnts for ll vribles included in the models except pternl nd mternl birthweight (90% nd 94% respectively). Missing dt were imputed for multivrible nlyses using the expecttion mximiztion lgorithm (23) for continuous vribles, while the mode ws used for ctegoricl/binry vribles (24). Results Of 2,535 women recruited, 23 (0.9%) were lost to follow-up nd five were excluded s the biologicl fther of the infnt ws unknown (Figure 1). Among the remining 2,507 women, 2,002 (80%) fthers prticipted. The women whose prtners prticipted were more likely to be white (87.7% vs. 82.8%, P < ), mrried or in stble reltionship (95.2% vs. 83.2%, P < ) nd employed (86.1% vs. 81.8% P = 0.02) compred with those whose prtners did not prticipte. There were no differences in mternl BMI, socioeconomic indexes, smoking rtes, or blood pressure between those whose prtners prticipted nd those who did not. Furthermore the rte of SGA infnts did not differ between groups, 10.4% (209 of 2,002) in women whose prtners prticipted nd 10.7% (54 of 505) in women whose prtners did not prticipte, P = Of the 2,002 men, 371 (18.5%) hd BMI 30 kg/m 2. Tble 1 shows the pternl nd mternl demogrphics nd the pternl clinicl chrcteristics mong those with SGA infnts compred with those with non-sga infnts. Men who fthered SGA infnts were themselves on verge 180 g lighter t birth (P < ) nd were 1.4 cm shorter (P = 0.008) thn men who fthered non-sga infnts. Men who fthered n SGA infnt were lso more likely to be obese nd to hve centrl diposity compred with men who fthered non- SGA infnt nd this effect persisted fter djusting for both pternl nd mternl fctors (Tble 2). Although there ws significnt but wek liner reltionship between pternl nd mternl BMI, the correltion coefficient ws very smll (r = 0.24, P < 0.001). Men who fthered SGA infnts were not Women recruited into SCOPE study n = 2,535 Study popultion n = 2,002 Prtner unknown* n = 5 Lost to follow-up n = 23 Prtners did not consent n = 505 SGA n = 209 (10.4%) Non-SGA n = 1,793 (89.6%) Figure 1 Flow chrt of prticipnts. 2

3 Tble 1 Pternl nd mternl chrcteristics ccording to SGA sttus of infnt SGA (n = 209) Non-SGA (n = 1,793) P vlue Pternl chrcteristics Age (yers) 31.1 (6.3) 31.0 (6.2) 0.80 Ethnicity 0.51 White 174 (84.2%) 1,549 (86.5%) Polynesin 12 (5.8%) 99 (5.5%) Asin 4 (1.9%) 45 (2.5%) Indin 7 (3.3%) 48 (2.7%) Other 10 (4.8%) 50 (2.8%) Socioeconomic index 42 (16) 43 (16) 0.37 Employed 191 (91.4%) 1,682 (93.8%) 0.18 Birthweight (g) 3,291 (530) 3,472 (584) < Medicl history 7 (3.3%) 66 (3.7%) 0.81 Height (cm) (6.9) (6.9) Weight (kg) 86.0 (15.8) 86.4 (15.2) 0.70 BMI 30 kg/m 2 50 (24.8%) 321 (18.3%) 0.03 Wist circumference 52 (25.1%) 341 (19.2%) 0.04 >102 cm Systolic blood 122 (13) 122 (13) 0.57 pressure (mm Hg) Distolic blood 76 (10) 77 (10) 0.16 pressure (mm Hg) Elevted blood 28 (13.7%) 273 (15.5%) 0.16 pressure b Mternl chrcteristics Age (yers) 28.8 (5.9) 28.4 (5.5) 0.31 Ethnicity 0.35 White 179 (85.7%) 1,576 (87.9%) Polynesin 5 (2.4%) 51 (2.8%) Asin 9 (4.3%) 83 (4.6%) Indin 8 (3.8%) 49 (2.8%) Other 8 (3.8%) 34 (1.9%) Socioeconomic index 42 (17) 42 (16) 0.61 Employed 171 (81.8%) 1,552 (86.6%) 0.06 BMI 30 kg/m 2 42 (20.1%) 272 (15.2%) 0.06 Results re expressed s men (s.d.) or n (%). SGA, smll for gesttionl ge. Includes previously dignosed hypertension, type 2 dibetes, or ischemic hert disese. (Seven men in the SGA group hd history of previous hypertension. In the non-sga group, 60 hd history of previous hypertension, two hd history of ischemic hert disese nd two hd type 2 dibetes, one hd both ischemic hert disese nd hypertension nd further hd type 2 dibetes plus hypertension.) b Defined s either systolic blood pressure 140 mm Hg or distolic blood pressure 90 mm Hg. more likely to hve elevted blood pressure compred with men who fthered non-sga infnt. To investigte our hypothesis suggesting link between low pternl birthweight, subsequent obesity nd n incresed risk of n SGA infnt, we explored the reltionship between pternl Tble 2 Pternl chrcteristics nd risk of fthering SGA infnt Undjusted OR (95% CI) OR djusted for pternl fctors (95% CI) OR djusted for mternl b nd pternl fctors (95% CI) BMI 30 kg/m ( ) 1.52 ( ) 1.50 ( ) Wist circumference >102 cm 1.41 ( ) 1.58 ( ) 1.53 ( ) Results re expressed s N (%). CI, confidence intervl; OR, odds rtio; SGA, smll for gesttionl ge. Pternl ge, ethnicity, socioeconomic index, employment, blood pressure, history of hypertension, type 2 dibetes, nd ischemic hert disese. b In ddition to pternl fctors djusted for mternl ge, ethnicity, BMI, men rteril pressure, smoking sttus, grvidity, nd mternl birthweight. Pternl BMI (kg/m 2 ) ,000 2,000 3,000 4,000 Pternl birthweight (g) 5,000 6,000 Figure 2 Correltion between pternl birthweight nd pternl BMI. birthweight nd pternl BMI. A very wek liner reltionship ws found (r = 0.07, P = 0.003, Figure 2). A similr wek liner reltionship ws found between pternl wist circumference nd pternl birthweight (r = 0.09, P = ). Pternl ge did not influence pternl BMI nd wist circumference s evidenced by no difference in men pternl BMI or wist circumference cross pternl ge tertiles (dt not shown). We then investigted the reltionship between the rtio of pternl birthweight to pternl BMI nd the rte of SGA offspring. SGA offspring were more common mong men with birthweight/bmi rtio in the lowest qurtile (14%, 63 of 438) compred to the rte of SGA offspring in the other qurtiles (birthweight/bmi rtio 2nd qurtile 10%, 3rd qurtile 9%, highest qurtile 7%, P = using the Cochrn Armitge trend test). A similr reltionship ws lso found for qurtiles of pternl birthweight/wist circumference rtios nd risk of SGA offspring P < using the Cochrn Armitge trend test (Tble 3). To investigte whether mternl BMI ws confounding the reltionship between the bove rtios nd risk of SGA offspring we then fitted logistic regression models. Mternl BMI did not hve significnt effect in either model. We fitted further logistic regression model to investigte whether there ws liner reltionship between birthweight/ BMI rtio nd rte of SGA. A wek positive reltionship ws demonstrted (OR 0.90 ( ), P = 0.01 for every 50 unit chnge in the rtio), consistent with the lower the birthweight/ BMI rtio the higher the risk of SGA. obesity 3

4 Tble 3 SGA offspring in reltion to pternl birthweight/bmi nd pternl birthweignt/wist circumference rtios SGA Non-SGA P vlue Pternl birthweight/bmi rtio n = 178 n = 1,583 Qurtile 1 (n = 438) 63 (14.4%) 375 (85.6%) Qurtile 2 (n = 446) 45 (10.1%) 401 (89.9%) Qurtile 3 (n = 446) 41 (9.2%) 405 (90.8%) Qurtile 4 (n = 431) 29 (6.7%) 402 (93.3%) Pternl birthweight/ n = 177 n = 1,580 wist circumference rtio b Qurtile 1 (n = 405) 55 (13.6%) 350 (86.4%) < Qurtile 2 (n = 493) 61 (12.4%) 432 (87.6%) Qurtile 3 (n = 445) 39 (8.8%) 406 (91.2%) Qurtile 4 (n = 414) 22 (5.3%) 392 (94.7%) P vlue bsed on Cochrn Armitge trend test. SGA, smll for gesttionl ge. Medin (interqurtile rnge) 130 ( ). b Medin (interqurtile rnge) 37 (32 42). Discussion Although number of studies hve explored the reltionship between pternl chrcteristics, including height nd weight, nd infnt birthweight, none hve specificlly investigted the influence of pternl obesity nd centrl diposity on the risk of SGA in the offspring. After djustment for both pternl nd mternl confounders, pternl obesity, nd centrl diposity were both ssocited with 60% increse in risk of fthering SGA infnt in our study. Consistent with previous reports, we found tht men who fthered SGA infnts were themselves ~180 g lighter t birth thn men who fthered non-sga infnts (15,17) suggesting tht birth size ppers to be, in prt, heritble through the pternl germ line. Contrry to our hypothesis, we did not confirm strong inverse ssocition or J curve between pternl birth weight nd pternl BMI or centrl obesity in our cohort. Others hve lso reported lck of cliniclly significnt reltionship between birthweight nd lter BMI, recently reviewed by Wells et l. (25). The reltionship between birthweight nd lter obesity hs vried in different popultions, by gender, by ge t follow-up nd ccording to which vribles were included in multivrite nlyses (25). To further explore whether the independent ssocition between pternl obesity nd offspring SGA my be mnifesttion of excessive ctch-up growth in those men with low birthweights, we used low rtio of pternl birthweight to BMI nd pternl birthweight to wist circumference s surrogte mesures for ctch-up growth in the subgroup of men with low birthweight who were now obese nd or hd centrl diposity. Men with birthweight to BMI rtio or birthweight to wist circumference rtio in the lowest qurtiles hd higher rte of SGA offspring nd this reltionship ws independent of mternl BMI. These dt provide some support for the concept of low birthweight being ssocited with lter obesity nd incresed risk of SGA offspring. Further reserch is required to better understnd the linkges between pternl birthweight or SGA sttus, obesity nd centrl obesity s n dult nd SGA offspring. We did not find reltionship between pternl elevted blood pressure nd SGA in the infnt despite the known ssocition between obesity nd hypertension. Becuse the men in this study hd men ge of 28 yers, it my be tht even if they hd predisposition to hypertension they were too young for it to be mnifested. The strengths of this study include its prospective design, very low loss to follow-up, nd the study popultion comprising lrge modern cohort with rtes of pternl obesity of nerly 20%. A limittion is tht we were not ble to investigte pternl SGA sttus t birth s we did not collect pternl dt relting to gesttion t delivery. Therefore the observed ssocition between reduced pternl birthweight nd SGA offspring could be prtly explined by n incresed rte of preterm birth in the fthers. In ddition, more ccurte mesures of diposity in fther nd child (e.g., s determined by mesurements of skin fold thickness or dul-energy X-ry bsorptiometry scn) would hve provided dditionl insight into the reltionships between fther nd child ft mss nd should be considered in future studies. Obesity rises from combintion of genetic nd environmentl fctors. Pternl effects on SGA could potentilly be explined by either common environment shred by the couple, genetic component or combintion of both. Recent dt from lrge cohort of obese nulliprous women hs reported n incresed risk of SGA offspring (10). Shred dietry hbits between the mother nd the fther, resulting in mternl s well s pternl obesity, is one potentil explntion for the effect of pternl obesity on SGA infnts. As the ssocition between pternl obesity nd birth of SGA offspring ws still present fter djustment for mternl BMI nd the reltionship between mternl nd pternl BMI ws wek, it is unlikely our findings re explined by mternl obesity. However s we did not collect dt bout mternl nd pternl dietry ptterns, contribution of shred dietry hbits between mother nd fther to the observed reltionship cnnot be excluded entirely. A potentil limittion of our study is therefore tht t lest prt of the reltionship we hve demonstrted between pternl obesity nd SGA offspring my be explined by residul mternl confounding. It is possible tht genetic mechnisms my contribute to the ssocition between pternl BMI nd SGA offspring. The IGF2 gene, encoding insulin-like growth fctor II, nd the INS gene, encoding insulin, re possible cndidtes since polymorphisms in both re ssocited with low circulting insulin-like growth fctor II, which is ssocited with dult obesity, s well s SGA bbies (26 29). Furthermore, insulin-like growth fctor II is imprinted nd expressed from the pternl copy of the gene nd regultes both plcentl nd fetl growth (30). In conclusion, we hve demonstrted novel reltionship between pternl obesity/centrl diposity nd delivery of n SGA infnt, which ppers to be independent of mternl fctors known to be ssocited with fetl growth restriction. Further prospective studies re required to confirm this 4

5 ssocition nd to provide insight into the underlying pthophysiology. It ppers unlikely tht the reltionship between SGA infnts nd obesity in the fthers simply reflects n ssocition with the fthers own low birthweight which ws then followed by rpid growth nd lter obesity, but this should be investigted further in future studies. In conclusion, studies which im to predict the risk of delivery of n SGA infnt in the future should explore the potentil dded vlue of incorporting pternl BMI with mternl dt in prediction models. Acknowledgments The SCOPE study ws funded in New Zelnd by: New Enterprise Reserch Fund, Foundtion for Reserch Science nd Technology; Helth Reserch Council; Evelyn Bond Fund, Aucklnd District Helth Bord Chritble Trust nd E.M.K. ws supported by grnt from the Reserch Development Fund, The University of Aucklnd. The SCOPE study ws funded in Austrli by the Premier s Science nd Reserch Fund, Government of South Austrli. 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